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This is a phase 1, multicenter, open-label, single-arm study to investigate the safety and tolerability of encorafenib 300 mg once daily (QD) monotherapy in adult Chinese participants with B-RAF Proto-oncogene, Serine/threonine Kinase V600E (BRAF V600E) mutant advanced solid tumors (unresectable metastatic melanoma or metastatic non-small cell lung cancer (NSCLC)), who are BRAF-inhibitor treatment-naïve and have failed the previous therapy(ies) in the metastatic setting or are not eligible to standard therapy. Participants will be eligible for the study based on identification of a BRAF V600E mutation in tumor tissue by a local National Medical Products Administration (NMPA) approved assay obtained prior to screening.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| encorafenib | Experimental | Encorafenib hard capsule will be orally self-administered. A fixed-flat dose of 300 mg (4 x 75 mg) Per Oral (PO) encorafenib will be administered once-daily (QD). |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Encorafenib | Drug | oral capsule |
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| Measure | Description | Time Frame |
|---|---|---|
| Dose Limiting Toxicities (DLTs) Experienced During Cycle 1 | The primary endpoint was the number of patients experiencing dose limiting toxicity (DLT) occurring within the first 28 days of study treatment (Cycle 1). A DLT was defined as any adverse event or abnormal laboratory value assessed as unrelated to disease, disease progression, intercurrent illness or concomitant medications/therapies resulting in the inability to tolerate at least 75% dose intensity [(administered dose in mg/planned dose in mg) × 100] that satisfied at least one of the prespecified criteria. | At the end of Cycle 1. Each cycle was 28 days. |
| Measure | Description | Time Frame |
|---|---|---|
| Occurrence of Treatment Emergent Adverse Events (TEAEs) | The occurrences of treatment emergent adverse events (TEAEs) graded as per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.03, TEAEs leading to dose interruption, reduction and discontinuation, treatment-emergent serious adverse events (SAEs) and deaths were reported. The number of events occurring in the three participants is presented. |
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Inclusion Criteria:
Exclusion Criteria:
Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to encorafenib, or its excipients.
For metastatic NSCLC: documented anaplastic lymphoma kinase (ALK) fusion oncogene, ROS1 (c-ros oncogene 1) rearrangement or epidermal growth factor receptor (EGFR) sensitizing or driver mutation.
Receipt of anticancer medications or investigational drugs within intervals before the first administration of study treatment.
Symptomatic brain metastasis.
Leptomeningeal disease.
Participant has not recovered to ≤Grade 1 from toxic effects of prior therapy and/or complications from prior surgical treatment before starting study treatment.
Current use of prohibited medication ≤1 week prior to start of the study treatment and/or concomitantly.
Impairment of gastrointestinal function or disease which may significantly alter the absorption of oral study treatment.
Impaired cardiovascular function or clinically significant cardiovascular diseases.
Participants with active Hepatitis B virus (HBV) or Hepatitis C virus (HCV) or any other severe viral active infection (e.g. severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] infection).
Evidence of active, non-infectious pneumonitis, history of interstitial lung disease that required oral or intravenous glucocorticoid steroids for management.
Known history of a positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS). Testing for HIV must be performed at sites where mandated locally.
Participants who have had major surgery (e.g. inpatient procedure with regional or general anesthesia) within 6 weeks prior to start of study treatment.
Previous or concurrent malignancy within 2 years of study entry.
Except:
Participant's conditions that contraindicates the use of study treatment and may affect interpretation of results or that may render the participant at high risk from treatment complications.
Pregnant (confirmed by positive serum beta-human Chorionic Gonadotropin (ß-HCG) test), lactating or breast-feeding women.
Is a family member of the Investigator or any associate, colleague, and employee assisting in the conduct of the study (secretary, nurse, technician).
Is in a position likely to represent a conflict of interest.
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| Name | Affiliation | Role |
|---|---|---|
| Li Zhang, MD | Sun Yat-sen University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Sun Yat-sen University Cancer Center | Guangzhou | Guangdong | 510060 | China |
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This study had no fixed duration and participants were expected to be treated until progressive disease. The three enrolled participants were to be treated until death, disease progression.
