BRAF/MEK/EGFR Inhibitor Combination Study in Colorectal C... | NCT01750918 | Trialant
NCT01750918
Sponsor
Novartis Pharmaceuticals
Status
Completed
Last Update Posted
Oct 29, 2021Actual
Enrollment
166Actual
Phase
Phase 1Phase 2
Conditions
Cancer
Interventions
Dabrafenib
Trametinib
Panitumumab
5-fluorouracil
Countries
United States
Belgium
France
Italy
Japan
Netherlands
Spain
United Kingdom
Protocol Section
Identification Module
NCT ID
NCT01750918
Obsolete or Duplicate NCT IDs
Not provided
Organization Study
116833
Secondary IDs
ID
Type
Description
Link
CDRB436C2201
Other Identifier
Novartis
2012-004802-81
EudraCT Number
Brief Title
BRAF/MEK/EGFR Inhibitor Combination Study in Colorectal Cancer (CRC)
Official Title
An Open-Label, Four-Part, Phase I/II Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics, and Clinical Activity of the MEK Inhibitor GSK1120212, BRAF Inhibitor GSK2118436 and the Anti-EGFR Antibody Panitumumab in Combination in Subjects With BRAF-mutation V600E Positive Colorectal Cancer and in Subjects With CRC With Secondary Resistance to Prior Anti-EGFR Therapy
Acronym
Not provided
Organization
NovartisINDUSTRY
Status Module
Record Verification Date
Sep 2021
Overall Recruitment Status or Expanded Access Status
Completed
Last Known Status
Not provided
Delayed Posting
Not provided
Why Stopped
Not provided
Expanded Access Info
No
Start Date
Dec 19, 2012Actual
Primary Completion Date
Jun 18, 2020Actual
Completion Date
Jun 18, 2020Actual
First Submitted Date
Dec 6, 2012
First Submission Date that Met QC Criteria
Dec 13, 2012
First Posted Date
Dec 17, 2012Estimated
Results Waived
Not provided
Results First Submitted Date
Jun 11, 2021
Results First Submitted that Met QC Criteria
Sep 30, 2021
Results First Posted Date
Oct 29, 2021Actual
Certification/Extension (aka Delayed Results) First Submitted Date
Not provided
Certification/Extension First Submitted that Passed QC Review
Not provided
Certification/Extension First Posted Date
Not provided
Last Update Submitted Date
Sep 30, 2021
Last Update Posted Date
Oct 29, 2021Actual
Sponsor/Collaborators Module
Responsible Party, by Official Title
Sponsor
Lead Sponsor
Novartis PharmaceuticalsINDUSTRY
Collaborators
Not provided
Oversight Module
Has Data Monitoring Committee (DMC)
No
Is FDA Regulated Drug
Yes
Is FDA Regulated Device
No
Is Unapproved Device
Not provided
Pediatric Postmarket Surveillance of a Device Product
Not provided
Product Exported from US
Not provided
FDAAA801 Violation
Not provided
Description Module
Brief Summary
This was a four part, phase I/II study aimed to evaluate the safety, tolerability and efficacy of combination of an anti-EGFR antibody panitumumab (P) either with a BRAF inhibitor (dabrafenib (D); GSK2118436) alone or with the combination of a BRAF inhibitor and a MEK inhibitor (trametinib (T); GSK1120212) in patients with BRAF-mutant V600E advanced or mCRC. The goal was to: 1) Determine RP2R/MTD for doublet (D+P) and triplet (D+T+P) combinations in Part 1; 2) Assess clinical activity for these combinations in Part 2; 3) Determine RP2R/MTD for double (T+P) combination in Part 4A, and assess clinical activity of this combination in two patient populations in Part 4B (patients with BRAF-V600E mutation-positive advanced or metastatic CRC and patients with advanced or metastatic CRC with secondary resistance to anti-EGFR therapy).
Detailed Description
Part 1: Dose escalation This was a dose escalation part intended to evaluate safety, tolerability, PK, PD, clinical activity and determine RP2R/MTD for the doublet (D+P) and the triplet (D+T+P) combinations in patients with BRAF-mutation V600E positive advanced or metastatic CRC. A 3+3 dose escalation procedure was followed. Dosing for dabrafenib and trametinib was continuous daily dosing while panitumumab was dosed once every two weeks (Q2W). Patients were evaluated for dose-limiting toxicities (DLTs) during the first 28 days of treatment.
Part 2A:
This was a cohort expansion part to assess the safety and preliminary clinical activity of the optimal safe and tolerable dose combinations (D+P)/(D+T+P) defined in Part 1.
Part 2B:
In this part, additional patients were enrolled into the triplet (D+T+P) combination at two dose levels in to further explore safety, tolerability and clinical activity. Up to 10 patients each with no prior treatment (First Line Population), and up to 20 patients each with at least one prior treatment (Second to Fourth Line Population) were planned to be enrolled in dose Cohorts 3A and 4.
Part 3: Randomized Phase 2 Study The randomized phase 2 portion (Phase 3) of the study was not pursued as the observed responses in any of the cohorts did not meet the predefined criteria at the time of the preliminary analysis (data cut-off date: 06-May-2016).
Part 4 This part was designed to identify the RP2R/MTD and initial clinical activity for the doublet (T+P) combination in patients BRAF-mutation V600E positive advanced or metastatic CRC, and advanced or metastatic CRC with secondary resistance to prior anti-EGFR therapy.
Part 4A: Dose Escalation This was a dose escalation part intended to determine RP2R/MTD for the doublet (T+P) combination in patients with BRAF-mutation V600E positive advanced or metastatic CRC. Approximately 18 patients (~6 each cohort) were planned to be enrolled in Part 4A. A 3+3 dose escalation procedure was followed. Dosing for trametinib was continuous daily dosing while panitumumab was dosed once every two weeks (Q2W). Patients were evaluated for DLTs during the first 28 days of treatment.
Part 4B: Cohort Expansion This was a cohort expansion part intended to evaluate safety and efficacy of the doublet (T+P) combination. Up to 20 patients in each of two expansion cohorts were planned to be enrolled at the starting dose cohort or MTD from Part 4A.
Conditions Module
Conditions
Cancer
Keywords
MEK inhibitor
anti-EGFR antibody
colorectal cancer
BRAF inhibitor
Design Module
Study Type
Interventional
Number of References to an Expanded Access Study
Not provided
Expanded Access Types
Not provided
Patient Registry
Not provided
Target Follow-Up Duration
Not provided
Phases
Phase 1Phase 2
Interventional Study Design
Allocation
Biospecimen
No data available
No data is available for this block.
Enrollment
166Actual
Arms/Interventions Module
Arm Groups
Label
Type
Description
Intervention Names
Part 1: Dabrafenib and Panitumumab
Experimental
In Part 1 subjects will be assigned to escalation cohort of the doublet of dabrafenib and panitumumab based on the monotherapy doses of dabrafenib (150 milligrams [mg] twice daily) and panitumumab (6 milligrams per kilogram [mg/kg] every-2-week [Q2W]). Dose escalation will follow a 3+3 dose escalation procedure. If the initial combination dose of dabrafenib and panitumumab in Cohort 1 (starting dose) is not tolerable, lower dose combination(s) may be evaluated.
Drug: Dabrafenib
Drug: Panitumumab
Part 1: Dabrafenib, Trametinib and Panitumumab
Experimental
In Part 1 after the dabrafenib/panitumumab combination dose is defined, subsequent cohorts will evaluate the addition of trametinib based on a panitumumab dose that is one dose level lower than the dabrafenib/panitumumab dose defined in Cohort 1. Trametinib starting at 1.5 mg once daily will be added to the combination of dabrafenib and panitumumab. Dose escalation will follow a 3+3 dose escalation procedure until the full monotherapy doses of all agents are evaluated or the maximum tolerated dose is determined.
Drug: Dabrafenib
Drug: Trametinib
Drug: Panitumumab
Part 2: Dabrafenib and panitumumab
Experimental
In Part 2, subjects will be assigned to expansion cohorts at a selected dose of dabrafenib in combination with panitumumab
Drug: Dabrafenib
Drug: Panitumumab
Part 2: Dabrafenib, Trametinib and Panitumumab
Experimental
Interventions
Name
Type
Description
Arm Group Labels
Other Names
Dabrafenib
Drug
Each capsule contains 50 mg or 75 mg of GSK2118436; 50 mg strength capsules are Swedish orange (dark red) opaque hypromellose size 2 capsules and 75 mg strength capsules are pink opaque hypromellose size 1 capsules. The initial dosing regimen will be twice daily (BID) continuous oral daily dosing.
Outcomes Module
Primary Outcomes
Measure
Description
Time Frame
Number of Participants With Adverse Events
The distribution of adverse events was done via the analysis of frequencies for Adverse Events, Serious Adverse Events and Deaths due to AEs, through the monitoring of relevant clinical and laboratory safety parameters. Only descriptive analysis performed.
From study treatment start date till 30 days safety follow-up, assessed up to approximately 90 months
Overall Response Rate (ORR)
Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) was used for efficacy based on radiological assessment of tumor burden: CR = Complete Response, disappearance of all target lesions; PR = Partial Response, >=30% decrease in the sum of the longest diameter of target lesions; PD = progressive disease, >=20% increase in sum of target lesions and/or presence of new lesions and/or substantial increase in non-target lesion; SD = stable disease, response not meeting CR or PR or PD; ORR = overall response rate, defined as CR+PR
From study treatment start date until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to approximately 90 months
Part 3: Progression Free Survival (PFS)
Progression Free Survival (PFS) was defined as the time from study treatment start date to the date of first radiologically documented progression or death due to any cause. If a patient did not progress or die at the time of the analysis data cut-off or start of new antineoplastic therapy, PFS was censored at the date of the last adequate tumor assessment before the earliest of the cut-off date or the start date of additional anti-neoplastic therapy. Progression was defined using Response Evaluation Criteria In Solid Tumors Criteria RECIST v1.1, as 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline and/or unequivocal progression of the non-target lesions and/or appearance of a new lesion. In addition to the relative increase of 20%, the sum must demonstrate an absolute increase of at least 5 mm.
From study treatment start date until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to approximately 90 months
Secondary Outcomes
Measure
Description
Time Frame
Duration of Response (DoR)
Duration of Response (DoR) was defined as the time from the first documented occurrence of response (PR or CR) until the date of the first documented progression based on RECIST v1.1 or death.
From study treatment start date until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to approximately 90 months
Other Outcomes
Not provided
Eligibility Module
Eligibility Criteria
Inclusion Criteria: Subjects eligible for enrolment in this study must meet all of the following criteria
Provided written informed consent,
Male or female >=18 years of age and able to swallow and retain orally administered study treatment and does not have any clinically significant gastrointestinal (GI) abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach and/or bowels.
Part 1 and Part 2: Histologically- or cytologically-confirmed diagnosis of advanced or metastatic BRAF V600E mutation positive CRC
Part 4A and 4B ONLY: Histologically- or cytologically-confirmed diagnosis of advanced or metastatic CRC that either harbours the BRAF V600E -mutation, as determined by relevant genetic testing OR has developed secondary resistance to anti-EGFR therapy, defined as patients that derived benefit (disease control based on investigator assessment for >6 months OR partial response [confirmed or unconfirmed] based on RECIST 1.1) from prior anti-EGFR-containing therapy (as defined below) and then subsequently progressed on therapy. The anti-EGFR therapy must have been the most recent therapy and the patient must have progressed based on investigator assessment within 3 months of screening. Acceptable prior anti-EGFR-containing therapies include: a. Monotherapy anti-EGFR, including cetuximab or panitumumab OR b. irinotecan/anti-EGFR combo after previously having disease progression (based on investigator assessment) on an irinotecan-containing regimen
Part 3: Histologically- or cytologically-confirmed diagnosis of BRAFV600E mutation positive advanced or metastatic colorectal cancer (CRC who are eligible to receive fluoropyrimidine-containing chemotherapy regimen that have experienced documented radiographic progression on one prior line of fluoropyrimidine-containing chemotherapy (previous anti-EGFR therapy is excluded), Second-line for advanced/metastatic disease, having failed or been intolerant to at least one regimen of fluoropyrimidine-containing chemotherapy including irinotecan or oxaliplatin in the advanced/metastatic setting. Enrollment in Part 3 may only occur following confirmation of KRAS wild-type cancer.
Archival tissue is required; if archival tissue is not available or found to not contain tumor tissue, a fresh biopsy is required.
Measurable disease per RECIST version 1.1.
Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
Men with a female partner of childbearing potential must have either had a prior vasectomy or agree to use one of the contraception methods listed in protocol.
Female subjects are eligible if: Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or post-menopausal female defined as 12 months of spontaneous amenorrhea to be verified with a follicle-stimulating hormone (FSH) level >40 Milli-international units per milliliter (MIU/mL) and estradiol level <40 picogram per milliliter (pg/mL). Child-bearing potential and agrees to use one of the contraceptive methods listed in protocol.
