A Phase I/II Study of MLN0128 in Metastatic Anaplastic Th... | NCT02244463 | Trialant
NCT02244463
Sponsor
Dana-Farber Cancer Institute
Status
Completed
Last Update Posted
Jan 12, 2024Actual
Enrollment
46Actual
Phase
Phase 1Phase 2
Conditions
Anaplastic Thyroid Cancer
Thyroid Cancer
Differentiated Thyroid Cancer
Interventions
MLN0128
Countries
United States
Protocol Section
Identification Module
NCT ID
NCT02244463
Obsolete or Duplicate NCT IDs
Not provided
Organization Study
14-223
Secondary IDs
Not provided
Brief Title
A Phase I/II Study of MLN0128 in Metastatic Anaplastic Thyroid Cancer and Incurably Poorly Differentiated or Radioidodine Refractory Differentiated Thyroid Cancer
Official Title
A Phase I/II Study of MLN0128 in Metastatic Anaplastic Thyroid Cancer and Incurably Poorly Differentiated or Radioidodine Refractory Differentiated Thyroid Cancer
Acronym
Not provided
Organization
Dana-Farber Cancer InstituteOTHER
Status Module
Record Verification Date
Dec 2023
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
Jul 2015Actual
Primary Completion Date
Apr 28, 2022Actual
Completion Date
Apr 28, 2022Actual
First Submitted Date
Sep 17, 2014
First Submission Date that Met QC Criteria
Sep 17, 2014
First Posted Date
Sep 19, 2014Estimated
Results Waived
Not provided
Results First Submitted Date
Apr 6, 2023
Results First Submitted that Met QC Criteria
Dec 15, 2023
Results First Posted Date
Jan 12, 2024Actual
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
Dec 15, 2023
Last Update Posted Date
Jan 12, 2024Actual
Sponsor/Collaborators Module
Responsible Party, by Official Title
Kartik Sehgal, MD, Principal Investigator, Dana-Farber Cancer InstitutePrincipal Investigator
Lead Sponsor
Dana-Farber Cancer InstituteOTHER
Collaborators
Name
Class
Millennium Pharmaceuticals, Inc.
INDUSTRY
Oversight Module
Has Data Monitoring Committee (DMC)
Yes
Is FDA Regulated Drug
Not provided
Is FDA Regulated Device
Not provided
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 research study is a phase I/II study of MLN0128 in metastatic anaplastic thyroid cancer(ATC) and incurably poorly differentiated or radioidodine refractory differentiated thyroid cancer (DTC).
Due to changes in the manufacturing process which resulted in increased absorption of MLN0128 from capsules, a run-in phase I prior to the phase II of the study was needed.
Phase II clinical trials test the safety and effectiveness of an investigational intervention to learn whether the intervention works in treating a specific disease. "Investigational" means that the intervention is being studied. The FDA (the U.S. Food and Drug Administration) has not approved MLN0128 as a treatment for any disease.
MLN0128 prevents tumor cells from dividing and growing by selectively and potently inhibiting a chemical, mTOR kinase, which regulates cell growth and survival. Patients with anaplastic thyroid cancer have been observed to sometimes carry genetic alterations in their tumor cells which may make the cancer more sensitive to inhibition by MLN0128.
Given the activity with everolimus in RAI refractory thyroid cancer, subjects wth metastatic, incurable differentiated RAI refractory and poorly differentiated thyroid cancer were included.
Detailed Description
Patients who fulfill eligibility criteria will be entered into the trial to receive MLN0128.
Conditions Module
Conditions
Anaplastic Thyroid Cancer
Thyroid Cancer
Differentiated Thyroid Cancer
Keywords
Anaplastic Thyroid Cancer
Thyroid Cancer
Differentiated Thyroid Cancer
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
46Actual
Arms/Interventions Module
Arm Groups
Label
Type
Description
Intervention Names
Phase I: Dose Level 1 (PI DL1)
Experimental
Phase I Dose Level 1 participants receive MLN0128 3 mg orally, daily for 28 days. Participants are treated until disease progression or withdrawal of consent.
Drug: MLN0128
Phase I: Dose Level 2 (PI DL2)
Experimental
Phase I Dose Level 3 (dose escalation) participants received MLN0128 5 mg orally, daily for 28 days. Participants are treated until disease progression or withdrawal of consent.
Drug: MLN0128
Phase I: Dose Level 3 (PI DL3)
Experimental
Phase I Dose Level 3 participants receive MLN0128 5 mg orally, daily for 28 days. Participants are treated until disease progression or withdrawal of consent.
Drug: MLN0128
Phase I: Dose Level 3 (PI DL3) Expansion
Experimental
Phase I Dose Level 3 participants receive MLN0128 5 mg orally, daily for 28 days. Participants are treated until disease progression or withdrawal of consent.
Drug: MLN0128
Phase II: ATC Cohort
Experimental
Phase II participants receive MLN0128 at the recommended phase II dose of 5 mg orally, daily for 28 days. Participants are treated until disease progression or withdrawal of consent. All phase I participants treated at the maximum tolerated dose/ recommended phase II dose (DL3) are enrolled in the phase II part of the study according to the appropriate disease cohort.
Interventions
Name
Type
Description
Arm Group Labels
Other Names
MLN0128
Drug
Phase I: Dose Level 1 (PI DL1)
Phase I: Dose Level 2 (PI DL2)
Phase I: Dose Level 3 (PI DL3)
Phase I: Dose Level 3 (PI DL3) Expansion
Phase II: ATC Cohort
Outcomes Module
Primary Outcomes
Measure
Description
Time Frame
Maximum Tolerated Dose (MTD) [Phase I Dose Escalation]
The MTD is determined by the number of participants who experience a dose limiting toxicity (DLT). The MTD is defined as the highest dose at which fewer than one-third of participants experience a DLT. If no DLTs are observed, the MTD is not reached but the highest dose received may be the Recommended Phase II Dose (RP2D).
cycle 1 (cycle duration=28 days)
Number of Participants With Dose Limiting Toxicity (DLT) [Phase I Dose Escalation]
DLT is defined as an adverse event based on the Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0) or abnormal laboratory value assessed as unrelated to disease, disease progression, intercurrent illness, or concomitant medications, that meets any of the criteria (hematologic, renal, hepatic, endocrine, metabolic/laboratory, pancreatitis, cardiac, neurotoxicity, mood alteration, dermatologic] listed in section 5.3.2 of the protocol.
PFS4 rate is the percentage of participants remaining alive and progression-free at 4-months from study entry. Per RECIST 1.1 for target lesions: disease progression (PD) is at least a 20% increase in sum longest diameter (LD), taking as reference the smallest sum on study with at least 5 mm absolute increase or the appearance of one or more new lesions. For non-target lesions, PD is appearance of one or more new lesions or unequivocal progression of existing non-target lesions.
Disease was assessed radiologically every 2 cycles/ 8 weeks on treatment until the earliest of first progression, death or 24 months from study entry. Relevant for this endpoint was observation at 4-months.
Secondary Outcomes
Measure
Description
Time Frame
Number of Participants With Grade 3-5 Treatment-related Toxicity [Phase I/Phase II]
All grade 3-5 adverse events (AE) with treatment attribution of possibly, probably or definite based on CTCAEv4 as reported on case report forms were counted. Maximum grade toxicity by AE type was then calculated. Incidence is the number of participants experiencing at least one grade 2-5 treatment-related AE during the time of observation.