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| ID | Title | Description |
|---|---|---|
| FG000 | Encorafenib | Encorafenib hard capsule was orally administered. A fixed-flat dose of 300 mg (4 x 75 mg) Per Oral (PO) encorafenib was administered once-daily (QD). |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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Safety Analysis Set
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| ID | Title | Description |
|---|---|---|
| BG000 | Encorafenib | Encorafenib hard capsule was orally administered. A fixed-flat dose of 300 mg (4 x 75 mg) Per Oral (PO) encorafenib was administered once-daily (QD). |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| 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 | Dose Limiting Toxicities (DLTs) Experienced During Cycle 1 | The primary endpoint was the number of patients experiencing dose limiting toxicity (DLT) occurring within the first 28 days of study treatment (Cycle 1). A DLT was defined as any adverse event or abnormal laboratory value assessed as unrelated to disease, disease progression, intercurrent illness or concomitant medications/therapies resulting in the inability to tolerate at least 75% dose intensity [(administered dose in mg/planned dose in mg) × 100] that satisfied at least one of the prespecified criteria. | Dose-determining Set. The Dose-determining set consisted of all evaluable participants from the Safety Analysis Set who either achieved the minimum exposure requirement (i.e., encorafenib dose intensity of 75% in Cycle 1) and had sufficient safety evaluations. | Posted | Number | participants | At the end of Cycle 1. Each cycle was 28 days. |
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All adverse events were collected for approximately 6 months, from when the participant first provided informed consent until the 30-day safety follow-up visit.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Encorafenib | Encorafenib hard capsule was orally administered. A fixed-flat dose of 300 mg (4 x 75 mg) Per Oral (PO) encorafenib was administered once-daily (QD). |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Diabetes mellitus | Metabolism and nutrition disorders | MedDRA 25.0 | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Constipation | Gastrointestinal disorders | MedDRA 25.0 | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Jean Claude Vedovato | Pierre Fabre Medicament | +33 609828746 | jean.claude.vedovato@pierre-fabre.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Sep 30, 2021 | Feb 1, 2023 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Jul 6, 2022 | Feb 1, 2023 | SAP_001.pdf |
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| ID | Term |
|---|---|
| D008545 | Melanoma |
| ID | Term |
|---|---|
| D018358 | Neuroendocrine Tumors |
| D017599 | Neuroectodermal Tumors |
| D009373 | Neoplasms, Germ Cell and Embryonal |
| D009370 | Neoplasms by Histologic Type |
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| ID | Term |
|---|---|
| C000601108 | encorafenib |
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| Cycle 1 Day 1 through safety follow-up visit (30 days after end of treatment (EOT) visit or 7 days after end EOT visit/last dose if EOT not performed), approximately up to 6 months. Each cycle was 28 days. |
| Notable Change From Baseline of Blood Hematology Parameters: Hemoglobin, Leukocytes, Neutrophils, Platelets, Lymphocytes. | Clinically notable shift from baseline in blood hematology parameters data [Hemoglobin (Low/High); Leukocytes (Low/ High); Neutrophils (Low); Platelets (Low); Lymphocytes (Low/High)] was graded using NCI CTCAE Version 4.03. Clinically notable shift was defined as a worsening from baseline by at least 2 grades, or to grade 3 or above. The number of participants with clinically notable shift from baseline is presented. | Screening (Days -28 to -1), Cycle 1 Day 1 (if not done within 72 hours before the first dose), Cycle 1 Day 15, on Day 1 each subsequent cycle, end of treatment visit 30 day safety follow up visit, approximately up to 6 months. Each cycle was 28 days. |