Female subjects must agree to use contraception from 7 days prior to the first dose of study drug(s) until 6 months after the last dose of panitumumab, until 4 months after the last dose of trametinib, or 4 weeks after the last dose of dabrafenib, whichever is longer. Additionally, women of childbearing potential must have had a negative serum pregnancy test within 7 days prior to the first dose of study drug(s).
Adequate organ system function as defined in absolute neutrophil count greater than or equal to 1.2X10^9/Liter (L), hemoglobin greater than or equal to 9 grams per deciliter (g/dL) or 5.6 millimoles per litre (mmol/L), platelets greater than or equal to 75 × 10^9/L, Prothrombin Time / International Normalized Ratio (PT/INR) and Partial Thromboplastin Time (PTT) less than or equal to 1.5X upper limit of normal (ULN); serum magnesium greater than or equal to the lower limit of normal (LLN); albumin greater than or equal to 2.5 g/dL or 25 grams per liter (g/L), total bilirubin less than or equal to 1.5XULN, and Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) less than or equal to 2.5X ULN; creatinine less than or equal to 1.5XULN or calculated creatinine clearance greater than or equal to 50mL/min; left ventricular ejection fraction (LVEF) greater than or equal to the LLN by echocardiography (ECHO) or multigated acquisition scan (MUGA).
Subjects enrolled in France or Italy: In France or Italy, a subject will be eligible for inclusion in this study only if either affiliated to, or a beneficiary of, a social security category.
Exclusion Criteria: Subjects meeting any of the following criteria must not be enrolled in the study
History of prior malignancy, other than colorectal cancer.
Any serious and/or unstable pre-existing medical, psychiatric disorder or other conditions that could interfere with subject's safety, obtaining informed consent or compliance to the study procedures.
Current active liver or biliary disease (with the exception of Gilbert's syndrome or asymptomatic gallstones, liver metastases or otherwise stable chronic liver disease per investigator's assessment).
History of sensitivity to heparin or heparin-induced thrombocytopenia.
Currently receiving cancer therapy (chemotherapy, radiation therapy, immunotherapy or biologic therapy).
Prior exposure to a MEK inhibitor.
Part 1, Part 2 and BRAF-mutant patients in Part 4 ONLY: Prior exposure to a BRAF inhibitor.
Part 1, Part 2 and BRAF-mutant patients in Part 4 ONLY: Known presence of KRAS-mutation based on previous KRAS-testing. Note: Prospective KRAS testing is not required. However, if the results of previous KRAS testing are known, they must be used in assessing eligibility. KRAS testing will be performed retrospectively for all patients.
Part 3: Prior exposure to EGFR inhibitors or an anti-EGFR antibody
Received an investigational or approved anti-cancer drug within 4 weeks, or within 5 half-lives (whichever is shorter) of the first dose of study drug(s). At least 14 days must have passed between the last dose of prior investigational agent and the first dose of study drug(s).
Part 3: Received more than one prior anti-cancer therapy in the metastatic setting, exclusive of previous adjuvant regimens. Previous investigational anti-cancer therapy in the metastatic setting is prohibited.
Current use of a prohibited medication or requirement to dose with any of these medications during treatment with study drug(s).
Known Hepatitis B, or Hepatitis C infection.
Any major surgery, radiotherapy or immunotherapy within the 4 weeks prior to first dose of study drug(s). Limited radiotherapy with in the 2 weeks prior to first dose of study drug(s).
Chemotherapy regimens with delayed toxicity within the 3 weeks prior to first dose of study drug(s). Chemotherapy regimens given continuously or on a weekly basis with limited potential for delayed toxicity within 2 weeks prior to first dose of study drug(s).
Unresolved toxicity greater than National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4 Grade 1 from previous anti-cancer therapy, with the exception of Grade 2 alopecia, Grade 2 neuropathy, or laboratory values that are allowed per inclusion criteria.
History of retinal vein occlusion (RVO).
Presence of active gastrointestinal disease or other condition that will interfere significantly with the absorption, distribution, metabolism or excretion of drugs. Previous colectomy is acceptable.
Subjects with brain metastases are excluded, unless: All known lesions must be previously treated with surgery or stereotactic radio-surgery, and Brain lesion(s), if present, must be confirmed stable (i.e., no increase in lesion size) for >=90 days prior to first dose of study drug(s). This must be documented with two consecutive MRI or CT scans using contrast, and Asymptomatic with no corticosteroids requirement for >=30 days prior to first dose of study drug(s), and No enzyme-inducing anticonvulsants for >=14 days prior to first dose of study drug(s). In addition, for subjects that had brain metastases but currently have no evidence of disease (NED), NED for >=12 weeks is required and must be confirmed by two consecutive MRI or CT scans (using contrast) separated by >=6 weeks, prior to randomization. Enrollment of a subject with brain metastases who meet the above criteria requires approval of a GlaxoSmithKline (GSK) Medical Monitor.
Psychological, familial, sociological or geographical conditions that do not permit compliance with the protocol.
History or evidence of cardiovascular risk including any of the following: LVEF<LLN; A QT interval corrected for heart rate using the Bazett's formula (QTcB;) ≥ 480 milliseconds (msec);.History or evidence of current clinically significant uncontrolled arrhythmias. Exception: Subjects with controlled atrial fibrillation for >30 days prior to randomization are eligible. History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to randomization. History or evidence of current >= Class II congestive heart failure as defined by New York Heart Association (NYHA). Treatment refractory hypertension defined as a blood pressure of systolic> 140 millimeter of mercury (mm Hg) and/or diastolic > 90 mm Hg which cannot be controlled by anti-hypertensive therapy; Subjects with intra-cardiac defibrillators or permanent pacemakers; Known cardiac metastases
Unstable pulmonary embolism, deep vein thrombosis, or other significant arterial/venous thromboembolic event <=30 days before randomization. If on anticoagulation, subject must be on stable therapeutic dose prior to randomization.
Subjects with a history of pneumonitis or interstitial lung disease (ILD).
Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study drug(s) or their excipients.
Pregnant or lactating female.
Unwillingness or inability to follow the procedures outlined in the protocol.
Uncontrolled diabetes or other medical condition that may interfere with assessment of toxicity.
Accepts Healthy Volunteers
No
Sex
All
Sex/Gender Based
Not provided
Sex/Gender Description
Not provided
Minimum Age
18 Years
Maximum Age
Not provided
Standard Ages
AdultOlder Adult
Study Population
Not provided
Sampling Method
Not provided
Contacts/Locations Module
Central Contacts
Not provided
Overall Officials
Name
Affiliation
Role
Novartis Pharmaceuticals
Novartis Pharmaceuticals
Study Director
Locations
Facility
Status
City
State
ZIP
Country
Contacts
Novartis Investigative Site
Scottsdale
Arizona
85259
United States
Novartis Investigative Site
References Module
No data available
No data is available for this block.
IPD Sharing Statement Module
Plan to Share IPD
Yes
Description
This product has been acquired by Novartis Pharmaceuticals. Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.
Since the tumor type enrolled in Part 1 and Part 2 was the same (metastatic colorectal cancer), the results were summarized by combination groups (and not by study parts) to allow a more meaningful interpretation of study results based on dose
Recruitment Details
This study was conducted in 20 study centers across eight countries: Belgium (2), France (2), Italy (2), Japan (2), Netherlands (2), Spain (1), UK (1) and USA (8).
Type of Units Analyzed
Not provided
Arm/Group Information
ID
Title
Description
FG000
Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W
Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W
Periods
Title
Milestones
Reasons Not Completed
Overall Study
Type
Comment
Milestone Data
STARTED
All patients who were treated with at least one dose of the study drug at the time of the final analysis.
Baseline Characteristics Module
Baseline Analysis Population Description
Outcome Measures Module
Outcome Measures
Adverse Events Module
Frequency Threshold
5
More Info Module
Limitations and Caveats
Not provided
Annotation Section
No data available
No data is available for this block.
Document Section
Large Document Module
Document Has No Statistical Analysis Plan (SAP)
Not provided
Uploaded Document Information
Type
Includes Protocol
Includes SAP
Includes ICF
Document Label
Document Date
Document Uploaded Date
Document File Name
Prot
Yes
No
No
Study Protocol
Feb 8, 2017
Jun 11, 2021
Derived Section
Miscellaneous Info Module
Version Holder
Jul 10, 2026
Removed Countries
Not provided
Submission Tracking
No data available
No data is available for this block.
Condition Browse Module
MeSH Terms
Intervention Browse Module
MeSH Terms
Randomized
Intervention Model
Parallel Assignment
Intervention Model Description
The original intention of the study was to include a randomized phase 2 portion of the study as a "Part 3"; however, a preliminary analysis did not meet predetermined criteria for efficacy. As a result, Part 3 of the study was not initiated.
Primary Purpose
Treatment
Observational Model
Not provided
Time Perspective
Not provided
Masking Info
Masking
None (Open Label)
Masking Description
Not provided
Who Masked
Not provided
In Part 2, subjects will be assigned to expansion cohorts at selected dose of trametinib plus dabrafenib in combination with panitumumab.
Drug: Dabrafenib
Drug: Trametinib
Drug: Panitumumab
Part 4a: Trametinib and Panitumumab
Experimental
Subject will be administered starting dose of Trametinib 2 mg once daily and Panitumumab 6mg/kg Q2W. If the initial combination dose of trametinib and panitumumab in Cohort 1 (starting dose) is not tolerable, the lower dose combination defined in de-escalation cohorts (Cohort -1A, -1B and/or -1C) may be evaluated. Cohort -1A: Trametinib 1.5 mg once daily and Panitumumab 6 mg/kg Q2W; Cohort -1B: Trametinib 2 mg once daily and Panitumumab 4.8 mg/kg Q2W; Cohort-1C: Trametinib 1.5 mg once daily and Panitumumab 4.8 mg/kg Q2W
Drug: Trametinib
Drug: Panitumumab
Part 4b: Trametinib and Panitumumab
Experimental
In Part 4B cohort expansion, subjects will be assigned to expansion cohorts at a selected dose of trametinib in combination with panitumumab. Enrollment in expansion cohorts will be initiated once dose escalation for the trametinib /panitumumab combination has been completed. Subjects with advanced/metastatic CRC with either a BRAF-mutation (Cohort 1E) or who developed secondary resistance to prior anti-EGFR therapy (Cohort 2E).
Drug: Trametinib
Drug: Panitumumab
Part 3a: Dabrafenib and Panitumumab
Experimental
Subjects will be randomized to receive dabrafenib plus panitumumab. Dose levels for dabrafenib, and panitumumab in Part 3 will be chosen based on emerging PK, PD, and tolerability data from Part 1 and Part 2.
Drug: Dabrafenib
Drug: Panitumumab
Part 3b: Dabrafenib, Trametinib and Panitumumab
Experimental
Subjects will be randomized to receive study treatment as dabrafenib plus trametinib plus panitumumab. Dose levels for dabrafenib, trametinib and panitumumab in Part 3 will be chosen based on emerging PK, PD, and tolerability data from Part 1 and Part 2.
Drug: Dabrafenib
Drug: Trametinib
Part 3c: Chemotherapy comparator
Experimental
Subjects will be randomized to receive chemotherapy comparator. The chemotherapy comparator will consist of a standard chemotherapy regimen with or without the addition of a biological agent, based on local practice preferences. The available chemotherapy regimens includes 5-fluorouracil-based chemotherapy
Device: 5-fluorouracil
Part 1: Dabrafenib and Panitumumab
Part 1: Dabrafenib, Trametinib and Panitumumab
Part 2: Dabrafenib and panitumumab
Part 2: Dabrafenib, Trametinib and Panitumumab
Part 3a: Dabrafenib and Panitumumab
Part 3b: Dabrafenib, Trametinib and Panitumumab
GSK2118436, DRB436
Trametinib
Drug
Each tablet contains 0.5mg or 2.0 mg GSK1120212; 0.5 mg is yellow modified oval biconvex film-coated tablets of size 4.8 mm X 8.9 mm and 2 mg as pink round biconvex film coated tablets;7.5 mm in diameter. The initial dosing regimen will be once daily continuous oral daily dosing.
Part 1: Dabrafenib, Trametinib and Panitumumab
Part 2: Dabrafenib, Trametinib and Panitumumab
Part 3b: Dabrafenib, Trametinib and Panitumumab
Part 4a: Trametinib and Panitumumab
Part 4b: Trametinib and Panitumumab
GSK1120212, TMT212
Panitumumab
Drug
Panitumumab is a sterile, colorless, translucent-to-white amorphous, proteinaceous powder available as 100 mg panitumumab in 5 mL (20 mg/mL) single-use vial; 200 mg panitumumab in 10 mL (20 mg/mL) single-use vial; 400 mg panitumumab in 20 mL (20 mg/mL) single-use vial; to be administered as an intravenous infusion over 60 minutes, every 14 days. Doses higher than 1000 mg should be administered over 90 minutes.