Other Outcomes
Not provided
Eligibility Module
Eligibility Criteria
Inclusion Criteria:
Male or female patients 18 years or older
Any number of prior chemotherapy or targeted agents including rapamycin analogues allowed
Newly diagnosed or refractory/metastatic anaplastic thyroid cancer confirmed by histology, incurable by surgery, radiotherapy or chemoradiotherapy alone or in combination
Must have measurable disease
ECOG performance status 0-2
No active intracranial metastases
Tissue for correlative studies must be available
Ability to swallow oral medications
Voluntary written consent must be given before performance of any study related procedure
Adequate organ function, as specified below, within 21 days:
Bone marrow reserve consistent with: absolute neutrophil count (ANC) ≥ 1.5 x 109/L; platelet count ≥ 100 x 109/L; hemoglobin ≥ 9 g/dL;
Hepatic: total bilirubin ≤1.5 x upper limit of normal (ULN), transaminases (aspartate aminotransferase/serum glutamic oxaloacetic transaminase-AST/SGOT and alanine aminotransferase/serum glutamic pyruvic transaminase-ALT/SGPT) ≤2.5 x ULN (≤5 x ULN if liver metastases are present);
Left ventricular ejection fraction (LVEF) within 5 absolute percentage points of institutional standard of normal as measured by echocardiogram (ECHO) or multiple gated acquisition scan (MUGA) within 4 weeks prior to first study drug administration (ie, if the institutional normal is 50%, subject's LVEF may be as low as 45% to be eligible for the study)
Female patients who:
Are postmenopausal for at least 1 year before the screening visit, OR
Are surgically sterile, OR
If they are of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent through 90 days after the last dose of study drug, or agree to completely abstain from heterosexual intercourse
Male patients, even if surgically sterilized (ie, status post-vasectomy), who:
Agree to practice effective barrier contraception during the entire study treatment period and through 90 days after the last dose of study drug, or
Agree to completely abstain from heterosexual intercourse
Treatment with strong CYP2C19, CYP3A4, and CYP2C9 inhibitors and/or inducers must be discontinued
Exclusion Criteria:
Female patients who are both lactating and breastfeeding or have a positive serum pregnancy test during the screening period
Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment
Treatment with any investigational products within 14 days
Failed to recover from the reversible effects of prior anticancer therapies
Manifestations of malabsorption due to prior gastrointestinal surgery or disease
Poorly controlled diabetes mellitus
History of any of the following within the last 6 months prior to study entry:
Ischemic myocardial event
Ischemic cerebrovascular event
Requirement for inotropic support (excluding digoxin) or serious (uncontrolled) cardiac arrhythmia
Placement of a pacemaker for control of rhythm
New York Heart Association Class III or IV heart failure
Pulmonary embolism
Significant active cardiovascular or pulmonary disease at the time of study entry, including:
Uncontrolled high blood pressure
Pulmonary hypertension
Uncontrolled asthma or O2 saturation < 90%
Significant valvular disease
Medically significant (symptomatic) bradycardia
History of arrhythmia requiring an implantable cardiac defibrillator
Baseline prolongation of the rate-corrected QT interval (QTc)
Treatment with hematopoietic growth factors, transfusions of blood and blood products, or systemic corticosteroids
Cabanillas ME, McFadden DG, Durante C. Thyroid cancer. Lancet. 2016 Dec 3;388(10061):2783-2795. doi: 10.1016/S0140-6736(16)30172-6. Epub 2016 May 27.
See Also Links
Not provided
Available IPD Information
Not provided
IPD Sharing Statement Module
Plan to Share IPD
No
Description
There are no plans to share individual participant data. Cumulative results will be posted here and published.
Types
Not provided
Time Frame
Not provided
Access Criteria
Not provided
URL
Not provided
Results Section
Participant Flow Module
Pre-assignment Details
Not provided
Recruitment Details
Participants enrolled from July 2015 to July 2020.
Type of Units Analyzed
Not provided
Arm/Group Information
ID
Title
Description
FG000
Phase I: Dose Level 1 (PI: DL1)
Phase I Dose Level 1 participants received MLN0128 3 mg orally, daily for 28 days. Participants are treated until disease progression or withdrawal of consent.
FG001
Phase I: Dose Level 2 (PI: DL2)
Periods
Title
Milestones
Reasons Not Completed
Period 1: PI DL1 Dose Escalation
Type
Comment
Milestone Data
STARTED
Baseline Characteristics Module
Baseline Analysis Population Description
Outcome Measures Module
Outcome Measures
Adverse Events Module
Frequency Threshold
0
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_SAP
Yes
Yes
No
Study Protocol and Statistical Analysis Plan
May 31, 2022
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
N/A
Intervention Model
Single Group Assignment
Intervention Model Description
Not provided
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
Drug: MLN0128
Phase II: DTC Cohort
Experimental
Phase II participants receive MLN0128 at the recommended phase II dose of 5 mg orally, daily for 28 days. Participants are treated until disease progression or withdrawal of consent. All phase I participants treated at the maximum tolerated dose/ recommended phase II dose (DL3) are enrolled in the phase II part of the study according to the appropriate disease cohort.
Drug: MLN0128
Phase II: DTC Cohort
INK128
Sapanisertib
Assessed on treatment at cycles 1 and 2 (days 1 and 15), cycle 3+ on day 1, at the end of treatment and up to 30 days post-treatment. Participants were on treatment up to 21.6 months (median 2.1 months).
PFS6 rate is the percentage of patients remaining alive and progression-free at 6-months from study entry. Per RECIST 1.1 for target lesions: disease progression (PD) is at least a 20% increase in sum longest diameter (LD), taking as reference the smallest sum on study with at least 5 mm absolute increase or the appearance of one or more new lesions. For non-target lesions, PD is appearance of one or more new lesions or unequivocal progression of existing non-target lesions.
Disease was assessed radiologically every 2 cycles/ 8 weeks on treatment until the earliest of first progression, death or 24 months from study entry. Relevant for this endpoint was observation at 6-months.
Overall Response Rate (ORR) [Phase II]
ORR was defined as the percentage of participants achieving complete response (CR) or partial response (PR) based on RECIST 1.1 criteria. Per RECIST 1.1 for target lesions: CR is complete disappearance of all target lesions; PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. Confirmatory scan obtained 8 weeks following initial documentation of objective response.
Disease was assessed radiologically every 2 cycles/ 8 weeks on treatment until the earliest of first progression, death or 24 months from study entry. Participants were on treatment up to 196 days (PII ATC) and 454 days (PII DTC).
Median Overall Survival (OS) [Phase II]
OS based on the Kaplan-Meier method is defined as the time from study entry to death or censored at date last known alive.
Long term follow-up for survival was every 3 months post-treatment end up to 24 months.
BRAF V600E Status [Phase II]
Participants were classified by BRAF V600E mutation status evaluated by next generation sequencing (NGS) platforms using tumor tissue collected at baseline.
Baseline
Clinical Benefit (CBR) by BRAF V600E Status [Phase II]
CBR was defined as the percentage of participants achieving complete response (CR), partial response (PR) or stable disease (SD) based on RECIST 1.1 criteria. Per RECIST 1.1 for target lesions: CR is complete disappearance of all target lesions; PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. Confirmatory scan obtained 8 weeks following initial documentation of CR or PR. SD is neither PR or better nor PD (defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum since treatment start, or the appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions). Participants were classified by BRAF V600E status based on established methods using tumor tissue collected at baseline.
BRAF V600E status per NGS at baseline. Disease response was assessed every 2 cycles on treatment until the first progression, death or 24 months from study entry. Participants were on treatment up to 196 days (PII ATC) and 454 days (PII DTC).