| Notable Change From Baseline of Blood Clinical Chemistry Parameters | Clinically notable shift from baseline in blood clinical chemistry parameter values [Phosphate (Low); Alanine Aminotransferase (High); Albumin (Low); Alkaline Phosphatase (High); Aspartate Aminotransferase (High); Bilirubin (High); Calcium Corrected (Low/High); Creatinine (High); Glucose (Low/High); Magnesium (Low/High); Potassium (Low/High); Sodium (Low/High); amylase (high); Gamma Glutamyl Transferase (High); Lipase (High) and Urate (High)] was graded using NCI-CTCAE, Version 4.03. Clinically notable shift was defined as a worsening from baseline by at least 2 grades, or to grade 3 or above. Number of participants with at least one clinically notable shift during study was reported. | Screening (Days -28 to -1), Cycle 1 Day 1 (if not done within 72 hours before the first dose), Cycle 1 Day 15, on Day 1 each subsequent cycle, end of treatment visit 30 day safety follow up visit, approximately up to 6 months. Each cycle was 28 days. |
| Notable Change From Baseline of Coagulation Parameters | The maximum post baseline values of coagulation parameters [activated partial thromboplastin time (seconds) and prothtombin international normalized ratio (INR)]. It was graded using NCI-CTCAE, Version 4.03. The number of participants is presented with their worst NCI-CTCAE grade post-baseline. Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting ageappropriate instrumental ADL*. Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL**. Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to AE. | Screening (Days -28 to -1), Cycle 1 Day 1 (if not done within 72 hours before the first dose), Cycle 1 Day 15, on Day 1 each subsequent cycle, end of treatment visit 30 day safety follow up visit, approximately up to 6 months. Each cycle was 28 days. |
| Notable Change From Baseline of Dipstick Urinalysis | The appearance of dipstick, at each visit by participant is presented. | Days -28 to -1, Cycle1 Day1 (if not within 72 hours before first dose),Cycle1 Day15,on Day1 each subsequent cycle,end of treatment visit 30 day safety follow up visit, up to 6 months. Additional urinalysis in Cycle 1 Days 8 and 22. Each cycle was 28 days. |
| Notable or Abnormal Changes in Vital Signs From Baseline of Vital Sign Examinations. | Clinically notable elevated values: Systolic blood pressure (SBP): ≥ 160 mmHg and an increase ≥ 20 mmHg from baseline; Diastolic blood pressure (DBP): ≥ 100 mmHg and an increase ≥ 15 mmHg from baseline; Heart rate : ≥ 120 beats/min (bpm) with increase from baseline of ≥ 15 bpm; Weight (kg) increase from baseline of ≥ 10%; Body temperature(°C) ≥ 37.5°C). Clinically notable low values: Systolic blood pressure (SBP): ≤ 90 mmHg with decrease from baseline of ≥ 20 mmHg; Diastolic blood pressure (DBP) : ≤ 50 mmHg with decrease from baseline of ≥ 15 mmHg; Heart rate: ≤ 50 bpm with decrease from baseline of ≥ 15 bpm; Weight: ≥ 20% decrease from baseline; Body temperature [°C]: ≤ 36 °C. Number of participants with clinically notable abnormalities in vital signs was reported. | Screening (Days -28 to -1), Cycle 1 Days 1, 8, 15 and 22, Day 1 of each subsequent cycle, the end of treatment visit and the 30-day safety follow-up visit, approximately up to 6 months. Each cycle was 28 days. |
| Notable or Abnormal Changes From Baseline of 12-lead Electrocardiograms (ECGs) | 12-lead ECGs were obtained using an internationally recognized 12-lead cardiograph. Clinically notable ECG values: QT [millisecond (ms)] and QT interval (ms) corrected for heart rate using Fridericia's formula (QTcF) intervals (ms): increase from baseline > 30 ms; increase from baseline > 60 ms, new > 450 ms, new > 480 ms, new > 500 ms. Heart rate (beats/min): increase from baseline > 25% to a value > 100 bpm, decrease from baseline > 25% and to a value < 50 bpm. Number of participants with clinically notable values was reported. | Screening (Days -28 to -1), Cycle 1 Day 8, 15 and 22, Day 1 of each subsequent even cycle, and the end of treatment visit, approximately up to 6 months. Each cycle was 28 days. |