Part 1: Dabrafenib and Panitumumab
Part 1: Dabrafenib, Trametinib and Panitumumab
Part 2: Dabrafenib and panitumumab
Part 2: Dabrafenib, Trametinib and Panitumumab
Part 3a: Dabrafenib and Panitumumab
Part 4a: Trametinib and Panitumumab
Part 4b: Trametinib and Panitumumab
5-fluorouracil
Device
5-fluorouracil-based chemotherapy
Part 3c: Chemotherapy comparator
Progression Free Survival (PFS)
Progression Free Survival (PFS) was defined as the time from study treatment start date to the date of first radiologically documented progression or death due to any cause. If a patient did not progress or die at the time of the analysis data cut-off or start of new antineoplastic therapy, PFS was censored at the date of the last adequate tumor assessment before the earliest of the cut-off date or the start date of additional anti-neoplastic therapy. Progression was defined using Response Evaluation Criteria In Solid Tumors Criteria RECIST v1.1, as 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline and/or unequivocal progression of the non-target lesions and/or appearance of a new lesion. In addition to the relative increase of 20%, the sum must demonstrate an absolute increase of at least 5 mm.
From study treatment start date until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to approximately 90 months
Overall Survival (OS)
Overall Survival (OS) was defined as the time to death due to any cause.
From study treatment start date until date of of death from any cause, assessed up to approximately 90 months
Cmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P)
Serial blood samples were collected pre-dose and post-dose on Day 1, Day 15 and pre-dose on Day 21 in the first 28 days of dosing. In the continuation period, blood samples were collected every 4 weeks up to and including Week 20 on study. Maximum observed concentration (Cmax) of Dabrafenib and derived metabolites were listed and summarized using descriptive statistics.
Day 1, Day 15, Week 8, Week 12, Week 16, Week 20
Cmax of Trametinib in the Triple Combination (D+T+P)
Serial blood samples were collected pre-dose and post-dose on Day 1, Day 15 and pre-dose on Day 21 in the first 28 days of dosing. In the continuation period, blood samples were collected every 4 weeks up to and including Week 20 on study. Maximum observed concentration (Cmax) of Trametinib was listed and summarized using descriptive statistics.
Day 1, Day 15, Week 8, Week 12, Week 16, Week 20
Tmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P)
Serial blood samples were collected pre-dose and post-dose on Day 1, Day 15 and pre-dose on Day 21 in the first 28 days of dosing. In the continuation period, blood samples were collected every 4 weeks up to and including Week 20 on study. Time of occurrence of Cmax (tmax) of Dabrafenib and derived metabolites were listed and summarized using descriptive statistics.
Day 1, Day 15, Week 8, Week 12, Week 16, Week 20
Tmax of Trametinib in the Triple Combination (D+T+P)
Serial blood samples were collected pre-dose and post-dose on Day 1, Day 15 and pre-dose on Day 21 in the first 28 days of dosing. In the continuation period, blood samples were collected every 4 weeks up to and including Week 20 on study. Time of occurrence of Cmax (tmax) of Trametinib was listed and summarized using descriptive statistics.
Day 1, Day 15, Week 8, Week 12, Week 16, Week 20
AUC[0-8] of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P)
Serial blood samples were collected pre-dose and post-dose on Day 1, Day 15 and pre-dose on Day 21 in the first 28 days of dosing. In the continuation period, blood samples were collected every 4 weeks up to and including Week 20 on study. Area under the concentration-time curve from zero (pre-dose) 8 hours (AUC[0-8]) of Dabrafenib and derived metabolites were listed and summarized using descriptive statistics.
Day 1, Day 15, Week 8 (Dabrafenib derived metabolites), Week 12, Week 16, Week 20
AUC[0-8] of Trametinib in the Triple Combination (D+T+P)
Serial blood samples were collected pre-dose and post-dose on Day 1, Day 15 and pre-dose on Day 21 in the first 28 days of dosing. In the continuation period, blood samples were collected every 4 weeks up to and including Week 20 on study. Area under the concentration-time curve from zero (pre-dose) 8 hours (AUC[0-8]) of Trametinib was listed and summarized using descriptive statistics.
Day 1, Day 15, Week 8, Week 12, Week 16, Week 20
Ctau of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P)
Serial blood samples were collected pre-dose and post-dose on Day 1, Day 15 and pre-dose on Day 21 in the first 28 days of dosing. In the continuation period, blood samples were collected every 4 weeks up to and including Week 20 on study. Pre-dose (trough) concentration at the end of the dosing interval (Ctau) of Dabrafenib and derived metabolites were listed and summarized using descriptive statistics.
Day 15, Week 8, Week 12, Week 16, Week 20
Ctau of Trametinib in the Triple Combination (D+T+P)
Serial blood samples were collected pre-dose and post-dose on Day 1, Day 15 and pre-dose on Day 21 in the first 28 days of dosing. In the continuation period, blood samples were collected every 4 weeks up to and including Week 20 on study. Pre-dose (trough) concentration at the end of the dosing interval (Ctau) of Trametinib was listed and summarized using descriptive statistics.
Day 15, Week 8, Week 12, Week 16, Week 20
Ctau of Panitumumab in the Triple Combination (D+T+P)
Serial blood samples were collected pre-dose and post-dose on Day 1, Day 15 and pre-dose on Day 21 in the first 28 days of dosing. In the continuation period, blood samples were collected every 4 weeks up to and including Week 20 on study. Pre-dose (trough) concentration at the end of the dosing interval (Ctau) of Panitumumab was listed and summarized using descriptive statistics.
Day 15, Week 4, Week 8, Week 12, Week 16, Week 20
Apparent Base Clearance (CL0/F) and Apparent Maximum Inducible Clearance at Steady State (CLIND,SS/F) of Dabrafenib in the Triple Combination (D+T+P) Estimated With a PopPK Model
The population pharmacokinetic (PopPK) model of Dabrafenib can be described using a two-compartment model with a delayed 1st order absorption (Alag1, Ka) and an inducible elimination (CL/F) that consists of a base clearance (constant over time, CL0/F) and a dose- and time-dependent inducible clearance (CLind/F). The PopPK analysis examined the influence of demographics (i.e., weight) on the pharmacokinetics of dabrafenib. The apparent base clearance (CL0/F) and apparent maximum inducible clearance at steady state (CLIND,SS/F) of Dabrafenib estimated with the PopPK model are summarized in this record.
Day 1, Day 15, Week 8, Week 12, Week 16, Week 20
Effect of Combination With Trametinib on Apparent Maximum Inducible Clearance at Steady State of Dabrafenib in the Triple Combination (D+T+P) Estimated With a PopPK Model
The population pharmacokinetic (PopPK) model of Dabrafenib can be described using a two-compartment model with a delayed 1st order absorption (Alag1, Ka) and an inducible elimination (CL/F) that consists of a base clearance (constant over time, CL0/F) and a dose- and time-dependent inducible clearance (CLind/F). The PopPK analysis examined the influence of demographics (i.e., weight) on the pharmacokinetics of dabrafenib. The effect of combination with trametinib on apparent maximum inducible clearance at steady state (CLIND,SS/F) (CLCOMBO) of Dabrafenib estimated with the PopPK model is summarized in this record.
The parameter in question is a covariate that describes the effect of Effect of combination with trametinib on apparent maximum inducible clearance: the number denoting the effect means that the including trametinib will decrease the apparent maximum inducible clearance as opposed to when dabrafenib is administered alone.
Day 1, Day 15, Week 8, Week 12, Week 16, Week 20
Oral Volume of Distribution (V/F) of Dabrafenib in the Triple Combination (D+T+P) Estimated With a PopPK Model
The population pharmacokinetic (PopPK) model of Dabrafenib can be described using a two-compartment model with a delayed 1st order absorption (Alag1, Ka) and an inducible elimination (CL/F) that consists of a base clearance (constant over time, CL0/F) and a dose- and time-dependent inducible clearance (CLind/F). The PopPK analysis examined the influence of demographics (i.e., weight) on the pharmacokinetics of dabrafenib. The oral volume of distribution (V/F) of Dabrafenib of Dabrafenib estimated with the PopPK model is summarized in this record.
Day 1, Day 15, Week 8, Week 12, Week 16, Week 20
Absorption Rate Constant (Ka) of Dabrafenib in the Triple Combination (D+T+P) Estimated With a PopPK Model
The population pharmacokinetic (PopPK) model of Dabrafenib can be described using a two-compartment model with a delayed 1st order absorption (Alag1, Ka) and an inducible elimination (CL/F) that consists of a base clearance (constant over time, CL0/F) and a dose- and time-dependent inducible clearance (CLind/F). The PopPK analysis examined the influence of demographics (i.e., weight) on the pharmacokinetics of dabrafenib. The absorption rate constant (Ka) of Dabrafenib estimated with the PopPK model is summarized in this record.
Day 1, Day 15, Week 8, Week 12, Week 16, Week 20
Cmax of Trametinib in the Double Combination (T+P)
Serial blood samples were collected pre-dose and post-dose on Day 1, Day 15 and pre-dose on Day 21 in the first 28 days of dosing. In the continuation period, blood samples were collected every 4 weeks up to and including Week 20 on study. Maximum observed concentration (Cmax) of Trametinib was listed and summarized using descriptive statistics.
Day 1, Day 15, Week 12, Week 20
Tmax of Trametinib in the Double Combination (T+P)
Serial blood samples were collected pre-dose and post-dose on Day 1, Day 15 and pre-dose on Day 21 in the first 28 days of dosing. In the continuation period, blood samples were collected every 4 weeks up to and including Week 20 on study. Time of occurrence of Cmax (tmax) of Trametinib was listed and summarized using descriptive statistics.
Day 1, Day 15, Week 12, Week 20
AUC[0-t] of Trametinib in the Double Combination (T+P)
Serial blood samples will be collected pre-dose and post-dose on Day 1, Day 15 and pre-dose on Day 21 in the first 28 days of dosing. In the continuation period, blood samples will be collected every 4 weeks up to and including Week 20 on study. Area under the concentration-time curve from zero (pre-dose) the time of the last quantifiable concentration (AUC[0-t]) of Trametinib was listed and summarized using descriptive statistics.
Day 1, Day 15, Week 12, Week 20
Ctau of Trametinib in the Double Combination (T+P)
Serial blood samples were collected pre-dose and post-dose on Day 1, Day 15 and pre-dose on Day 21 in the first 28 days of dosing. In the continuation period, blood samples were collected every 4 weeks up to and including Week 20 on study. Pre-dose (trough) concentration at the end of the dosing interval (Ctau) of Trametinib was listed and summarized using descriptive statistics.
Day 15, Week 8, Week 12, Week 16, Week 20
Ctau of Panitumumab in the Double Combination (T+P)
Serial blood samples were collected pre-dose and post-dose on Day 1, Day 15 and pre-dose on Day 21 in the first 28 days of dosing. In the continuation period, blood samples were collected every 4 weeks up to and including Week 20 on study. Pre-dose (trough) concentration at the end of the dosing interval (Ctau) of Panitumumab was listed and summarized using descriptive statistics.
Day 15, Week 8, Week 12, Week 16, Week 20
Apparent Base Clearance (CL0/F) and Apparent Maximum Inducible Clearance at Steady State (CLIND,SS/F) of Dabrafenib in the Double Combination (T+P) Estimated With a PopPK Model
The population pharmacokinetic (PopPK) model of Dabrafenib can be described using a two-compartment model with a delayed 1st order absorption (Alag1, Ka) and an inducible elimination (CL/F) that consists of a base clearance (constant over time, CL0/F) and a dose- and time-dependent inducible clearance (CLind/F). The PopPK analysis examined the influence of demographics (i.e., weight) on the pharmacokinetics of dabrafenib. The apparent base clearance (CL0/F) and apparent maximum inducible clearance at steady state (CLIND,SS/F) dabrafenib estimated with the PopPK model are summarized in this record.
Day 1, Day 15, Week 8, Week 12, Week 16, Week 20
Oral Volume of Distribution (V/F) of Dabrafenib in the Double Combination (T+P) Estimated With a PopPK Model
The population pharmacokinetic (PopPK) model of Dabrafenib can be described using a two-compartment model with a delayed 1st order absorption (Alag1, Ka) and an inducible elimination (CL/F) that consists of a base clearance (constant over time, CL0/F) and a dose- and time-dependent inducible clearance (CLind/F). The PopPK analysis examined the influence of demographics (i.e., weight) on the pharmacokinetics of dabrafenib. The oral volume of distribution (V/F) of Dabrafenib estimated with the PopPK model is summarized in this record.