Boston
Massachusetts
02115
United States
University of Michigan Medical School
Ann Arbor
Michigan
48109
United States
Phase I Dose Level 2 participants received MLN0128 4 mg orally, daily for 28 days. Participants are treated until disease progression or withdrawal of consent.
FG002
Phase I: Dose Level 3 (PI: DL3)
Phase I Dose Level 3 (dose escalation) participants received MLN0128 5 mg orally, daily for 28 days. Participants are treated until disease progression or withdrawal of consent.
FG003
Phase I: Dose Level 3 Expansion (PI: DL3 Exp)
Phase 1 Dose Level 3 participants receive MLN0128 5 mg orally, daily for 28 days. Participants are treated until disease progression or withdrawal of consent.
FG004
Phase II: ATC Cohort
Phase II participants receive MLN0128 at the recommended phase II dose of 5 mg orally, daily for 28 days. Participants are treated until disease progression or withdrawal of consent. All phase I participants treated at the maximum tolerated dose/ recommended phase II dose (DL3) were also enrolled in the phase II part of the study according to the appropriate disease cohort.
FG005
Phase II: DTC Cohort
Phase II participants receive MLN0128 at the recommended phase II dose of 5 mg orally, daily for 28 days. Participants are treated until disease progression or withdrawal of consent. All phase I participants treated at the maximum tolerated dose/ recommended phase II dose (DL3) were also enrolled in the phase II part of the study according to the appropriate disease cohort.
FG0003 subjects
FG0010 subjects
FG0020 subjects
FG0030 subjects
FG0040 subjects
FG0050 subjects
COMPLETED
Given treatment duration is not fixed, all participants are considered as 'Non Completed' and reason off-treatment provided.
FG0000 subjects
FG0010 subjects
FG0020 subjects
FG0030 subjects
FG0040 subjects
FG0050 subjects
NOT COMPLETED
FG0003 subjects
FG0010 subjects
FG0020 subjects
FG0030 subjects
FG0040 subjects
FG0050 subjects
Type
Comment
Reasons
Disease Progression
FG0003 subjects
FG0010 subjects
FG0020 subjects
FG0030 subjects
FG0040 subjects
FG0050 subjects
Period 2: PI DL2 Dose Escalation
Type
Comment
Milestone Data
STARTED
The 'NOTE' here is an error: Each subsequent period in the PI study involves new participants.
FG0000 subjects
FG0013 subjects
FG0020 subjects
FG0030 subjects
FG0040 subjects
FG0050 subjects
COMPLETED
Given treatment duration is not fixed, all participants are considered as 'Non Completed' and reason off-treatment provided.
FG0000 subjects
FG0010 subjects
FG0020 subjects
FG003
NOT COMPLETED
FG0000 subjects
FG0013 subjects
FG0020 subjects
FG0030 subjects
FG004
Type
Comment
Reasons
Death
FG0000 subjects
FG0011 subjects
FG0020 subjects
FG003
Period 3: PI DL3 Dose Escalation
Type
Comment
Milestone Data
STARTED
The 'NOTE' here is an error: Each subsequent period in the PI study involves new participants.
FG0000 subjects
FG0010 subjects
FG0023 subjects
FG0030 subjects
FG0040 subjects
FG0050 subjects
COMPLETED
Given treatment duration is not fixed, all participants are considered as 'Non Completed' and reason off-treatment provided.
FG0000 subjects
FG0010 subjects
FG0020 subjects
FG003
NOT COMPLETED
FG0000 subjects
FG0010 subjects
FG0023 subjects
FG0030 subjects
FG004
Type
Comment
Reasons
Disease Progression
FG0000 subjects
FG0010 subjects
FG0023 subjects
FG003
Period 4: PI DL3 Dose Expansion
Type
Comment
Milestone Data
STARTED
The 'NOTE' here is an error: Each subsequent period in the PI study involves new participants.
FG0000 subjects
FG0010 subjects
FG0020 subjects
FG00310 subjects
FG0040 subjects
FG0050 subjects
COMPLETED
Given treatment duration is not fixed, all participants are considered as 'Non Completed' and reason off-treatment provided.
FG0000 subjects
FG0010 subjects
FG0020 subjects
FG003
NOT COMPLETED
FG0000 subjects
FG0010 subjects
FG0020 subjects
FG00310 subjects
FG004
Type
Comment
Reasons
Adverse Event
FG0000 subjects
FG0010 subjects
FG0020 subjects
FG003
Period 5: Phase II
Type
Comment
Milestone Data
STARTED
The 'NOTE' here is an error: the PII study total sample size is unrelated to the previous PI study. Per design, all participants treated at the maximum tolerated dose would be enrolled in the PII study. In the ATC and DTC PII cohorts, there were n=6 and n=7 participants, respectively, who received the RP2D in the PI study (DL3 escalation and expansion). There were n=12 (ATC) and n=15 (DTC) participants who subsequently enrolled in the PII study.
FG0000 subjects
FG0010 subjects
FG0020 subjects
FG0030 subjects
FG00418 subjects
FG00522 subjects
COMPLETED
Given treatment duration is not fixed, all participants are considered as 'Non Completed' and reason off-treatment provided.
FG0000 subjects
FG0010 subjects
FG0020 subjects
FG003
NOT COMPLETED
FG0000 subjects
FG0010 subjects
FG0020 subjects
FG0030 subjects
FG004
Type
Comment
Reasons
Disease Progression
FG0000 subjects
FG0010 subjects
FG0020 subjects
FG003
The analysis dataset is comprised of all enrolled participants.
Type of Units Analyzed
Not provided
Arm/Group Information
ID
Title
Description
BG000
P1: DL1
Phase I Dose Level 1 participants received MLN0128 3 mg orally, daily for 28 days. Participants are treated until disease progression or withdrawal of consent.
BG001
PI: DL2
Phase I Dose Level 2 participants received MLN0128 4 mg orally, daily for 28 days. Participants are treated until disease progression or withdrawal of consent.
BG002
PI: DL3
Phase I Dose Level 3 (dose escalation) participants received MLN0128 5 mg orally, daily for 28 days. Participants are treated until disease progression or withdrawal of consent.
BG003
P1: DL3 EXP
Phase 1 Dose Level 3 participants receive MLN0128 5 mg orally, daily for 28 days. Participants are treated until disease progression or withdrawal of consent.
BG004
Phase II: ATC Cohort (Including DL3 PI)
Phase II participants receive MLN0128 at the maximum tolerated dose/ recommended phase II dose of 5 mg orally, daily for 28 days. Participants are treated until disease progression or withdrawal of consent. Per design, all participants treated at the maximum tolerated dose (DL3) would be enrolled in the PII study.
BG005
Phase II: DTC Cohort (Including DL3 PI)
Phase II participants receive MLN0128 at the maximum tolerated dose/ recommended phase II dose of 5 mg orally, daily for 28 days. Participants are treated until disease progression or withdrawal of consent. Per design, all participants treated at the maximum tolerated dose (DL3) would be enrolled in the PII study.
BG006
Total
Total of all reporting groups
Denominators
Units
Counts
Participants
BG0003
BG0013
BG0023
BG00310
BG00418
BG00522
BG00659
Baseline Measures
Title
Description
Population Description
Parameter Type
Dispersion Type
Unit of Measure
Calculate Percentage
Denominator Units Selected
Denominators
Classes
Age, Continuous
Per design, all participants treated at the maximum tolerated dose (DL3) would be enrolled in the PII study and, as such, these participants are included for both PI and PII representation. PII data include n=6 ATC participants and n=7 DTC participants from the PI study.