| Occurrence of Targeted Treatment Emergent Adverse Events (TEAEs) of Special Interest | Adverse event of special interest (AESI) were as follows: Cutaneous non-squamous cell carcinoma, cutaneous squamous cell carcinoma, melanomas, facial paresis, uveitis-type events, QT prolongation, non-cutaneous malignancies with RAS mutation. Number of participants with at least one event of any AESI is presented. | Cycle 1 Day 1 through safety follow-up visit (30 days after end of treatment [EOT] visit or 7 days after end EOT visit/last dose if EOT not performed), approximately up to 6 months. |
| Plasma Pharmacokinetics (PK) of Encorafenib: Area Under the Curve (AUC) After Single and Repeated Administration of Encorafenib | All enrolled participants (n=3) received at least two doses of Encorafenib, did all the planned PK blood collection with associated bioanalytical results and were therefore included in the PK Set. The Area under the curve of Encorafenib was assessed after single and repeated administrations. AUC0-tlast = area under the concentration curve from time 0 to time of last measurable concentration | First day of treatment (Cycle 1 Day 1) and at steady state after 1 month treatment (Cycle 2 Day 1). Each cycle was 28 days. |
| Plasma Pharmacokinetics (PK) of Encorafenib Metabolite (LHY746): Area Under the Curve (AUC) After Single and Repeated Administration of Encorafenib Metabolite (LHY746) | All enrolled participants (n=3) received at least two doses of Encorafenib, did all the planned PK blood collection with associated bioanalytical results and were therefore included in the PK Set. The Area under the curve of Encorafenib metabolite (LHY746) was assessed after single and repeated administrations. AUC0-tlast = area under the concentration curve from time 0 to time of last measurable concentration | First day of treatment (Cycle 1 Day 1) and at steady state after 1 month treatment (Cycle 2 Day 1). Each cycle was 28 days. |
| Plasma Pharmacokinetics (PK) of Encorafenib: Maximum Concentration (Cmax) After Single and Repeated Administration of Encorafenib | All enrolled participants (n=3) received at least two doses of encorafenib, did all the planned PK blood collection with associated bioanalytical results and were therefore included in the PK Set. The Maximum Concentration of encorafenib was assessed after single and repeated administrations. | First day of treatment (Cycle 1 Day 1) and at steady state after 1 month treatment (Cycle 2 Day 1). Each cycle was 28 days. |
| Plasma Pharmacokinetics (PK) of Encorafenib Metabolite (LHY746): Maximum Concentration (Cmax) After Single and Repeated Administration of Encorafenib | All enrolled participants (n=3) received at least two doses of encorafenib, did all the planned PK blood collection with associated bioanalytical results and were therefore included in the PK Set. The Maximum Concentration of encorafenib metabolite (LHY746) was assessed after single and repeated administrations. | First day of treatment (Cycle 1 Day 1) and at steady state after 1 month treatment (Cycle 2 Day 1). Each cycle was 28 days. |
| Plasma Pharmacokinetics (PK) of Encorafenib: Minimum Concentration (Cmin) After Single and Repeated Administration of Encorafenib | All enrolled participants (n=3) received at least two doses of encorafenib, did all the planned PK blood collection with associated bioanalytical results and were therefore included in the PK Set. The Minimum concentration of encorafenib was assessed after single and repeated administrations. | First day of treatment (Cycle 1 Day 1) and at steady state after 1 month treatment (Cycle 2 Day 1). Each cycle was 28 days. |
| Plasma Pharmacokinetics (PK) of Encorafenib Metabolite (LHY746): Minimum Concentration (Cmin) After Single and Repeated Administration of Encorafenib | All enrolled participants (n=3) received at least two doses of encorafenib, did all the planned PK blood collection with associated bioanalytical results and were therefore included in the PK Set. The Minimum concentration of encorafenib metabolite (LHY746) was assessed after single and repeated administrations. | First day of treatment (Cycle 1 Day 1) and at steady state after 1 month treatment (Cycle 2 Day 1). Each cycle was 28 days. |