Day 1, Day 15, Week 8, Week 12, Week 16, Week 20
Absorption Rate Constant (Ka) of Dabrafenib in the Double Combination (T+P) Estimated With a PopPK Model
The population pharmacokinetic (PopPK) model of Dabrafenib can be described using a two-compartment model with a delayed 1st order absorption (Alag1, Ka) and an inducible elimination (CL/F) that consists of a base clearance (constant over time, CL0/F) and a dose- and time-dependent inducible clearance (CLind/F). The PopPK analysis examined the influence of demographics (i.e., weight) on the pharmacokinetics of dabrafenib. The absorption rate constant (Ka) of Dabrafenib estimated with the PopPK model is summarized in this record.
Day 1, Day 15, Week 8, Week 12, Week 16, Week 20
Apparent Clearance (CL/F) of Trametinib in the Double Combination (T+P) Estimated With a PopPK Model
The population pharmacokinetic (PopPK) model of Trametinib can be described using a two-compartment model with dual sequential 1st order absorption (Ka1, Ka2) and 1st order elimination (CL/F). The PopPK analysis examined the influence of demographics (i.e., weight) on the pharmacokinetics of trametinib. The apparent clearance (CL/F) of Trametinib estimated with the PopPK model is summarized in this record.
Day 1, Day 15, Week 8, Week 12, Week 16, Week 20
Apparent Central Volume (V/F) of Trametinib in the Double Combination (T+P) Estimated With a PopPK Model
The population pharmacokinetic (PopPK) model of Trametinib can be described using a two-compartment model with dual sequential 1st order absorption (Ka1, Ka2) and 1st order elimination (CL/F). The PopPK analysis examined the influence of demographics (i.e., weight) on the pharmacokinetics of trametinib. The apparent central volume (V/F) of Trametinib estimated with the PopPK model is summarized in this record.
Day 1, Day 15, Week 8, Week 12, Week 16, Week 20
Absorption Rate Constant 1 (Ka1) and Absorption Rate Constant 2 (Ka2) of Trametinib in the Double Combination (T+P) Estimated With a PopPK Model
The population pharmacokinetic (PopPK) model of Trametinib can be described using a two-compartment model with dual sequential 1st order absorption (Ka1, Ka2) and 1st order elimination (CL/F). The PopPK analysis examined the influence of demographics (i.e., weight) on the pharmacokinetics of trametinib. The absorption rate constant 1 (Ka1) and absorption rate constant 2 (Ka2) of Trametinib estimated with the PopPK model are summarized in this record.
Day 1, Day 15, Week 8, Week 12, Week 16, Week 20
Time When Ka1 Transitions to Ka2 of Trametinib in the Double Combination (T+P) Estimated With a PopPK Model
The population pharmacokinetic (PopPK) model of Trametinib can be described using a two-compartment model with dual sequential 1st order absorption (Ka1, Ka2) and 1st order elimination (CL/F). The PopPK analysis examined the influence of demographics (i.e., weight) on the pharmacokinetics of trametinib. The time when Ka1 transitions to Ka2 of Trametinib estimated with the PopPK model is summarized in this record.
Day 1, Day 15, Week 8, Week 12, Week 16, Week 20
Change in Levels of Proteins/Ribonucleic Acid (RNA)
H-score or "Histo-score" measures cell membrane immunohistochemistry staining intensity in a fixed field. Membrane staining is categorized as 1+, 2+, or 3+. Minimum score is 0, maximum score is 300 (no subscale values are reported). H-score values themselves are not considered to be better or worse - measurements for levels of proteins/ribonucleic acid (RNA) are surrogate for MAPK pathway activity. Low values = low pathway activity. High values = high pathway activity. Changes in mean phosphorylated-ERK (pERK) and phosphorylated ribosomal protein S6 (pS6) H-score from baseline indicate changes in MAPK pathway activity that may be associated with treatment arms. A positive change from baseline suggests increased pathway activity. A negative change from baseline suggests decreased pathway activity. Total score is calculated as follows: [1 x (% cells 1+) + 2 x (% cells 2+) + 3 x (% cells 3+)].
Baseline, Day 15
Part 3: Overall Response Rate (ORR)
Overall Response Rate (ORR) was defined as the proportion of participants with Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR) using RECIST 1.1
From study treatment start date until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to approximately 90 months
Part 3: Duration of Response (DoR)
Duration of Response (DoR) was defined as the time from the first documented occurrence of response (PR or CR) until the date of the first documented progression based on RECIST v1.1 or death.
From study treatment start date until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to approximately 90 months
Part 3: Overall Survival (OS)
Overall Survival (OS) was defined as the time to death due to any cause.
From study treatment start date until date of of death from any cause, assessed up to approximately 90 months
Part 3: Number of Participants With Treatment Emergent Adverse Events
The distribution of adverse events (AE) will be done via the analysis of frequencies for treatment emergent Adverse Event (TEAEs), Serious Adverse Event (TESAEs) and Deaths due to AEs, through the monitoring of relevant clinical and laboratory safety parameters.
From study treatment start date till 30 days safety follow-up, assessed up to approximately 90 months
All patients in the All Treated Population for whom a PK sample was obtained and analyzed.
FG0003 subjects
FG0014 subjects
FG00235 subjects
FG00348 subjects
FG00412 subjects
FG00519 subjects
FG00618 subjects
FG00720 subjects
Biomarker Population
All patients in the All Treated Population whom a tumor biopsy/tissue was obtained and analyzed.
FG0003 subjects
FG0014 subjects
FG00236 subjects
FG00350 subjects
FG00413 subjects
FG00517 subjects
FG00619 subjects
FG00720 subjects
Crossover Population
Subset of patients in double combination who crossed over to triplet combination.
FG0000 subjects
FG0010 subjects
FG0020 subjects
FG0030 subjects
FG0044 subjects
FG0052 subjects
FG0065 subjects
FG0075 subjects
COMPLETED
FG0003 subjects
FG0014 subjects
FG00228 subjects
FG00344 subjects
FG00412 subjects
FG00517 subjects
FG00617 subjects
FG00716 subjects
NOT COMPLETED
FG0000 subjects
FG0010 subjects
FG0028 subjects
FG0036 subjects
FG0041 subjects
FG0053 subjects
FG0063 subjects
FG0074 subjects
Type
Comment
Reasons
Last patient transitioned to a rollover protocol
FG0000 subjects
FG0010 subjects
FG0025 subjects
FG0032 subjects
FG0040 subjects
FG0052 subjects
FG0061 subjects
FG0071 subjects
Lost to Follow-up
FG0000 subjects
FG0010 subjects
FG0022 subjects
FG0032 subjects
FG004
Withdrawal by Subject
FG0000 subjects
FG0010 subjects
FG0021 subjects
FG0032 subjects
FG004
Since, BRAF V600 mutant patients (MBRAF population) and KRAS wildtype patients progressing after EGFR based therapy (anti-EGFR population) were categorized as biologically distinct populations, doublet combination Trametinib + Panitumumab (T+P) was split into MBRAF and anti-EGFR patients for Baseline Characteristics and efficacy analysis to allow a more meaningful interpretation of study results.
Type of Units Analyzed
Not provided
Arm/Group Information
ID
Title
Description
BG000
Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W
The Eastern Cooperative Oncology Group Performance Status (ECOG PS) score classifies participants according to their functional impairment, with scores ranging from 0 (fully active) to 5 (dead). ECOG PS: 0 = Fully active, able to carry on all pre-disease performance without restriction; 1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work.
Count of Participants
Participants
Title
Denominators
Categories
Title
Measurements
Grade 0
BG0002
BG001
Type
Title
Description
Population Description
Reporting Status
Anticipated Posting Date
Parameter Type
Dispersion Type
Unit of Measure
Calculate Percentage
Time Frame
Units Analyzed
Denominator Units Selected
Arm/Group Information
Denominators
Classes
Analyses
Primary
Number of Participants With Adverse Events
The distribution of adverse events was done via the analysis of frequencies for Adverse Events, Serious Adverse Events and Deaths due to AEs, through the monitoring of relevant clinical and laboratory safety parameters. Only descriptive analysis performed.
All treated population.
Posted
Count of Participants
Participants
From study treatment start date till 30 days safety follow-up, assessed up to approximately 90 months
ID
Title
Description
OG000
Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W
Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) was used for efficacy based on radiological assessment of tumor burden: CR = Complete Response, disappearance of all target lesions; PR = Partial Response, >=30% decrease in the sum of the longest diameter of target lesions; PD = progressive disease, >=20% increase in sum of target lesions and/or presence of new lesions and/or substantial increase in non-target lesion; SD = stable disease, response not meeting CR or PR or PD; ORR = overall response rate, defined as CR+PR
All treated population
Posted
Number
95% Confidence Interval
Percentage of Participants
From study treatment start date until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to approximately 90 months
ID
Title
Description
OG000
Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W
Progression Free Survival (PFS) was defined as the time from study treatment start date to the date of first radiologically documented progression or death due to any cause. If a patient did not progress or die at the time of the analysis data cut-off or start of new antineoplastic therapy, PFS was censored at the date of the last adequate tumor assessment before the earliest of the cut-off date or the start date of additional anti-neoplastic therapy. Progression was defined using Response Evaluation Criteria In Solid Tumors Criteria RECIST v1.1, as 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline and/or unequivocal progression of the non-target lesions and/or appearance of a new lesion. In addition to the relative increase of 20%, the sum must demonstrate an absolute increase of at least 5 mm.
All treated population. The original intention of the study was to include a randomized phase 2 portion of the study as a "Part 3"; however, a preliminary analysis did not meet predetermined criteria for efficacy. As a result, Part 3 of the study was not initiated.
Posted
From study treatment start date until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to approximately 90 months
ID
Title
Description
OG000
Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W
Duration of Response (DoR) was defined as the time from the first documented occurrence of response (PR or CR) until the date of the first documented progression based on RECIST v1.1 or death.
All treated population. Only participants with an evaluable DoR events were included in the analysis.
Posted
Median
95% Confidence Interval
Months
From study treatment start date until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to approximately 90 months
ID
Title
Description
OG000
Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W
Progression Free Survival (PFS) was defined as the time from study treatment start date to the date of first radiologically documented progression or death due to any cause. If a patient did not progress or die at the time of the analysis data cut-off or start of new antineoplastic therapy, PFS was censored at the date of the last adequate tumor assessment before the earliest of the cut-off date or the start date of additional anti-neoplastic therapy. Progression was defined using Response Evaluation Criteria In Solid Tumors Criteria RECIST v1.1, as 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline and/or unequivocal progression of the non-target lesions and/or appearance of a new lesion. In addition to the relative increase of 20%, the sum must demonstrate an absolute increase of at least 5 mm.
All treated population. Only participants with an evaluable PFS events were included in the analysis.
Posted
Median
95% Confidence Interval
Months
From study treatment start date until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to approximately 90 months
ID
Title
Description
OG000
Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W
Cmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P)
Serial blood samples were collected pre-dose and post-dose on Day 1, Day 15 and pre-dose on Day 21 in the first 28 days of dosing. In the continuation period, blood samples were collected every 4 weeks up to and including Week 20 on study. Maximum observed concentration (Cmax) of Dabrafenib and derived metabolites were listed and summarized using descriptive statistics.
Pharmacokinetic population. Only participants with an evaluable PK sample collected at each timepoint were included in the analysis.
Posted
Geometric Mean
Geometric Coefficient of Variation
ng/mL
Day 1, Day 15, Week 8, Week 12, Week 16, Week 20
ID
Title
Description
OG000
Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W
Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W
Secondary
Cmax of Trametinib in the Triple Combination (D+T+P)
Serial blood samples were collected pre-dose and post-dose on Day 1, Day 15 and pre-dose on Day 21 in the first 28 days of dosing. In the continuation period, blood samples were collected every 4 weeks up to and including Week 20 on study. Maximum observed concentration (Cmax) of Trametinib was listed and summarized using descriptive statistics.
Pharmacokinetic population. Only participants with an evaluable PK sample collected at each timepoint were included in the analysis.
Posted
Geometric Mean
Geometric Coefficient of Variation
ng/mL
Day 1, Day 15, Week 8, Week 12, Week 16, Week 20
ID
Title
Description
OG000
Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W
Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W
Secondary
Tmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P)
Serial blood samples were collected pre-dose and post-dose on Day 1, Day 15 and pre-dose on Day 21 in the first 28 days of dosing. In the continuation period, blood samples were collected every 4 weeks up to and including Week 20 on study. Time of occurrence of Cmax (tmax) of Dabrafenib and derived metabolites were listed and summarized using descriptive statistics.
Pharmacokinetic population. Only participants with an evaluable PK sample collected at each timepoint were included in the analysis.