Median
Full Range
years
Title
Denominators
Categories
Phase I
ParticipantsBG0003
ParticipantsBG0013
ParticipantsBG0023
ParticipantsBG003
Sex: Female, Male
Per design, all participants treated at the maximum tolerated dose (DL3) would be enrolled in the PII study and, as such, these participants are included for both PI and PII representation. PII data include n=6 ATC participants and n=7 DTC participants from the PI study.
Count of Participants
Participants
Title
Denominators
Categories
Phase I
ParticipantsBG0003
ParticipantsBG0013
ParticipantsBG002
Ethnicity (NIH/OMB)
Per design, all participants treated at the maximum tolerated dose (DL3) would be enrolled in the PII study and, as such, these participants are included for both PI and PII representation. PII data include n=6 ATC participants and n=7 DTC participants from the PI study.
Count of Participants
Participants
Title
Denominators
Categories
Phase I
ParticipantsBG0003
ParticipantsBG0013
ParticipantsBG002
Race/Ethnicity, Customized
Per design, all participants treated at the maximum tolerated dose (DL3) would be enrolled in the PII study and, as such, these participants are included for both PI and PII representation. PII data include n=6 ATC participants and n=7 DTC participants from the PI study.
Count of Participants
Participants
Title
Denominators
Categories
Phase I
ParticipantsBG0003
ParticipantsBG0013
ParticipantsBG002
Eastern Cooperative Oncology Group Performance Score (ECOG PS)
ECOG PS0: Fully active, able to carry on all pre-disease performance without restriction ECOG PS1: Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature ECOG PS2: Ambulatory and capable of all self-care but unable to carry out any work activities; Up and about more than 50% of waking hours
Per design, all participants treated at the maximum tolerated dose (DL3) would be enrolled in the PII study and, as such, these participants are included for both PI and PII representation. PII data include n=6 ATC participants and n=7 DTC participants from the PI study.
Count of Participants
Participants
Title
Denominators
Categories
Phase I
ParticipantsBG0003
ParticipantsBG001
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
Maximum Tolerated Dose (MTD) [Phase I Dose Escalation]
The MTD is determined by the number of participants who experience a dose limiting toxicity (DLT). The MTD is defined as the highest dose at which fewer than one-third of participants experience a DLT. If no DLTs are observed, the MTD is not reached but the highest dose received may be the Recommended Phase II Dose (RP2D).
The analysis datasets reflects participants who enrolled on the phase I dose escalation study.
Posted
Number
mg
cycle 1 (cycle duration=28 days)
ID
Title
Description
OG000
All Phase I Dose Escalation Participants
All phase I dose escalation participants receive MLN0128 orally, daily for 28 days according to the dose escalation schedule. Participants are treated until disease progression or withdrawal of consent.
Units
Counts
Participants
OG0009
Title
Denominators
Categories
Title
Measurements
OG0005
Primary
Number of Participants With Dose Limiting Toxicity (DLT) [Phase I Dose Escalation]
DLT is defined as an adverse event based on the Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0) or abnormal laboratory value assessed as unrelated to disease, disease progression, intercurrent illness, or concomitant medications, that meets any of the criteria (hematologic, renal, hepatic, endocrine, metabolic/laboratory, pancreatitis, cardiac, neurotoxicity, mood alteration, dermatologic] listed in section 5.3.2 of the protocol.
The analysis population is comprised of all participants enrolled in the PI dose escalation design.
Posted
Count of Participants
Participants
cycle 1 (cycle duration=28 days)
ID
Title
Description
OG000
Phase I: Dose Level 1 (PI DL1)
Phase I Dose Level 1 participants receive MLN0128 3 mg orally, daily for 28 days. Participants are treated until disease progression or withdrawal of consent.
OG001
Phase I: Dose Level 2 (PI DL2)
Phase I Dose Level 2 participants receive MLN0128 4 mg orally, daily for 28 days. Participants are treated until disease progression or withdrawal of consent.
OG002
Phase I: Dose Level 3 (PI DL3)
Phase I Dose Level 3 participants receive MLN0128 5 mg orally, daily for 28 days. Participants are treated until disease progression or withdrawal of consent.
PFS4 rate is the percentage of participants remaining alive and progression-free at 4-months from study entry. Per RECIST 1.1 for target lesions: disease progression (PD) is at least a 20% increase in sum longest diameter (LD), taking as reference the smallest sum on study with at least 5 mm absolute increase or the appearance of one or more new lesions. For non-target lesions, PD is appearance of one or more new lesions or unequivocal progression of existing non-target lesions.
The analysis dataset is comprised of all participants enrolled to the Phase II ATC cohort.
Posted
Number
90% Confidence Interval
percentage of participants
Disease was assessed radiologically every 2 cycles/ 8 weeks on treatment until the earliest of first progression, death or 24 months from study entry. Relevant for this endpoint was observation at 4-months.
ID
Title
Description
OG000
Phase II: ATC Cohort
Phase II participants receive MLN0128 at the recommended phase II dose of 5 mg orally, daily for 28 days. Participants are treated until disease progression or withdrawal of consent. All phase I participants treated at the maximum tolerated dose/ recommended phase II dose (DL3) were also enrolled in the phase II part of the study according to the appropriate disease cohort.
Units
Counts
Participants
Secondary
Number of Participants With Grade 3-5 Treatment-related Toxicity [Phase I/Phase II]
All grade 3-5 adverse events (AE) with treatment attribution of possibly, probably or definite based on CTCAEv4 as reported on case report forms were counted. Maximum grade toxicity by AE type was then calculated. Incidence is the number of participants experiencing at least one grade 2-5 treatment-related AE during the time of observation.
The analysis dataset is comprised of all participants enrolled to the study.
Posted
Count of Participants
Participants
Assessed on treatment at cycles 1 and 2 (days 1 and 15), cycle 3+ on day 1, at the end of treatment and up to 30 days post-treatment. Participants were on treatment up to 21.6 months (median 2.1 months).
ID
Title
Description
OG000
PI DL1
Phase I Dose Level 1 participants received MLN0128 3 mg orally, daily for 28 days. Participants are treated until disease progression or withdrawal of consent.
OG001
PI DL2
Phase I Dose Level 2 participants received MLN0128 4 mg orally, daily for 28 days. Participants are treated until disease progression or withdrawal of consent.
OG002
PI DL3
Phase I Dose Level 3 (dose escalation) participants received MLN0128 5 mg orally, daily for 28 days. Participants are treated until disease progression or withdrawal of consent.
PFS6 rate is the percentage of patients remaining alive and progression-free at 6-months from study entry. Per RECIST 1.1 for target lesions: disease progression (PD) is at least a 20% increase in sum longest diameter (LD), taking as reference the smallest sum on study with at least 5 mm absolute increase or the appearance of one or more new lesions. For non-target lesions, PD is appearance of one or more new lesions or unequivocal progression of existing non-target lesions.
The analysis dataset is comprised of all participants enrolled to the Phase II DTC cohort.
Posted
Number
90% Confidence Interval
percentage of participants
Disease was assessed radiologically every 2 cycles/ 8 weeks on treatment until the earliest of first progression, death or 24 months from study entry. Relevant for this endpoint was observation at 6-months.
ID
Title
Description
OG000
Phase II: DTC Cohort
Phase II participants receive MLN0128 at the recommended phase II dose of 5 mg orally, daily for 28 days. Participants are treated until disease progression or withdrawal of consent. All phase I participants treated at the maximum tolerated dose/ recommended phase II dose (DL3) were also enrolled in the phase II part of the study according to the appropriate disease cohort.