| Plasma Pharmacokinetics (PK) of Encorafenib: Time Taken to Reach Maximum Concentration (Tmax) After Single and Repeated Administration of Encorafenib | All enrolled participants (n=3) received at least two doses of encorafenib, did all the planned PK blood collection with associated bioanalytical results and were therefore included in the PK Set. The time taken to reach maximum concentration of Encorafenib was assessed after single and repeated administrations. | First day of treatment (Cycle 1 Day 1) and at steady state after 1 month treatment (Cycle 2 Day 1). Each cycle was 28 days. |
| Plasma Pharmacokinetics (PK) of Encorafenib Metabolite (LHY746): Time Taken to Reach Maximum Concentration (Tmax) After Single and Repeated Administration of Encorafenib Metabolite (LHY746) | All enrolled participants (n=3) received at least two doses of encorafenib, did all the planned PK blood collection with associated bioanalytical results and were therefore included in the PK Set. The time taken to reach maximum concentration of Encorafenib Metabolite (LHY746) was assessed after single and repeated administrations. | First day of treatment (Cycle 1 Day 1) and at steady state after 1 month treatment (Cycle 2 Day 1). Each cycle was 28 days. |
| Plasma Pharmacokinetics (PK) of Encorafenib: ARAUC After Single and Repeated Administration of Encorafenib | All enrolled participants (n=3) received at least two doses of Encorafenib, did all the planned PK blood collection with associated bioanalytical results and were therefore included in the PK Set. The ARAUC of Encorafenib was assessed after single and repeated administrations. ARAUC = Observed accumulation ratio based on AUC0-6 | at steady state after 1 month treatment (Cycle 2 Day 1). Each cycle was 28 days. |
| Plasma Pharmacokinetics (PK) of Encorafenib Metabolite (LHY746): ARAUC After Single and Repeated Administration of Encorafenib Metabolite (LHY746) | All enrolled participants (n=3) received at least two doses of encorafenib, did all the planned PK blood collection with associated bioanalytical results and were therefore included in the PK Set. The ARAUC of encorafenib metabolite (LHY746) was assessed after single and repeated administrations. ARAUC = Observed accumulation ratio based on AUC0-6 | at steady state after 1 month treatment (Cycle 2 Day 1). Each cycle was 28 days. |
| Plasma Pharmacokinetics (PK) of Encorafenib Metabolite (LHY746): MRAUC After Single and Repeated Administration of Encorafenib Metabolite (LHY746) | All enrolled participants (n=3) received at least two doses of encorafenib, did all the planned PK blood collection with associated bioanalytical results and were therefore included in the PK Set. The MRAUC of encorafenib metabolite (LHY746) was assessed after single and repeated administrations. MRAUC = Metabolite Parent ratio based on AUC0-6 | First day of treatment (Cycle 1 Day 1) and at steady state after 1 month treatment (Cycle 2 Day 1). Each cycle was 28 days. |
| years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
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| Weight | Mean | Standard Deviation | kilograms |
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| Height | Mean | Standard Deviation | centimeters |
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| Body Mass Index | Mean | Standard Deviation | kilograms/meters squared |
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| Eastern Cooperative Oncology Group (ECOG) Performance Status | The Performance status was assessed by the investigator using the ECOG Performance Status scale Performance status 0 = Fully active, able to carry on all pre-disease performance without restriction Performance status 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 |
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| Smoking history | Count of Participants | Participants |
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| BRAF V600E Mutation Result (Local) | Count of Participants | Participants |
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| Diagnosis at study entry | Count of Participants | Participants |
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Encorafenib hard capsule was orally administered. A fixed-flat dose of 300 mg (4 x 75 mg) Per Oral (PO) encorafenib was administered once-daily (QD).