Posted
Median
Full Range
Hour (hr)
Day 1, Day 15, Week 8, Week 12, Week 16, Week 20
ID
Title
Description
OG000
Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W
Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W
Secondary
Tmax of Trametinib in the Triple Combination (D+T+P)
Serial blood samples were collected pre-dose and post-dose on Day 1, Day 15 and pre-dose on Day 21 in the first 28 days of dosing. In the continuation period, blood samples were collected every 4 weeks up to and including Week 20 on study. Time of occurrence of Cmax (tmax) of Trametinib was listed and summarized using descriptive statistics.
Pharmacokinetic population. Only participants with an evaluable PK sample collected at each timepoint were included in the analysis.
Posted
Median
Full Range
Hour (hr)
Day 1, Day 15, Week 8, Week 12, Week 16, Week 20
ID
Title
Description
OG000
Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W
Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W
Secondary
AUC[0-8] of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P)
Serial blood samples were collected pre-dose and post-dose on Day 1, Day 15 and pre-dose on Day 21 in the first 28 days of dosing. In the continuation period, blood samples were collected every 4 weeks up to and including Week 20 on study. Area under the concentration-time curve from zero (pre-dose) 8 hours (AUC[0-8]) of Dabrafenib and derived metabolites were listed and summarized using descriptive statistics.
Pharmacokinetic population. Only participants with an evaluable PK sample collected at each timepoint were included in the analysis.
Posted
Geometric Mean
Geometric Coefficient of Variation
h*ng/mL
Day 1, Day 15, Week 8 (Dabrafenib derived metabolites), Week 12, Week 16, Week 20
ID
Title
Description
OG000
Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W
Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W
Secondary
AUC[0-8] of Trametinib in the Triple Combination (D+T+P)
Serial blood samples were collected pre-dose and post-dose on Day 1, Day 15 and pre-dose on Day 21 in the first 28 days of dosing. In the continuation period, blood samples were collected every 4 weeks up to and including Week 20 on study. Area under the concentration-time curve from zero (pre-dose) 8 hours (AUC[0-8]) of Trametinib was listed and summarized using descriptive statistics.
Pharmacokinetic population. Only participants with an evaluable PK sample collected at each timepoint were included in the analysis.
Posted
Geometric Mean
Geometric Coefficient of Variation
h*ng/mL
Day 1, Day 15, Week 8, Week 12, Week 16, Week 20
ID
Title
Description
OG000
Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W
Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W
Secondary
Ctau of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P)
Serial blood samples were collected pre-dose and post-dose on Day 1, Day 15 and pre-dose on Day 21 in the first 28 days of dosing. In the continuation period, blood samples were collected every 4 weeks up to and including Week 20 on study. Pre-dose (trough) concentration at the end of the dosing interval (Ctau) of Dabrafenib and derived metabolites were listed and summarized using descriptive statistics.
Pharmacokinetic population. Only participants with an evaluable PK sample collected at each timepoint were included in the analysis.
Posted
Geometric Mean
Geometric Coefficient of Variation
ng/mL
Day 15, Week 8, Week 12, Week 16, Week 20
ID
Title
Description
OG000
Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W
Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W
Secondary
Ctau of Trametinib in the Triple Combination (D+T+P)
Serial blood samples were collected pre-dose and post-dose on Day 1, Day 15 and pre-dose on Day 21 in the first 28 days of dosing. In the continuation period, blood samples were collected every 4 weeks up to and including Week 20 on study. Pre-dose (trough) concentration at the end of the dosing interval (Ctau) of Trametinib was listed and summarized using descriptive statistics.
Pharmacokinetic population. Only participants with an evaluable PK sample collected at each timepoint were included in the analysis.
Posted
Geometric Mean
Geometric Coefficient of Variation
ng/mL
Day 15, Week 8, Week 12, Week 16, Week 20
ID
Title
Description
OG000
Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W
Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W
Secondary
Ctau of Panitumumab in the Triple Combination (D+T+P)
Serial blood samples were collected pre-dose and post-dose on Day 1, Day 15 and pre-dose on Day 21 in the first 28 days of dosing. In the continuation period, blood samples were collected every 4 weeks up to and including Week 20 on study. Pre-dose (trough) concentration at the end of the dosing interval (Ctau) of Panitumumab was listed and summarized using descriptive statistics.
Pharmacokinetic population. Only participants with an evaluable PK sample collected at each timepoint were included in the analysis.
Posted
Geometric Mean
Geometric Coefficient of Variation
ng/mL
Day 15, Week 4, Week 8, Week 12, Week 16, Week 20
ID
Title
Description
OG000
Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W
Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W
Secondary
Apparent Base Clearance (CL0/F) and Apparent Maximum Inducible Clearance at Steady State (CLIND,SS/F) of Dabrafenib in the Triple Combination (D+T+P) Estimated With a PopPK Model
The population pharmacokinetic (PopPK) model of Dabrafenib can be described using a two-compartment model with a delayed 1st order absorption (Alag1, Ka) and an inducible elimination (CL/F) that consists of a base clearance (constant over time, CL0/F) and a dose- and time-dependent inducible clearance (CLind/F). The PopPK analysis examined the influence of demographics (i.e., weight) on the pharmacokinetics of dabrafenib. The apparent base clearance (CL0/F) and apparent maximum inducible clearance at steady state (CLIND,SS/F) of Dabrafenib estimated with the PopPK model are summarized in this record.
All subjects who received at least one dose of dabrafenib in Part 1, 2A and 2B and provided an evaluable PK profile. All trametinib and dabrafenib concentration-time data were combined and included in a population PK analysis that examined the influence of demographics on the PK of study treatment.
Posted
Number
95% Confidence Interval
L/h
Day 1, Day 15, Week 8, Week 12, Week 16, Week 20
ID
Title
Description
OG000
Part 1+2A+2B - Triple Combination (D+T+P): All Participants With PK Data
Participants in Part 1+2A+2B - Triple combination (D+T+P) of the study (all doses) with available pharmacokinetic data
Units
Counts
Secondary
Effect of Combination With Trametinib on Apparent Maximum Inducible Clearance at Steady State of Dabrafenib in the Triple Combination (D+T+P) Estimated With a PopPK Model
The population pharmacokinetic (PopPK) model of Dabrafenib can be described using a two-compartment model with a delayed 1st order absorption (Alag1, Ka) and an inducible elimination (CL/F) that consists of a base clearance (constant over time, CL0/F) and a dose- and time-dependent inducible clearance (CLind/F). The PopPK analysis examined the influence of demographics (i.e., weight) on the pharmacokinetics of dabrafenib. The effect of combination with trametinib on apparent maximum inducible clearance at steady state (CLIND,SS/F) (CLCOMBO) of Dabrafenib estimated with the PopPK model is summarized in this record.
The parameter in question is a covariate that describes the effect of Effect of combination with trametinib on apparent maximum inducible clearance: the number denoting the effect means that the including trametinib will decrease the apparent maximum inducible clearance as opposed to when dabrafenib is administered alone.
All subjects who received at least one dose of dabrafenib in Part 1, 2A and 2B and provided an evaluable PK profile. All trametinib and dabrafenib concentration-time data were combined and included in a population PK analysis that examined the influence of demographics on the PK of study treatment.
Posted
Number
95% Confidence Interval
no unit of measure
Day 1, Day 15, Week 8, Week 12, Week 16, Week 20
ID
Title
Description
OG000
Part 1+2A+2B - Triple Combination (D+T+P): All Participants With PK Data
Participants in Part 1+2A+2B - Triple combination (D+T+P) of the study (all doses) with available pharmacokinetic data
Secondary
Oral Volume of Distribution (V/F) of Dabrafenib in the Triple Combination (D+T+P) Estimated With a PopPK Model
The population pharmacokinetic (PopPK) model of Dabrafenib can be described using a two-compartment model with a delayed 1st order absorption (Alag1, Ka) and an inducible elimination (CL/F) that consists of a base clearance (constant over time, CL0/F) and a dose- and time-dependent inducible clearance (CLind/F). The PopPK analysis examined the influence of demographics (i.e., weight) on the pharmacokinetics of dabrafenib. The oral volume of distribution (V/F) of Dabrafenib of Dabrafenib estimated with the PopPK model is summarized in this record.
All subjects who received at least one dose of dabrafenib in Part 1, 2A and 2B and provided an evaluable PK profile. All trametinib and dabrafenib concentration-time data were combined and included in a population PK analysis that examined the influence of demographics on the PK of study treatment.
Posted
Number
95% Confidence Interval
Liter (L)
Day 1, Day 15, Week 8, Week 12, Week 16, Week 20
ID
Title
Description
OG000
Part 1+2A+2B - Triple Combination (D+T+P): All Participants With PK Data
Participants in Part 1+2A+2B - Triple combination (D+T+P) of the study (all doses) with available pharmacokinetic data
Units
Counts
Participants
Secondary
Absorption Rate Constant (Ka) of Dabrafenib in the Triple Combination (D+T+P) Estimated With a PopPK Model
The population pharmacokinetic (PopPK) model of Dabrafenib can be described using a two-compartment model with a delayed 1st order absorption (Alag1, Ka) and an inducible elimination (CL/F) that consists of a base clearance (constant over time, CL0/F) and a dose- and time-dependent inducible clearance (CLind/F). The PopPK analysis examined the influence of demographics (i.e., weight) on the pharmacokinetics of dabrafenib. The absorption rate constant (Ka) of Dabrafenib estimated with the PopPK model is summarized in this record.
All subjects who received at least one dose of dabrafenib in Part 1, 2A and 2B and provided an evaluable PK profile. All trametinib and dabrafenib concentration-time data were combined and included in a population PK analysis that examined the influence of demographics on the PK of study treatment.
Posted
Number
95% Confidence Interval
1/h
Day 1, Day 15, Week 8, Week 12, Week 16, Week 20
ID
Title
Description
OG000
Part 1+2A+2B - Triple Combination (D+T+P): All Participants With PK Data
Participants in Part 1+2A+2B - Triple combination (D+T+P) of the study (all doses) with available pharmacokinetic data
Units
Counts
Participants
Secondary
Cmax of Trametinib in the Double Combination (T+P)
Serial blood samples were collected pre-dose and post-dose on Day 1, Day 15 and pre-dose on Day 21 in the first 28 days of dosing. In the continuation period, blood samples were collected every 4 weeks up to and including Week 20 on study. Maximum observed concentration (Cmax) of Trametinib was listed and summarized using descriptive statistics.
Pharmacokinetic population. Only participants with an evaluable PK sample collected at each timepoint were included in the analysis.
Posted
Geometric Mean
Geometric Coefficient of Variation
ng/mL
Day 1, Day 15, Week 12, Week 20
ID
Title
Description
OG000
Part 4A+4B - Double Combination (T+P): TRA 2MG QD, PAN 6MG/KG Q2W
Tmax of Trametinib in the Double Combination (T+P)
Serial blood samples were collected pre-dose and post-dose on Day 1, Day 15 and pre-dose on Day 21 in the first 28 days of dosing. In the continuation period, blood samples were collected every 4 weeks up to and including Week 20 on study. Time of occurrence of Cmax (tmax) of Trametinib was listed and summarized using descriptive statistics.
Pharmacokinetic population. Only participants with an evaluable PK sample collected at each timepoint were included in the analysis.
Posted
Median
Full Range
Hour (hr)
Day 1, Day 15, Week 12, Week 20
ID
Title
Description
OG000
Part 4A+4B - Double Combination (T+P): TRA 2MG QD, PAN 6MG/KG Q2W
AUC[0-t] of Trametinib in the Double Combination (T+P)
Serial blood samples will be collected pre-dose and post-dose on Day 1, Day 15 and pre-dose on Day 21 in the first 28 days of dosing. In the continuation period, blood samples will be collected every 4 weeks up to and including Week 20 on study. Area under the concentration-time curve from zero (pre-dose) the time of the last quantifiable concentration (AUC[0-t]) of Trametinib was listed and summarized using descriptive statistics.
Pharmacokinetic population. Only participants with an evaluable PK sample collected at each timepoint were included in the analysis.
Posted
Geometric Mean
Geometric Coefficient of Variation
h*ng/mL
Day 1, Day 15, Week 12, Week 20
ID
Title
Description
OG000
Part 4A+4B - Double Combination (T+P): TRA 2MG QD, PAN 6MG/KG Q2W
Part 4A+4B - Double Combination (T+P): TRA 2MG QD, PAN 4.8MG/KG Q2W
Secondary
Ctau of Trametinib in the Double Combination (T+P)
Serial blood samples were collected pre-dose and post-dose on Day 1, Day 15 and pre-dose on Day 21 in the first 28 days of dosing. In the continuation period, blood samples were collected every 4 weeks up to and including Week 20 on study. Pre-dose (trough) concentration at the end of the dosing interval (Ctau) of Trametinib was listed and summarized using descriptive statistics.