Units
Counts
Participants
Secondary
Overall Response Rate (ORR) [Phase II]
ORR was defined as the percentage of participants achieving complete response (CR) or partial response (PR) based on RECIST 1.1 criteria. Per RECIST 1.1 for target lesions: CR is complete disappearance of all target lesions; PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. Confirmatory scan obtained 8 weeks following initial documentation of objective response.
The analysis dataset is comprised of all participants enrolled to the Phase II ATC and DTC cohorts.
Posted
Number
90% Confidence Interval
percentage of participants
Disease was assessed radiologically every 2 cycles/ 8 weeks on treatment until the earliest of first progression, death or 24 months from study entry. Participants were on treatment up to 196 days (PII ATC) and 454 days (PII DTC).
ID
Title
Description
OG000
Phase II: ATC Cohort
Phase II participants receive MLN0128 at the recommended phase II dose of 5 mg orally, daily for 28 days. Participants are treated until disease progression or withdrawal of consent. All phase I participants treated at the maximum tolerated dose/ recommended phase II dose (DL3) were also enrolled in the phase II part of the study according to the appropriate disease cohort.
OG001
Phase II: DTC Cohort
Phase II participants receive MLN0128 at the recommended phase II dose of 5 mg orally, daily for 28 days. Participants are treated until disease progression or withdrawal of consent. All phase I participants treated at the maximum tolerated dose/ recommended phase II dose (DL3) were also enrolled in the phase II part of the study according to the appropriate disease cohort.
Secondary
Median Overall Survival (OS) [Phase II]
OS based on the Kaplan-Meier method is defined as the time from study entry to death or censored at date last known alive.
The analysis dataset is comprised of all participants enrolled to the Phase II ATC and DTC cohorts.
Posted
Median
95% Confidence Interval
months
Long term follow-up for survival was every 3 months post-treatment end up to 24 months.
ID
Title
Description
OG000
Phase II: ATC Cohort
Phase II participants receive MLN0128 at the recommended phase II dose of 5 mg orally, daily for 28 days. Participants are treated until disease progression or withdrawal of consent. All phase I participants treated at the maximum tolerated dose/ recommended phase II dose (DL3) were also enrolled in the phase II part of the study according to the appropriate disease cohort.
OG001
Phase II: DTC Cohort
Phase II participants receive MLN0128 at the recommended phase II dose of 5 mg orally, daily for 28 days. Participants are treated until disease progression or withdrawal of consent. All phase I participants treated at the maximum tolerated dose/ recommended phase II dose (DL3) were also enrolled in the phase II part of the study according to the appropriate disease cohort.
Secondary
BRAF V600E Status [Phase II]
Participants were classified by BRAF V600E mutation status evaluated by next generation sequencing (NGS) platforms using tumor tissue collected at baseline.
The analysis dataset is comprised of participants with evaluable baseline samples.
Posted
Count of Participants
Participants
Baseline
ID
Title
Description
OG000
Phase II: ATC Cohort
Phase II participants receive MLN0128 at the maximum tolerated dose/ recommended phase II dose of 5 mg orally, daily for 28 days. Participants are treated until disease progression or withdrawal of consent. Per design, all participants treated at the maximum tolerated dose (DL3) would be enrolled in the PII study.
OG001
Phase II: DTC Cohort
Phase II participants receive MLN0128 at the maximum tolerated dose/ recommended phase II dose of 5 mg orally, daily for 28 days. Participants are treated until disease progression or withdrawal of consent. Per design, all participants treated at the maximum tolerated dose (DL3) would be enrolled in the PII study.
Units
Counts
Participants
Secondary
Clinical Benefit (CBR) by BRAF V600E Status [Phase II]
CBR was defined as the percentage of participants achieving complete response (CR), partial response (PR) or stable disease (SD) based on RECIST 1.1 criteria. Per RECIST 1.1 for target lesions: CR is complete disappearance of all target lesions; PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. Confirmatory scan obtained 8 weeks following initial documentation of CR or PR. SD is neither PR or better nor PD (defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum since treatment start, or the appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions). Participants were classified by BRAF V600E status based on established methods using tumor tissue collected at baseline.
The analysis dataset is comprised of participants with evaluable baseline samples.
Posted
Number
90% Confidence Interval
percentage of participants
BRAF V600E status per NGS at baseline. Disease response was assessed every 2 cycles on treatment until the first progression, death or 24 months from study entry. Participants were on treatment up to 196 days (PII ATC) and 454 days (PII DTC).
ID
Title
Description
OG000
Phase II: ATC Cohort BRAF V600E Present
Phase II participants receive MLN0128 at the recommended phase II dose of 5 mg orally, daily for 28 days. Participants are treated until disease progression or withdrawal of consent. All phase I participants treated at the maximum tolerated dose/ recommended phase II dose (DL3) were also enrolled in the phase II part of the study according to the appropriate disease cohort. BRAF V600E status was determined at baseline.
Time Frame
Assessed on treatment at cycles 1 and 2 (days 1 and 15), cycle 3+ on day 1, at the end of treatment and up to 30 days post-treatment. Participants were on treatment up to 21.6 months (median 2.1 months).
Description
Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
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
PI: DL1
Phase I: DL1 participants receive MLN0128 3 mg orally, daily for 28 days according to the dose escalation schedule. Participants are treated until disease progression or withdrawal of consent.
0
3
0
3
3
3
EG001
PI: DL2
Phase I: DL2 participants receive MLN0128 4mg orally, daily for 28 days according to the dose escalation schedule. Participants are treated until disease progression or withdrawal of consent.
1
3
1
3
3
3
EG002
PI: DL3
Phase I Dose Level 3 (dose escalation) participants received MLN0128 5 mg orally, daily for 28 days. Participants are treated until disease progression or withdrawal of consent.
0
3
0
3
3
3
EG003
PI: DL3 Exp
Phase 1 Dose Level 3 participants receive MLN0128 5 mg orally, daily for 28 days. Participants are treated until disease progression or withdrawal of consent.
0
10
3
10
10
10
EG004
Phase II: ATC Cohort
Phase II participants receive MLN0128 at the recommended phase II dose of 5 mg orally, daily for 28 days. Participants are treated until disease progression or withdrawal of consent. All phase I participants treated at the maximum tolerated dose/ recommended phase II dose (DL3) were also enrolled in the phase II part of the study according to the appropriate disease cohort.
0
12
3
12
12
12
EG005
Phase II: DTC Cohort
Phase II participants receive MLN0128 at the recommended phase II dose of 5 mg orally, daily for 28 days. Participants are treated until disease progression or withdrawal of consent. All phase I participants treated at the maximum tolerated dose/ recommended phase II dose (DL3) were also enrolled in the phase II part of the study according to the appropriate disease cohort.
0
15
6
15
15
15
EG006
Phase II: ATC Cohort (Including P1 DL3)
Phase II participants receive MLN0128 at the recommended phase II dose of 5 mg orally, daily for 28 days. Participants are treated until disease progression or withdrawal of consent. All phase I participants treated at the maximum tolerated dose/ recommended phase II dose (DL3) were also enrolled in the phase II part of the study according to the appropriate disease cohort.
0
18
4
18
18
18
EG007
Phase II: DTC Cohort (Including P1 DL3)
Phase II participants receive MLN0128 at the recommended phase II dose of 5 mg orally, daily for 28 days. Participants are treated until disease progression or withdrawal of consent. All phase I participants treated at the maximum tolerated dose/ recommended phase II dose (DL3) were also enrolled in the phase II part of the study according to the appropriate disease cohort.