Pharmacokinetic population. Only participants with an evaluable PK sample collected at each timepoint were included in the analysis.
Posted
Geometric Mean
Geometric Coefficient of Variation
ng/mL
Day 15, Week 8, Week 12, Week 16, Week 20
ID
Title
Description
OG000
Part 4A+4B - Double Combination (T+P): TRA 2MG QD, PAN 6MG/KG Q2W
Ctau of Panitumumab in the Double Combination (T+P)
Serial blood samples were collected pre-dose and post-dose on Day 1, Day 15 and pre-dose on Day 21 in the first 28 days of dosing. In the continuation period, blood samples were collected every 4 weeks up to and including Week 20 on study. Pre-dose (trough) concentration at the end of the dosing interval (Ctau) of Panitumumab was listed and summarized using descriptive statistics.
Pharmacokinetic population. Only participants with an evaluable PK sample collected at each timepoint were included in the analysis.
Posted
Geometric Mean
Geometric Coefficient of Variation
ng/mL
Day 15, Week 8, Week 12, Week 16, Week 20
ID
Title
Description
OG000
Part 4A+4B - Double Combination (T+P): TRA 2MG QD, PAN 6MG/KG Q2W
Apparent Base Clearance (CL0/F) and Apparent Maximum Inducible Clearance at Steady State (CLIND,SS/F) of Dabrafenib in the Double Combination (T+P) Estimated With a PopPK Model
The population pharmacokinetic (PopPK) model of Dabrafenib can be described using a two-compartment model with a delayed 1st order absorption (Alag1, Ka) and an inducible elimination (CL/F) that consists of a base clearance (constant over time, CL0/F) and a dose- and time-dependent inducible clearance (CLind/F). The PopPK analysis examined the influence of demographics (i.e., weight) on the pharmacokinetics of dabrafenib. The apparent base clearance (CL0/F) and apparent maximum inducible clearance at steady state (CLIND,SS/F) dabrafenib estimated with the PopPK model are summarized in this record.
All subjects who received at least one dose of dabrafenib in Part 4A and 4B and provided an evaluable PK profile. All trametinib and dabrafenib concentration-time data were combined and included in a population PK analysis that examined the influence of demographics on the PK of study treatment.
Posted
Number
95% Confidence Interval
L/h
Day 1, Day 15, Week 8, Week 12, Week 16, Week 20
ID
Title
Description
OG000
Part 4A+4B - Double Combination (T+P): All Participants With PK Data
Participants in Part 4A+4B of the study (all doses) with available pharmacokinetic data
Units
Counts
Participants
Secondary
Oral Volume of Distribution (V/F) of Dabrafenib in the Double Combination (T+P) Estimated With a PopPK Model
The population pharmacokinetic (PopPK) model of Dabrafenib can be described using a two-compartment model with a delayed 1st order absorption (Alag1, Ka) and an inducible elimination (CL/F) that consists of a base clearance (constant over time, CL0/F) and a dose- and time-dependent inducible clearance (CLind/F). The PopPK analysis examined the influence of demographics (i.e., weight) on the pharmacokinetics of dabrafenib. The oral volume of distribution (V/F) of Dabrafenib estimated with the PopPK model is summarized in this record.
All subjects who received at least one dose of dabrafenib in Part 4A and 4B and provided an evaluable PK profile. All trametinib and dabrafenib concentration-time data were combined and included in a population PK analysis that examined the influence of demographics on the PK of study treatment.
Posted
Number
95% Confidence Interval
Liter (L)
Day 1, Day 15, Week 8, Week 12, Week 16, Week 20
ID
Title
Description
OG000
Part 4A+4B - Double Combination (T+P): All Participants With PK Data
Participants in Part 4A+4B of the study (all doses) with available pharmacokinetic data
Units
Counts
Participants
Secondary
Absorption Rate Constant (Ka) of Dabrafenib in the Double Combination (T+P) Estimated With a PopPK Model
The population pharmacokinetic (PopPK) model of Dabrafenib can be described using a two-compartment model with a delayed 1st order absorption (Alag1, Ka) and an inducible elimination (CL/F) that consists of a base clearance (constant over time, CL0/F) and a dose- and time-dependent inducible clearance (CLind/F). The PopPK analysis examined the influence of demographics (i.e., weight) on the pharmacokinetics of dabrafenib. The absorption rate constant (Ka) of Dabrafenib estimated with the PopPK model is summarized in this record.
All subjects who received at least one dose of dabrafenib in Part 4A and 4B and provided an evaluable PK profile. All trametinib and dabrafenib concentration-time data were combined and included in a population PK analysis that examined the influence of demographics on the PK of study treatment.
Posted
Number
95% Confidence Interval
1/h
Day 1, Day 15, Week 8, Week 12, Week 16, Week 20
ID
Title
Description
OG000
Part 4A+4B - Double Combination (T+P): All Participants With PK Data
Participants in Part 4A+4B of the study (all doses) with available pharmacokinetic data
Units
Counts
Participants
Secondary
Apparent Clearance (CL/F) of Trametinib in the Double Combination (T+P) Estimated With a PopPK Model
The population pharmacokinetic (PopPK) model of Trametinib can be described using a two-compartment model with dual sequential 1st order absorption (Ka1, Ka2) and 1st order elimination (CL/F). The PopPK analysis examined the influence of demographics (i.e., weight) on the pharmacokinetics of trametinib. The apparent clearance (CL/F) of Trametinib estimated with the PopPK model is summarized in this record.
All subjects who received at least one dose of dabrafenib in Part 4A and 4B and provided an evaluable PK profile. All trametinib and dabrafenib concentration-time data were combined and included in a population PK analysis that examined the influence of demographics on the PK of study treatment.
Posted
Number
95% Confidence Interval
L/h
Day 1, Day 15, Week 8, Week 12, Week 16, Week 20
ID
Title
Description
OG000
Part 4A+4B - Double Combination (T+P): All Participants With PK Data
Participants in Part 4A+4B of the study (all doses) with available pharmacokinetic data
Units
Counts
Participants
OG000
Secondary
Apparent Central Volume (V/F) of Trametinib in the Double Combination (T+P) Estimated With a PopPK Model
The population pharmacokinetic (PopPK) model of Trametinib can be described using a two-compartment model with dual sequential 1st order absorption (Ka1, Ka2) and 1st order elimination (CL/F). The PopPK analysis examined the influence of demographics (i.e., weight) on the pharmacokinetics of trametinib. The apparent central volume (V/F) of Trametinib estimated with the PopPK model is summarized in this record.
All subjects who received at least one dose of dabrafenib in Part 4A and 4B and provided an evaluable PK profile. All trametinib and dabrafenib concentration-time data were combined and included in a population PK analysis that examined the influence of demographics on the PK of study treatment.
Posted
Number
95% Confidence Interval
Liter (L)
Day 1, Day 15, Week 8, Week 12, Week 16, Week 20
ID
Title
Description
OG000
Part 4A+4B - Double Combination (T+P): All Participants With PK Data
Participants in Part 4A+4B of the study (all doses) with available pharmacokinetic data
Units
Counts
Participants
OG000
Secondary
Absorption Rate Constant 1 (Ka1) and Absorption Rate Constant 2 (Ka2) of Trametinib in the Double Combination (T+P) Estimated With a PopPK Model
The population pharmacokinetic (PopPK) model of Trametinib can be described using a two-compartment model with dual sequential 1st order absorption (Ka1, Ka2) and 1st order elimination (CL/F). The PopPK analysis examined the influence of demographics (i.e., weight) on the pharmacokinetics of trametinib. The absorption rate constant 1 (Ka1) and absorption rate constant 2 (Ka2) of Trametinib estimated with the PopPK model are summarized in this record.
All subjects who received at least one dose of dabrafenib in Part 4A and 4B and provided an evaluable PK profile. All trametinib and dabrafenib concentration-time data were combined and included in a population PK analysis that examined the influence of demographics on the PK of study treatment.
Posted
Number
95% Confidence Interval
1/h
Day 1, Day 15, Week 8, Week 12, Week 16, Week 20
ID
Title
Description
OG000
Part 4A+4B - Double Combination (T+P): All Participants With PK Data
Participants in Part 4A+4B of the study (all doses) with available pharmacokinetic data
Units
Counts
Participants
Secondary
Time When Ka1 Transitions to Ka2 of Trametinib in the Double Combination (T+P) Estimated With a PopPK Model
The population pharmacokinetic (PopPK) model of Trametinib can be described using a two-compartment model with dual sequential 1st order absorption (Ka1, Ka2) and 1st order elimination (CL/F). The PopPK analysis examined the influence of demographics (i.e., weight) on the pharmacokinetics of trametinib. The time when Ka1 transitions to Ka2 of Trametinib estimated with the PopPK model is summarized in this record.
All subjects who received at least one dose of dabrafenib in Part 4A and 4B and provided an evaluable PK profile. All trametinib and dabrafenib concentration-time data were combined and included in a population PK analysis that examined the influence of demographics on the PK of study treatment.
Posted
Number
95% Confidence Interval
hour (h)
Day 1, Day 15, Week 8, Week 12, Week 16, Week 20
ID
Title
Description
OG000
Part 4A+4B - Double Combination (T+P): All Participants With PK Data
Participants in Part 4A+4B of the study (all doses) with available pharmacokinetic data
Units
Counts
Participants
OG000
Secondary
Change in Levels of Proteins/Ribonucleic Acid (RNA)
H-score or "Histo-score" measures cell membrane immunohistochemistry staining intensity in a fixed field. Membrane staining is categorized as 1+, 2+, or 3+. Minimum score is 0, maximum score is 300 (no subscale values are reported). H-score values themselves are not considered to be better or worse - measurements for levels of proteins/ribonucleic acid (RNA) are surrogate for MAPK pathway activity. Low values = low pathway activity. High values = high pathway activity. Changes in mean phosphorylated-ERK (pERK) and phosphorylated ribosomal protein S6 (pS6) H-score from baseline indicate changes in MAPK pathway activity that may be associated with treatment arms. A positive change from baseline suggests increased pathway activity. A negative change from baseline suggests decreased pathway activity. Total score is calculated as follows: [1 x (% cells 1+) + 2 x (% cells 2+) + 3 x (% cells 3+)].
All treated population. Parameter information at baseline of patients with two different baseline were excluded. Day 15 included post-baseline information between study day 13 - 18.
Posted
Mean
Standard Deviation
H-Score
Baseline, Day 15
ID
Title
Description
OG000
Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W
Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W
Secondary
Part 3: Overall Response Rate (ORR)
Overall Response Rate (ORR) was defined as the proportion of participants with Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR) using RECIST 1.1
All treated population. The original intention of the study was to include a randomized phase 2 portion of the study as a "Part 3"; however, a preliminary analysis did not meet predetermined criteria for efficacy. As a result, Part 3 of the study was not initiated.
Posted
From study treatment start date until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to approximately 90 months
ID
Title
Description
OG000
Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W
Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W
Secondary
Part 3: Duration of Response (DoR)
Duration of Response (DoR) was defined as the time from the first documented occurrence of response (PR or CR) until the date of the first documented progression based on RECIST v1.1 or death.
All treated population. The original intention of the study was to include a randomized phase 2 portion of the study as a "Part 3"; however, a preliminary analysis did not meet predetermined criteria for efficacy. As a result, Part 3 of the study was not initiated.
Posted
From study treatment start date until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to approximately 90 months
ID
Title
Description
OG000
Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W
Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W
Secondary
Part 3: Overall Survival (OS)
Overall Survival (OS) was defined as the time to death due to any cause.
All treated population. The original intention of the study was to include a randomized phase 2 portion of the study as a "Part 3"; however, a preliminary analysis did not meet predetermined criteria for efficacy. As a result, Part 3 of the study was not initiated.
Posted
From study treatment start date until date of of death from any cause, assessed up to approximately 90 months
ID
Title
Description
OG000
Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W
Part 3: Number of Participants With Treatment Emergent Adverse Events
The distribution of adverse events (AE) will be done via the analysis of frequencies for treatment emergent Adverse Event (TEAEs), Serious Adverse Event (TESAEs) and Deaths due to AEs, through the monitoring of relevant clinical and laboratory safety parameters.
All treated population. The original intention of the study was to include a randomized phase 2 portion of the study as a "Part 3"; however, a preliminary analysis did not meet predetermined criteria for efficacy. As a result, Part 3 of the study was not initiated.
Posted
From study treatment start date till 30 days safety follow-up, assessed up to approximately 90 months
ID
Title
Description
OG000
Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W
Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W
Post-Hoc
All Collected Deaths
On treatment deaths were collected from FPFT up to 30 days after study drug discontinuation, for a maximum duration of 2454 days (treatment duration ranged from 1 to 2424 days).
Deaths post treatment survival follow up were collected after the on- treatment period, up to approximately 7 years. Patients who didn't die during the on-treatment period and had not stopped study participation at the time of data cut-off (end of study) were censored.
Clinical database population; all treated patients.
Posted
Count of Participants
Participants
up to 2454 days (on-treatment), up to approximately 7 years (study duration)
ID
Title
Description
OG000
Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W
Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W
Time Frame
On-treatment Adverse events (AEs) and serious AEs (including the All-Cause Mortality data table) are presented from first dose of study treatment until last dose of study treatment plus 30 days post treatment, for a maximum duration of 2454 days (treatment duration ranged from 1 to 2424 days).
Description
Any sign or symptom that occurs during the study treatment and 30 days post treatment follow up.
Maximum exposure to study treatments = 2424 days in the Trametinib (T) plus Dabrafenib (D) plus Panitumumab (P) Triplet Combination (T+D+P), 508 days in the Trametinib (T) plus Panitumumab (P) Doublet Combination (T+P) and 652 days in the Dabrafenib (D) plus Panitumumab (P) Doublet Combination (D+P).
All-Cause Mortality Comment
Not provided
Arm/Groups
ID
Title
Description
Deaths (Affected)
Deaths (At Risk)
Serious Events (Affected)
Serious Events (At Risk)
Other Events (Affected)
Other Events (At Risk)
EG000
Part 1+2A+2B - Triple Combination (T+D+P): DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0021 affected36 at risk
EG003
Squamous cell carcinoma
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0020 affected36 at risk
EG003
Delirium
Psychiatric disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0020 affected36 at risk
EG003
Acute kidney injury
Renal and urinary disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0020 affected36 at risk
EG003
Calculus urinary
Renal and urinary disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0020 affected36 at risk
EG003
Hydronephrosis
Renal and urinary disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0020 affected36 at risk
EG003
Renal failure
Renal and urinary disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0022 affected36 at risk
EG003
Ureteric obstruction
Renal and urinary disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0020 affected36 at risk
EG003
Urinary retention
Renal and urinary disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0020 affected36 at risk
EG003
Urinoma
Renal and urinary disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0020 affected36 at risk
EG003
Dyspnoea
Respiratory, thoracic and mediastinal disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0011 affected4 at risk
EG0020 affected36 at risk
EG003
Lung disorder
Respiratory, thoracic and mediastinal disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0021 affected36 at risk
EG003
Pulmonary embolism
Respiratory, thoracic and mediastinal disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0021 affected36 at risk
EG003
Dermatitis acneiform
Skin and subcutaneous tissue disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0020 affected36 at risk
EG003
Drug eruption
Skin and subcutaneous tissue disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0020 affected36 at risk
EG003
Rash maculo-papular
Skin and subcutaneous tissue disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0021 affected36 at risk
EG003
Stevens-Johnson syndrome
Skin and subcutaneous tissue disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0021 affected36 at risk
EG003
Deep vein thrombosis
Vascular disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0020 affected36 at risk
EG003
Hypotension
Vascular disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0020 affected36 at risk
EG003
Peripheral artery thrombosis
Vascular disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0020 affected36 at risk
EG003
Other Adverse Events
Term
Organ System
Source Vocabulary
Assessment Type
Notes
Statistical Information
Anaemia
Blood and lymphatic system disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0012 affected4 at risk
EG0028 affected36 at risk
EG00318 affected50 at risk
EG0042 affected13 at risk
EG0057 affected20 at risk
EG0065 affected20 at risk
EG0071 affected20 at risk
Iron deficiency anaemia
Blood and lymphatic system disorders
MedDRA (23.1)
Systematic Assessment
EG0001 affected3 at risk
EG0010 affected4 at risk
EG0020 affected36 at risk
EG003
Leukocytosis
Blood and lymphatic system disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0020 affected36 at risk
EG003
Thrombocytopenia
Blood and lymphatic system disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0020 affected36 at risk
EG003
Palpitations
Cardiac disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0022 affected36 at risk
EG003
Sinus tachycardia
Cardiac disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0020 affected36 at risk
EG003
Tachycardia
Cardiac disorders
MedDRA (23.1)
Systematic Assessment
EG0001 affected3 at risk
EG0010 affected4 at risk
EG0020 affected36 at risk
EG003
Dry eye
Eye disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0024 affected36 at risk
EG003
Eye inflammation
Eye disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0020 affected36 at risk
EG003
Eye swelling
Eye disorders
MedDRA (23.1)
Systematic Assessment
EG0001 affected3 at risk
EG0010 affected4 at risk
EG0020 affected36 at risk
EG003
Eyelid irritation
Eye disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0020 affected36 at risk
EG003
Lacrimation increased
Eye disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0022 affected36 at risk
EG003
Ocular hyperaemia
Eye disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0022 affected36 at risk
EG003
Trichomegaly
Eye disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0011 affected4 at risk
EG0022 affected36 at risk
EG003
Vision blurred
Eye disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0022 affected36 at risk
EG003
Visual acuity reduced
Eye disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0020 affected36 at risk
EG003
Visual impairment
Eye disorders
MedDRA (23.1)
Systematic Assessment
EG0001 affected3 at risk
EG0010 affected4 at risk
EG0020 affected36 at risk
EG003
Abdominal distension
Gastrointestinal disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0023 affected36 at risk
EG003
Abdominal pain
Gastrointestinal disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0011 affected4 at risk
EG0024 affected36 at risk
EG003
Abdominal pain upper
Gastrointestinal disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0026 affected36 at risk
EG003
Angular cheilitis
Gastrointestinal disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0020 affected36 at risk
EG003
Cheilitis
Gastrointestinal disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0022 affected36 at risk
EG003
Constipation
Gastrointestinal disorders
MedDRA (23.1)
Systematic Assessment
EG0001 affected3 at risk
EG0011 affected4 at risk
EG00211 affected36 at risk
EG003
Diarrhoea
Gastrointestinal disorders
MedDRA (23.1)
Systematic Assessment
EG0003 affected3 at risk
EG0013 affected4 at risk
EG00221 affected36 at risk
EG003
Dry mouth
Gastrointestinal disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0024 affected36 at risk
EG003
Dyspepsia
Gastrointestinal disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0025 affected36 at risk
EG003
Dysphagia
Gastrointestinal disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0011 affected4 at risk
EG0020 affected36 at risk
EG003
Flatulence
Gastrointestinal disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0022 affected36 at risk
EG003
Gastrooesophageal reflux disease
Gastrointestinal disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0022 affected36 at risk
EG003
Gingival bleeding
Gastrointestinal disorders
MedDRA (23.1)
Systematic Assessment
EG0001 affected3 at risk
EG0010 affected4 at risk
EG0020 affected36 at risk
EG003
Glossodynia
Gastrointestinal disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0020 affected36 at risk
EG003
Haemorrhoids
Gastrointestinal disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0020 affected36 at risk
EG003
Lip swelling
Gastrointestinal disorders
MedDRA (23.1)
Systematic Assessment
EG0001 affected3 at risk
EG0010 affected4 at risk
EG0020 affected36 at risk
EG003
Nausea
Gastrointestinal disorders
MedDRA (23.1)
Systematic Assessment
EG0002 affected3 at risk
EG0013 affected4 at risk
EG00222 affected36 at risk
EG003
Oral pain
Gastrointestinal disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0020 affected36 at risk
EG003
Stomatitis
Gastrointestinal disorders
MedDRA (23.1)
Systematic Assessment
EG0001 affected3 at risk
EG0011 affected4 at risk
EG0028 affected36 at risk
EG003
Vomiting
Gastrointestinal disorders
MedDRA (23.1)
Systematic Assessment
EG0003 affected3 at risk
EG0013 affected4 at risk
EG00216 affected36 at risk
EG003
Asthenia
General disorders
MedDRA (23.1)
Systematic Assessment
EG0001 affected3 at risk
EG0012 affected4 at risk
EG0026 affected36 at risk
EG003
Chest pain
General disorders
MedDRA (23.1)
Systematic Assessment
EG0001 affected3 at risk
EG0010 affected4 at risk
EG0020 affected36 at risk
EG003
Chills
General disorders
MedDRA (23.1)
Systematic Assessment
EG0001 affected3 at risk
EG0010 affected4 at risk
EG0026 affected36 at risk
EG003
Fatigue
General disorders
MedDRA (23.1)
Systematic Assessment
EG0001 affected3 at risk
EG0011 affected4 at risk
EG00218 affected36 at risk
EG003
Influenza like illness
General disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0021 affected36 at risk
EG003
Malaise
General disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0023 affected36 at risk
EG003
Mucosal inflammation
General disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0011 affected4 at risk
EG0026 affected36 at risk
EG003
Non-cardiac chest pain
General disorders
MedDRA (23.1)
Systematic Assessment
EG0001 affected3 at risk
EG0010 affected4 at risk
EG0020 affected36 at risk
EG003
Oedema
General disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0022 affected36 at risk
EG003
Oedema peripheral
General disorders
MedDRA (23.1)
Systematic Assessment
EG0003 affected3 at risk
EG0010 affected4 at risk
EG00210 affected36 at risk
EG003
Peripheral swelling
General disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0022 affected36 at risk
EG003
Pyrexia
General disorders
MedDRA (23.1)
Systematic Assessment
EG0003 affected3 at risk
EG0011 affected4 at risk
EG00216 affected36 at risk
EG003
Xerosis
General disorders
MedDRA (23.1)
Systematic Assessment
EG0001 affected3 at risk
EG0010 affected4 at risk
EG0022 affected36 at risk
EG003
Bacteriuria
Infections and infestations
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0011 affected4 at risk
EG0020 affected36 at risk
EG003
Erysipelas
Infections and infestations
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0022 affected36 at risk
EG003
Folliculitis
Infections and infestations
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0012 affected4 at risk
EG0024 affected36 at risk
EG003
Fungal skin infection
Infections and infestations
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0020 affected36 at risk
EG003
Furuncle
Infections and infestations
MedDRA (23.1)
Systematic Assessment
EG0001 affected3 at risk
EG0010 affected4 at risk
EG0020 affected36 at risk
EG003
Gastroenteritis viral
Infections and infestations
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0011 affected4 at risk
EG0020 affected36 at risk
EG003
Herpes zoster
Infections and infestations
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0021 affected36 at risk
EG003
Impetigo
Infections and infestations
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0011 affected4 at risk
EG0020 affected36 at risk
EG003
Nail infection
Infections and infestations
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0021 affected36 at risk
EG003
Nasopharyngitis
Infections and infestations
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0021 affected36 at risk
EG003
Oral candidiasis
Infections and infestations
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0021 affected36 at risk
EG003
Oral herpes
Infections and infestations
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0021 affected36 at risk
EG003
Paronychia
Infections and infestations
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG00214 affected36 at risk
EG003
Pneumonia
Infections and infestations
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0020 affected36 at risk
EG003
Pustule
Infections and infestations
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0022 affected36 at risk
EG003
Rash pustular
Infections and infestations
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0021 affected36 at risk
EG003
Respiratory tract infection
Infections and infestations
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0021 affected36 at risk
EG003
Skin candida
Infections and infestations
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0020 affected36 at risk
EG003
Skin infection
Infections and infestations
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0022 affected36 at risk
EG003
Staphylococcal infection
Infections and infestations
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0020 affected36 at risk
EG003
Tinea pedis
Infections and infestations
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0022 affected36 at risk
EG003
Upper respiratory tract infection
Infections and infestations
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0022 affected36 at risk
EG003
Urinary tract infection
Infections and infestations
MedDRA (23.1)
Systematic Assessment
EG0001 affected3 at risk
EG0010 affected4 at risk
EG0023 affected36 at risk
EG003
Limb injury
Injury, poisoning and procedural complications
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0022 affected36 at risk
EG003
Skin laceration
Injury, poisoning and procedural complications
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0022 affected36 at risk
EG003
Alanine aminotransferase increased
Investigations
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0012 affected4 at risk
EG0024 affected36 at risk
EG003
Aspartate aminotransferase increased
Investigations
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0012 affected4 at risk
EG0025 affected36 at risk
EG003