0
22
8
22
22
22
Serious Adverse Events
Term
Organ System
Source Vocabulary
Assessment Type
Notes
Statistical Information
Acute kidney injury
Renal and urinary disorders
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected3 at risk
EG0020 affected3 at risk
EG0030 affected10 at risk
EG0040 affected12 at risk
EG0051 affected15 at risk
EG0060 affected18 at risk
EG0071 affected22 at risk
Anorexia
Metabolism and nutrition disorders
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected3 at risk
EG0020 affected3 at risk
EG003
Dehydration
Metabolism and nutrition disorders
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected3 at risk
EG0020 affected3 at risk
EG003
Diarrhea
Gastrointestinal disorders
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected3 at risk
EG0020 affected3 at risk
EG003
Fatigue
General disorders
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected3 at risk
EG0020 affected3 at risk
EG003
Generalized muscle weakness
Musculoskeletal and connective tissue disorders
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected3 at risk
EG0020 affected3 at risk
EG003
Hyperglycemia
Metabolism and nutrition disorders
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0011 affected3 at risk
EG0020 affected3 at risk
EG003
Hypophosphatemia
Metabolism and nutrition disorders
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected3 at risk
EG0020 affected3 at risk
EG003
Nausea
Gastrointestinal disorders
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected3 at risk
EG0020 affected3 at risk
EG003
Pain
General disorders
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected3 at risk
EG0020 affected3 at risk
EG003
Rash acneiform
Skin and subcutaneous tissue disorders
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected3 at risk
EG0020 affected3 at risk
EG003
Rash maculo-papular
Skin and subcutaneous tissue disorders
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected3 at risk
EG0020 affected3 at risk
EG003
Thromboembolic event
Vascular disorders
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected3 at risk
EG0020 affected3 at risk
EG003
Other Adverse Events
Term
Organ System
Source Vocabulary
Assessment Type
Notes
Statistical Information
Abdominal distension
Gastrointestinal disorders
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected3 at risk
EG0021 affected3 at risk
EG0030 affected10 at risk
EG0040 affected12 at risk
EG0050 affected15 at risk
EG0060 affected18 at risk
EG0071 affected22 at risk
Abdominal pain
Gastrointestinal disorders
CTCAE (4.0)
Systematic Assessment
EG0002 affected3 at risk
EG0010 affected3 at risk
EG0020 affected3 at risk
EG003
Adrenal insufficiency
Endocrine disorders
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected3 at risk
EG0020 affected3 at risk
EG003
Agitation
Psychiatric disorders
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected3 at risk
EG0020 affected3 at risk
EG003
Alanine aminotransferase increased
Investigations
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0011 affected3 at risk
EG0021 affected3 at risk
EG003
Alkaline phosphatase increased
Investigations
CTCAE (4.0)
Systematic Assessment
EG0001 affected3 at risk
EG0010 affected3 at risk
EG0021 affected3 at risk
EG003
Allergic rhinitis
Respiratory, thoracic and mediastinal disorders
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected3 at risk
EG0020 affected3 at risk
EG003
Alopecia
Skin and subcutaneous tissue disorders
CTCAE (4.0)
Systematic Assessment
EG0001 affected3 at risk
EG0010 affected3 at risk
EG0020 affected3 at risk
EG003
Anemia
Blood and lymphatic system disorders
CTCAE (4.0)
Systematic Assessment
EG0001 affected3 at risk
EG0010 affected3 at risk
EG0020 affected3 at risk
EG003
Anorexia
Metabolism and nutrition disorders
CTCAE (4.0)
Systematic Assessment
EG0003 affected3 at risk
EG0012 affected3 at risk
EG0020 affected3 at risk
EG003
Anxiety
Psychiatric disorders
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0011 affected3 at risk
EG0020 affected3 at risk
EG003
Arthralgia
Musculoskeletal and connective tissue disorders
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0011 affected3 at risk
EG0020 affected3 at risk
EG003
Aspartate aminotransferase increased
Investigations
CTCAE (4.0)
Systematic Assessment
EG0001 affected3 at risk
EG0011 affected3 at risk
EG0022 affected3 at risk
EG003
Back pain
Musculoskeletal and connective tissue disorders
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected3 at risk
EG0020 affected3 at risk
EG003
Blood and lymphatic system disorders - Other, specify
Blood and lymphatic system disorders
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected3 at risk
EG0020 affected3 at risk
EG003
Blood bilirubin increased
Investigations
CTCAE (4.0)
Systematic Assessment
EG0001 affected3 at risk
EG0010 affected3 at risk
EG0020 affected3 at risk
EG003
Blurred vision
Eye disorders
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected3 at risk
EG0020 affected3 at risk
EG003
Bruising
Injury, poisoning and procedural complications
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected3 at risk
EG0020 affected3 at risk
EG003
Cardiac disorders - Other, specify
Cardiac disorders
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected3 at risk
EG0020 affected3 at risk
EG003
Cheilitis
Gastrointestinal disorders
CTCAE (4.0)
Systematic Assessment
EG0001 affected3 at risk
EG0010 affected3 at risk
EG0020 affected3 at risk
EG003
Chest pain - cardiac
Cardiac disorders
CTCAE (4.0)
Systematic Assessment
EG0001 affected3 at risk
EG0010 affected3 at risk
EG0020 affected3 at risk
EG003
Chills
General disorders
CTCAE (4.0)
Systematic Assessment
EG0001 affected3 at risk
EG0011 affected3 at risk
EG0020 affected3 at risk
EG003
Cholesterol high
Investigations
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected3 at risk
EG0020 affected3 at risk
EG003
Chronic kidney disease
Renal and urinary disorders
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected3 at risk
EG0021 affected3 at risk
EG003
Confusion
Psychiatric disorders
CTCAE (4.0)
Systematic Assessment
EG0001 affected3 at risk
EG0011 affected3 at risk
EG0020 affected3 at risk
EG003
Constipation
Gastrointestinal disorders
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0011 affected3 at risk
EG0021 affected3 at risk
EG003
Cough
Respiratory, thoracic and mediastinal disorders
CTCAE (4.0)
Systematic Assessment
EG0002 affected3 at risk
EG0013 affected3 at risk
EG0021 affected3 at risk
EG003
Creatinine increased
Investigations
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected3 at risk
EG0022 affected3 at risk
EG003
Dehydration
Metabolism and nutrition disorders
CTCAE (4.0)
Systematic Assessment
EG0001 affected3 at risk
EG0011 affected3 at risk
EG0021 affected3 at risk
EG003
Dental caries
Gastrointestinal disorders
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected3 at risk
EG0020 affected3 at risk
EG003
Depression
Psychiatric disorders
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected3 at risk
EG0020 affected3 at risk
EG003
Diarrhea
Gastrointestinal disorders
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0011 affected3 at risk
EG0020 affected3 at risk
EG003
Dizziness
Nervous system disorders
CTCAE (4.0)
Systematic Assessment
EG0001 affected3 at risk
EG0011 affected3 at risk
EG0021 affected3 at risk
EG003
Dry eye
Eye disorders
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected3 at risk
EG0021 affected3 at risk
EG003
Dry mouth
Gastrointestinal disorders
CTCAE (4.0)
Systematic Assessment
EG0001 affected3 at risk
EG0010 affected3 at risk
EG0021 affected3 at risk
EG003
Dry skin
Skin and subcutaneous tissue disorders
CTCAE (4.0)
Systematic Assessment
EG0001 affected3 at risk
EG0011 affected3 at risk
EG0020 affected3 at risk
EG003
Dysgeusia
Nervous system disorders