Blood alkaline phosphatase increased
Investigations
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0011 affected4 at risk
EG0021 affected36 at risk
EG003
Blood creatine phosphokinase increased
Investigations
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0020 affected36 at risk
EG003
Blood creatinine increased
Investigations
MedDRA (23.1)
Systematic Assessment
EG0001 affected3 at risk
EG0010 affected4 at risk
EG0022 affected36 at risk
EG003
Blood lactate dehydrogenase increased
Investigations
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0022 affected36 at risk
EG003
Blood phosphorus decreased
Investigations
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0011 affected4 at risk
EG0020 affected36 at risk
EG003
Blood urea increased
Investigations
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0020 affected36 at risk
EG003
C-reactive protein increased
Investigations
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0022 affected36 at risk
EG003
Ejection fraction decreased
Investigations
MedDRA (23.1)
Systematic Assessment
EG0001 affected3 at risk
EG0010 affected4 at risk
EG0020 affected36 at risk
EG003
Gamma-glutamyltransferase increased
Investigations
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0011 affected4 at risk
EG0021 affected36 at risk
EG003
Globulins increased
Investigations
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0020 affected36 at risk
EG003
Haemoglobin decreased
Investigations
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0011 affected4 at risk
EG0020 affected36 at risk
EG003
Protein total decreased
Investigations
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0021 affected36 at risk
EG003
Weight decreased
Investigations
MedDRA (23.1)
Systematic Assessment
EG0002 affected3 at risk
EG0011 affected4 at risk
EG0027 affected36 at risk
EG003
White blood cell count increased
Investigations
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0020 affected36 at risk
EG003
Decreased appetite
Metabolism and nutrition disorders
MedDRA (23.1)
Systematic Assessment
EG0002 affected3 at risk
EG0012 affected4 at risk
EG00213 affected36 at risk
EG003
Dehydration
Metabolism and nutrition disorders
MedDRA (23.1)
Systematic Assessment
EG0001 affected3 at risk
EG0011 affected4 at risk
EG0022 affected36 at risk
EG003
Hyperglycaemia
Metabolism and nutrition disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0021 affected36 at risk
EG003
Hyperkalaemia
Metabolism and nutrition disorders
MedDRA (23.1)
Systematic Assessment
EG0001 affected3 at risk
EG0010 affected4 at risk
EG0021 affected36 at risk
EG003
Hypoalbuminaemia
Metabolism and nutrition disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0011 affected4 at risk
EG0026 affected36 at risk
EG003
Hypocalcaemia
Metabolism and nutrition disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0025 affected36 at risk
EG003
Hypokalaemia
Metabolism and nutrition disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0012 affected4 at risk
EG0024 affected36 at risk
EG003
Hypomagnesaemia
Metabolism and nutrition disorders
MedDRA (23.1)
Systematic Assessment
EG0003 affected3 at risk
EG0012 affected4 at risk
EG0028 affected36 at risk
EG003
Hyponatraemia
Metabolism and nutrition disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0024 affected36 at risk
EG003
Hypophosphataemia
Metabolism and nutrition disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0011 affected4 at risk
EG0024 affected36 at risk
EG003
Arthralgia
Musculoskeletal and connective tissue disorders
MedDRA (23.1)
Systematic Assessment
EG0001 affected3 at risk
EG0010 affected4 at risk
EG0023 affected36 at risk
EG003
Back pain
Musculoskeletal and connective tissue disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0025 affected36 at risk
EG003
Flank pain
Musculoskeletal and connective tissue disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0011 affected4 at risk
EG0022 affected36 at risk
EG003
Muscle spasms
Musculoskeletal and connective tissue disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0011 affected4 at risk
EG0024 affected36 at risk
EG003
Musculoskeletal chest pain
Musculoskeletal and connective tissue disorders
MedDRA (23.1)
Systematic Assessment
EG0001 affected3 at risk
EG0010 affected4 at risk
EG0020 affected36 at risk
EG003
Myalgia
Musculoskeletal and connective tissue disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0022 affected36 at risk
EG003
Pain in extremity
Musculoskeletal and connective tissue disorders
MedDRA (23.1)
Systematic Assessment
EG0001 affected3 at risk
EG0010 affected4 at risk
EG0022 affected36 at risk
EG003
Skin papilloma
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0021 affected36 at risk
EG003
Dizziness
Nervous system disorders
MedDRA (23.1)
Systematic Assessment
EG0001 affected3 at risk
EG0011 affected4 at risk
EG0021 affected36 at risk
EG003
Dysgeusia
Nervous system disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0027 affected36 at risk
EG003
Headache
Nervous system disorders
MedDRA (23.1)
Systematic Assessment
EG0002 affected3 at risk
EG0010 affected4 at risk
EG0021 affected36 at risk
EG003
Hyperaesthesia
Nervous system disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0020 affected36 at risk
EG003
Neuralgia
Nervous system disorders
MedDRA (23.1)
Systematic Assessment
EG0001 affected3 at risk
EG0010 affected4 at risk
EG0020 affected36 at risk
EG003
Seizure
Nervous system disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0020 affected36 at risk
EG003
Somnolence
Nervous system disorders
MedDRA (23.1)
Systematic Assessment
EG0001 affected3 at risk
EG0010 affected4 at risk
EG0020 affected36 at risk
EG003
Syncope
Nervous system disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0022 affected36 at risk
EG003
Taste disorder
Nervous system disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0022 affected36 at risk
EG003
Tremor
Nervous system disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0020 affected36 at risk
EG003
Abnormal dreams
Psychiatric disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0011 affected4 at risk
EG0020 affected36 at risk
EG003
Confusional state
Psychiatric disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0020 affected36 at risk
EG003
Depression
Psychiatric disorders
MedDRA (23.1)
Systematic Assessment
EG0001 affected3 at risk
EG0010 affected4 at risk
EG0020 affected36 at risk
EG003
Insomnia
Psychiatric disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0024 affected36 at risk
EG003
Haematuria
Renal and urinary disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0011 affected4 at risk
EG0024 affected36 at risk
EG003
Nephrolithiasis
Renal and urinary disorders
MedDRA (23.1)
Systematic Assessment
EG0001 affected3 at risk
EG0010 affected4 at risk
EG0020 affected36 at risk
EG003
Proteinuria
Renal and urinary disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0020 affected36 at risk
EG003
Breast mass
Reproductive system and breast disorders
MedDRA (23.1)
Systematic Assessment
EG0001 affected3 at risk
EG0010 affected4 at risk
EG0020 affected36 at risk
EG003
Cough
Respiratory, thoracic and mediastinal disorders
MedDRA (23.1)
Systematic Assessment
EG0002 affected3 at risk
EG0010 affected4 at risk
EG0024 affected36 at risk
EG003
Dyspnoea
Respiratory, thoracic and mediastinal disorders
MedDRA (23.1)
Systematic Assessment
EG0001 affected3 at risk
EG0010 affected4 at risk
EG0025 affected36 at risk
EG003
Dyspnoea exertional
Respiratory, thoracic and mediastinal disorders
MedDRA (23.1)
Systematic Assessment
EG0001 affected3 at risk
EG0010 affected4 at risk
EG0020 affected36 at risk
EG003
Epistaxis
Respiratory, thoracic and mediastinal disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0021 affected36 at risk
EG003
Hiccups
Respiratory, thoracic and mediastinal disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0011 affected4 at risk
EG0020 affected36 at risk
EG003
Oropharyngeal pain
Respiratory, thoracic and mediastinal disorders
MedDRA (23.1)
Systematic Assessment
EG0001 affected3 at risk
EG0010 affected4 at risk
EG0020 affected36 at risk
EG003
Pneumonitis
Respiratory, thoracic and mediastinal disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0020 affected36 at risk
EG003
Productive cough
Respiratory, thoracic and mediastinal disorders
MedDRA (23.1)
Systematic Assessment
EG0001 affected3 at risk
EG0010 affected4 at risk
EG0022 affected36 at risk
EG003
Rhinorrhoea
Respiratory, thoracic and mediastinal disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0022 affected36 at risk
EG003
Sputum discoloured
Respiratory, thoracic and mediastinal disorders
MedDRA (23.1)
Systematic Assessment
EG0001 affected3 at risk
EG0010 affected4 at risk
EG0020 affected36 at risk
EG003
Actinic keratosis
Skin and subcutaneous tissue disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0011 affected4 at risk
EG0020 affected36 at risk
EG003
Alopecia
Skin and subcutaneous tissue disorders
MedDRA (23.1)
Systematic Assessment
EG0001 affected3 at risk
EG0011 affected4 at risk
EG0020 affected36 at risk
EG003
Dermal cyst
Skin and subcutaneous tissue disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0011 affected4 at risk
EG0020 affected36 at risk
EG003
Dermatitis
Skin and subcutaneous tissue disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0011 affected4 at risk
EG0021 affected36 at risk
EG003
Dermatitis acneiform
Skin and subcutaneous tissue disorders
MedDRA (23.1)
Systematic Assessment
EG0002 affected3 at risk
EG0013 affected4 at risk
EG00225 affected36 at risk
EG003
Drug eruption
Skin and subcutaneous tissue disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0020 affected36 at risk
EG003
Dry skin
Skin and subcutaneous tissue disorders
MedDRA (23.1)
Systematic Assessment
EG0001 affected3 at risk
EG0012 affected4 at risk
EG00220 affected36 at risk
EG003
Eczema
Skin and subcutaneous tissue disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0021 affected36 at risk
EG003
Erythema
Skin and subcutaneous tissue disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0029 affected36 at risk
EG003
Hair growth abnormal
Skin and subcutaneous tissue disorders
MedDRA (23.1)
Systematic Assessment
EG0001 affected3 at risk
EG0010 affected4 at risk
EG0021 affected36 at risk
EG003
Hand dermatitis
Skin and subcutaneous tissue disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0011 affected4 at risk
EG0021 affected36 at risk
EG003
Hirsutism
Skin and subcutaneous tissue disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0022 affected36 at risk
EG003
Hyperkeratosis
Skin and subcutaneous tissue disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0022 affected36 at risk
EG003
Hypertrichosis
Skin and subcutaneous tissue disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0011 affected4 at risk
EG0025 affected36 at risk
EG003
Nail disorder
Skin and subcutaneous tissue disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0020 affected36 at risk
EG003
Onycholysis
Skin and subcutaneous tissue disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0022 affected36 at risk
EG003
Pain of skin
Skin and subcutaneous tissue disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0022 affected36 at risk
EG003
Palmar-plantar erythrodysaesthesia syndrome
Skin and subcutaneous tissue disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0022 affected36 at risk
EG003
Papule
Skin and subcutaneous tissue disorders
MedDRA (23.1)
Systematic Assessment
EG0001 affected3 at risk
EG0010 affected4 at risk
EG0022 affected36 at risk
EG003
Petechiae
Skin and subcutaneous tissue disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0020 affected36 at risk
EG003
Pruritus
Skin and subcutaneous tissue disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0011 affected4 at risk
EG00214 affected36 at risk
EG003
Rash
Skin and subcutaneous tissue disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0011 affected4 at risk
EG0028 affected36 at risk
EG003
Rash erythematous
Skin and subcutaneous tissue disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0020 affected36 at risk
EG003
Rash maculo-papular
Skin and subcutaneous tissue disorders
MedDRA (23.1)
Systematic Assessment
EG0001 affected3 at risk
EG0010 affected4 at risk
EG0028 affected36 at risk
EG003
Rash papular
Skin and subcutaneous tissue disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0020 affected36 at risk
EG003
Skin burning sensation
Skin and subcutaneous tissue disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0020 affected36 at risk
EG003
Skin exfoliation
Skin and subcutaneous tissue disorders
MedDRA (23.1)
Systematic Assessment
EG0002 affected3 at risk
EG0010 affected4 at risk
EG0020 affected36 at risk
EG003
Skin fissures
Skin and subcutaneous tissue disorders
MedDRA (23.1)
Systematic Assessment
EG0002 affected3 at risk
EG0011 affected4 at risk
EG0029 affected36 at risk
EG003
Skin irritation
Skin and subcutaneous tissue disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0020 affected36 at risk
EG003
Skin wrinkling
Skin and subcutaneous tissue disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0020 affected36 at risk
EG003
Deep vein thrombosis
Vascular disorders
MedDRA (23.1)
Systematic Assessment
EG0001 affected3 at risk
EG0010 affected4 at risk
EG0020 affected36 at risk
EG003
Hot flush
Vascular disorders
MedDRA (23.1)
Systematic Assessment
EG0001 affected3 at risk
EG0010 affected4 at risk
EG0021 affected36 at risk
EG003
Hypertension
Vascular disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0023 affected36 at risk
EG003
Hypotension
Vascular disorders
MedDRA (23.1)
Systematic Assessment
EG0001 affected3 at risk
EG0010 affected4 at risk
EG0023 affected36 at risk
EG003
Orthostatic hypotension
Vascular disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected4 at risk
EG0022 affected36 at risk
EG003
Vena cava thrombosis
Vascular disorders
MedDRA (23.1)
Systematic Assessment
EG0000 affected3 at risk
EG0011 affected4 at risk
EG0020 affected36 at risk
EG003
Certain Agreements
Are all PI(s) employees of the sponsor?
No
Restriction Type
OTHER
Results Disclosure Restriction on PI(s)?
Yes
Other Details
The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (ie, data from all sites) in the clinical trial.