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0011 affected3 at risk
EG0020 affected3 at risk
EG003
Dysphagia
Gastrointestinal disorders
CTCAE (4.0)
Systematic Assessment
EG0002 affected3 at risk
EG0011 affected3 at risk
EG0020 affected3 at risk
EG003
Dyspnea
Respiratory, thoracic and mediastinal disorders
CTCAE (4.0)
Systematic Assessment
EG0001 affected3 at risk
EG0011 affected3 at risk
EG0022 affected3 at risk
EG003
Ear pain
Ear and labyrinth disorders
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected3 at risk
EG0020 affected3 at risk
EG003
Edema face
General disorders
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected3 at risk
EG0020 affected3 at risk
EG003
Edema limbs
General disorders
CTCAE (4.0)
Systematic Assessment
EG0001 affected3 at risk
EG0010 affected3 at risk
EG0022 affected3 at risk
EG003
Electrocardiogram QT corrected interval prolonged
Investigations
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected3 at risk
EG0020 affected3 at risk
EG003
Endocrine disorders - Other, specify
Endocrine disorders
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected3 at risk
EG0020 affected3 at risk
EG003
Epistaxis
Respiratory, thoracic and mediastinal disorders
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected3 at risk
EG0020 affected3 at risk
EG003
Erythema multiforme
Skin and subcutaneous tissue disorders
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected3 at risk
EG0020 affected3 at risk
EG003
Esophageal pain
Gastrointestinal disorders
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected3 at risk
EG0020 affected3 at risk
EG003
Eye disorders - Other, specify
Eye disorders
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0011 affected3 at risk
EG0020 affected3 at risk
EG003
Facial pain
General disorders
CTCAE (4.0)
Systematic Assessment
EG0001 affected3 at risk
EG0010 affected3 at risk
EG0020 affected3 at risk
EG003
Fatigue
General disorders
CTCAE (4.0)
Systematic Assessment
EG0003 affected3 at risk
EG0013 affected3 at risk
EG0023 affected3 at risk
EG003
Fever
General disorders
CTCAE (4.0)
Systematic Assessment
EG0002 affected3 at risk
EG0012 affected3 at risk
EG0020 affected3 at risk
EG003
Flatulence
Gastrointestinal disorders
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected3 at risk
EG0020 affected3 at risk
EG003
Gait disturbance
General disorders
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected3 at risk
EG0020 affected3 at risk
EG003
Gastrointestinal disorders - Other, specify
Gastrointestinal disorders
CTCAE (4.0)
Systematic Assessment
EG0001 affected3 at risk
EG0010 affected3 at risk
EG0020 affected3 at risk
EG003
General disorders and administration site conditions - Other, specify
General disorders
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected3 at risk
EG0020 affected3 at risk
EG003
Generalized muscle weakness
Musculoskeletal and connective tissue disorders
CTCAE (4.0)
Systematic Assessment
EG0001 affected3 at risk
EG0010 affected3 at risk
EG0020 affected3 at risk
EG003
Headache
Nervous system disorders
CTCAE (4.0)
Systematic Assessment
EG0001 affected3 at risk
EG0011 affected3 at risk
EG0020 affected3 at risk
EG003
Hearing impaired
Ear and labyrinth disorders
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected3 at risk
EG0020 affected3 at risk
EG003
Heart failure
Cardiac disorders
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected3 at risk
EG0020 affected3 at risk
EG003
Hematuria
Renal and urinary disorders
CTCAE (4.0)
Systematic Assessment
EG0001 affected3 at risk
EG0010 affected3 at risk
EG0021 affected3 at risk
EG003
Hemorrhoids
Gastrointestinal disorders
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected3 at risk
EG0020 affected3 at risk
EG003
Hepatobiliary disorders - Other, specify
Hepatobiliary disorders
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected3 at risk
EG0020 affected3 at risk
EG003
Hiccups
Respiratory, thoracic and mediastinal disorders
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected3 at risk
EG0020 affected3 at risk
EG003
Hot flashes
Vascular disorders
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected3 at risk
EG0020 affected3 at risk
EG003
Hyperglycemia
Metabolism and nutrition disorders
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0012 affected3 at risk
EG0022 affected3 at risk
EG003
Hyperhidrosis
Skin and subcutaneous tissue disorders
CTCAE (4.0)
Systematic Assessment
EG0001 affected3 at risk
EG0010 affected3 at risk
EG0020 affected3 at risk
EG003
Hyperkalemia
Metabolism and nutrition disorders
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected3 at risk
EG0020 affected3 at risk
EG003
Hypertension
Vascular disorders
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0012 affected3 at risk
EG0023 affected3 at risk
EG003
Hypertriglyceridemia
Metabolism and nutrition disorders
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected3 at risk
EG0021 affected3 at risk
EG003
Hypoalbuminemia
Metabolism and nutrition disorders
CTCAE (4.0)
Systematic Assessment
EG0001 affected3 at risk
EG0010 affected3 at risk
EG0020 affected3 at risk
EG003
Hypocalcemia
Metabolism and nutrition disorders
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected3 at risk
EG0020 affected3 at risk
EG003
Hypokalemia
Metabolism and nutrition disorders
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected3 at risk
EG0020 affected3 at risk
EG003
Hypomagnesemia
Metabolism and nutrition disorders
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected3 at risk
EG0020 affected3 at risk
EG003
Hyponatremia
Metabolism and nutrition disorders
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected3 at risk
EG0021 affected3 at risk
EG003
Hypophosphatemia
Metabolism and nutrition disorders
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected3 at risk
EG0020 affected3 at risk
EG003
Hypotension
Vascular disorders
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected3 at risk
EG0020 affected3 at risk
EG003
Hypothyroidism
Endocrine disorders
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected3 at risk
EG0020 affected3 at risk
EG003
Hypoxia
Respiratory, thoracic and mediastinal disorders
CTCAE (4.0)
Systematic Assessment
EG0001 affected3 at risk
EG0010 affected3 at risk
EG0020 affected3 at risk
EG003
INR increased
Investigations
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected3 at risk
EG0020 affected3 at risk
EG003
Infections and infestations - Other, specify
Infections and infestations
CTCAE (4.0)
Systematic Assessment
EG0001 affected3 at risk
EG0011 affected3 at risk
EG0020 affected3 at risk
EG003
Insomnia
Psychiatric disorders
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0012 affected3 at risk
EG0020 affected3 at risk
EG003
Investigations - Other, specify
Investigations
CTCAE (4.0)
Systematic Assessment
EG0001 affected3 at risk
EG0011 affected3 at risk
EG0021 affected3 at risk
EG003
Localized edema
General disorders
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected3 at risk
EG0020 affected3 at risk
EG003
Lung infection
Infections and infestations
CTCAE (4.0)
Systematic Assessment
EG0001 affected3 at risk
EG0012 affected3 at risk
EG0020 affected3 at risk
EG003
Lymphedema
Vascular disorders
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected3 at risk
EG0020 affected3 at risk
EG003
Memory impairment
Nervous system disorders
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected3 at risk
EG0020 affected3 at risk
EG003
Mucositis oral
Gastrointestinal disorders
CTCAE (4.0)
Systematic Assessment
EG0001 affected3 at risk
EG0012 affected3 at risk
EG0022 affected3 at risk
EG003
Muscle weakness lower limb
Musculoskeletal and connective tissue disorders
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected3 at risk
EG0020 affected3 at risk
EG003
Muscle weakness right-sided
Musculoskeletal and connective tissue disorders
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected3 at risk
EG0020 affected3 at risk
EG003
Musculoskeletal and connective tissue disorder - Other, specify
Musculoskeletal and connective tissue disorders
CTCAE (4.0)
Systematic Assessment
EG0001 affected3 at risk
EG0011 affected3 at risk
EG0021 affected3 at risk
EG003
Myalgia
Musculoskeletal and connective tissue disorders
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0012 affected3 at risk
EG0020 affected3 at risk
EG003
Nausea
Gastrointestinal disorders
CTCAE (4.0)
Systematic Assessment
EG0003 affected3 at risk
EG0012 affected3 at risk
EG0021 affected3 at risk
EG003
Nervous system disorders - Other, specify
Nervous system disorders
CTCAE (4.0)
Systematic Assessment
EG0001 affected3 at risk
EG0010 affected3 at risk
EG0020 affected3 at risk
EG003
Neutrophil count decreased
Investigations
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected3 at risk
EG0020 affected3 at risk
EG003
Non-cardiac chest pain
General disorders
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected3 at risk
EG0021 affected3 at risk
EG003
Oral hemorrhage
Gastrointestinal disorders
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected3 at risk
EG0021 affected3 at risk
EG003
Oral pain
Gastrointestinal disorders
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected3 at risk
EG0021 affected3 at risk
EG003
Pain
General disorders
CTCAE (4.0)
Systematic Assessment
EG0001 affected3 at risk
EG0011 affected3 at risk
EG0021 affected3 at risk
EG003
Pain in extremity
Musculoskeletal and connective tissue disorders
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0012 affected3 at risk
EG0020 affected3 at risk
EG003
Palmar-plantar erythrodysesthesia syndrome
Skin and subcutaneous tissue disorders
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected3 at risk
EG0020 affected3 at risk
EG003
Palpitations
Cardiac disorders
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected3 at risk
EG0020 affected3 at risk
EG003
Pelvic pain
Reproductive system and breast disorders
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected3 at risk
EG0020 affected3 at risk
EG003
Peripheral motor neuropathy
Nervous system disorders
CTCAE (4.0)
Systematic Assessment
EG0001 affected3 at risk
EG0010 affected3 at risk
EG0020 affected3 at risk
EG003
Peripheral sensory neuropathy
Nervous system disorders
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected3 at risk
EG0020 affected3 at risk
EG003
Platelet count decreased
Investigations
CTCAE (4.0)
Systematic Assessment
EG0001 affected3 at risk
EG0010 affected3 at risk
EG0021 affected3 at risk
EG003
Pleural effusion
Respiratory, thoracic and mediastinal disorders
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected3 at risk
EG0021 affected3 at risk
EG003
Pneumonitis
Respiratory, thoracic and mediastinal disorders
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected3 at risk
EG0020 affected3 at risk
EG003
Pneumothorax
Respiratory, thoracic and mediastinal disorders
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected3 at risk
EG0020 affected3 at risk
EG003
Proteinuria
Renal and urinary disorders
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected3 at risk
EG0020 affected3 at risk
EG003
Pruritus
Skin and subcutaneous tissue disorders
CTCAE (4.0)
Systematic Assessment
EG0003 affected3 at risk
EG0012 affected3 at risk
EG0023 affected3 at risk
EG003
Rash acneiform
Skin and subcutaneous tissue disorders
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0012 affected3 at risk
EG0021 affected3 at risk
EG003
Rash maculo-papular
Skin and subcutaneous tissue disorders
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0011 affected3 at risk
EG0020 affected3 at risk
EG003
Renal and urinary disorders - Other, specify
Renal and urinary disorders
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected3 at risk
EG0020 affected3 at risk
EG003
Respiratory failure
Respiratory, thoracic and mediastinal disorders
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected3 at risk
EG0020 affected3 at risk
EG003
Respiratory, thoracic and mediastinal disorders - Other, specify
Respiratory, thoracic and mediastinal disorders
CTCAE (4.0)
Systematic Assessment
EG0002 affected3 at risk
EG0011 affected3 at risk
EG0020 affected3 at risk
EG003
Scalp pain
Skin and subcutaneous tissue disorders
CTCAE (4.0)
Systematic Assessment
EG0000 affected3 at risk
EG0010 affected3 at risk
EG0020 affected3 at risk
EG003
Sinus tachycardia
Cardiac disorders
CTCAE (4.0)
Systematic Assessment
EG0001 affected3 at risk
EG0010 affected3 at risk
EG0020 affected3 at risk
EG003
Skin and subcutaneous tissue disorders - Other, specify
Phase 1 Dose Level 3 participants receive MLN0128 5 mg orally, daily for 28 days. Participants are treated until disease progression or withdrawal of consent.
OG004
Phase II: ATC Cohort
Phase II participants receive MLN0128 at the recommended phase II dose of 5 mg orally, daily for 28 days. Participants are treated until disease progression or withdrawal of consent. All phase I participants treated at the maximum tolerated dose/ recommended phase II dose (DL3) were also enrolled in the phase II part of the study according to the appropriate disease cohort.
OG005
Phase II: DTC Cohort
Phase II participants receive MLN0128 at the recommended phase II dose of 5 mg orally, daily for 28 days. Participants are treated until disease progression or withdrawal of consent. All phase I participants treated at the maximum tolerated dose/ recommended phase II dose (DL3) were also enrolled in the phase II part of the study according to the appropriate disease cohort.
Units
Counts
Participants
OG0003
OG0013
OG0023
OG00310
OG00418
OG00522
Title
Denominators
Categories
Title
Measurements
OG0000
OG0011
OG0020
OG0033
OG0044
OG0058
OG00022
Title
Denominators
Categories
Title
Measurements
OG00045.5(27.1 to 64.7)
Units
Counts
Participants
OG00018
OG00122
Title
Denominators
Categories
Title
Measurements
OG0000(0 to 15.3)
OG0011(0.2 to 19.8)
Units
Counts
Participants
OG00018
OG00122
Title
Denominators
Categories
Title
Measurements
OG0006.1(4 to 10.3)
OG00120.4(17.3 to NA)The upper limit of the 95% confidence interval was not calculable because an insufficient number of participants had experienced an event (death) as of the final analysis.
OG00011
OG00116
Title
Denominators
Categories
Absent
Title
Measurements
OG0007
OG0018
Present
Title
Measurements
OG0004
OG0018
OG001
Phase II: ATC Cohort BRAF V600E Absent
Phase II participants receive MLN0128 at the recommended phase II dose of 5 mg orally, daily for 28 days. Participants are treated until disease progression or withdrawal of consent. All phase I participants treated at the maximum tolerated dose/ recommended phase II dose (DL3) were also enrolled in the phase II part of the study according to the appropriate disease cohort. BRAF V600E status was determined at baseline.
OG002
Phase II: DTC Cohort BRAF V600E Present Status
Phase II participants receive MLN0128 at the recommended phase II dose of 5 mg orally, daily for 28 days. Participants are treated until disease progression or withdrawal of consent. All phase I participants treated at the maximum tolerated dose/ recommended phase II dose (DL3) were also enrolled in the phase II part of the study according to the appropriate disease cohort. BRAF V600E status was determined at baseline.
OG003
Phase II: DTC Cohort BRAF V600E Absent Status
Phase II participants receive MLN0128 at the recommended phase II dose of 5 mg orally, daily for 28 days. Participants are treated until disease progression or withdrawal of consent. All phase I participants treated at the maximum tolerated dose/ recommended phase II dose (DL3) were also enrolled in the phase II part of the study according to the appropriate disease cohort. BRAF V600E status was determined at baseline.