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| Secondary | Occurrence of Treatment Emergent Adverse Events (TEAEs) | The occurrences of treatment emergent adverse events (TEAEs) graded as per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.03, TEAEs leading to dose interruption, reduction and discontinuation, treatment-emergent serious adverse events (SAEs) and deaths were reported. The number of events occurring in the three participants is presented. | Safety Analysis Set | Posted | Number | events | Cycle 1 Day 1 through safety follow-up visit (30 days after end of treatment (EOT) visit or 7 days after end EOT visit/last dose if EOT not performed), approximately up to 6 months. Each cycle was 28 days. |
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| Secondary | Notable Change From Baseline of Blood Hematology Parameters: Hemoglobin, Leukocytes, Neutrophils, Platelets, Lymphocytes. | Clinically notable shift from baseline in blood hematology parameters data [Hemoglobin (Low/High); Leukocytes (Low/ High); Neutrophils (Low); Platelets (Low); Lymphocytes (Low/High)] was graded using NCI CTCAE Version 4.03. Clinically notable shift was defined as a worsening from baseline by at least 2 grades, or to grade 3 or above. The number of participants with clinically notable shift from baseline is presented. | Safety Analysis Set | Posted | Count of Participants | Participants | Screening (Days -28 to -1), Cycle 1 Day 1 (if not done within 72 hours before the first dose), Cycle 1 Day 15, on Day 1 each subsequent cycle, end of treatment visit 30 day safety follow up visit, approximately up to 6 months. Each cycle was 28 days. |
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| Secondary | Notable Change From Baseline of Blood Clinical Chemistry Parameters | Clinically notable shift from baseline in blood clinical chemistry parameter values [Phosphate (Low); Alanine Aminotransferase (High); Albumin (Low); Alkaline Phosphatase (High); Aspartate Aminotransferase (High); Bilirubin (High); Calcium Corrected (Low/High); Creatinine (High); Glucose (Low/High); Magnesium (Low/High); Potassium (Low/High); Sodium (Low/High); amylase (high); Gamma Glutamyl Transferase (High); Lipase (High) and Urate (High)] was graded using NCI-CTCAE, Version 4.03. Clinically notable shift was defined as a worsening from baseline by at least 2 grades, or to grade 3 or above. Number of participants with at least one clinically notable shift during study was reported. | Safety Analysis Set | Posted | Count of Participants | Participants | Screening (Days -28 to -1), Cycle 1 Day 1 (if not done within 72 hours before the first dose), Cycle 1 Day 15, on Day 1 each subsequent cycle, end of treatment visit 30 day safety follow up visit, approximately up to 6 months. Each cycle was 28 days. |
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| Secondary | Notable Change From Baseline of Coagulation Parameters | The maximum post baseline values of coagulation parameters [activated partial thromboplastin time (seconds) and prothtombin international normalized ratio (INR)]. It was graded using NCI-CTCAE, Version 4.03. The number of participants is presented with their worst NCI-CTCAE grade post-baseline. Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting ageappropriate instrumental ADL*. Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL**. Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to AE. | Safety Analysis Set | Posted | Count of Participants | Participants | Screening (Days -28 to -1), Cycle 1 Day 1 (if not done within 72 hours before the first dose), Cycle 1 Day 15, on Day 1 each subsequent cycle, end of treatment visit 30 day safety follow up visit, approximately up to 6 months. Each cycle was 28 days. |
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| Secondary | Notable Change From Baseline of Dipstick Urinalysis | The appearance of dipstick, at each visit by participant is presented. | Safety Analysis Set | Posted | Count of Participants | Participants | Days -28 to -1, Cycle1 Day1 (if not within 72 hours before first dose),Cycle1 Day15,on Day1 each subsequent cycle,end of treatment visit 30 day safety follow up visit, up to 6 months. Additional urinalysis in Cycle 1 Days 8 and 22. Each cycle was 28 days. |
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| Secondary | Notable or Abnormal Changes in Vital Signs From Baseline of Vital Sign Examinations. | Clinically notable elevated values: Systolic blood pressure (SBP): ≥ 160 mmHg and an increase ≥ 20 mmHg from baseline; Diastolic blood pressure (DBP): ≥ 100 mmHg and an increase ≥ 15 mmHg from baseline; Heart rate : ≥ 120 beats/min (bpm) with increase from baseline of ≥ 15 bpm; Weight (kg) increase from baseline of ≥ 10%; Body temperature(°C) ≥ 37.5°C). Clinically notable low values: Systolic blood pressure (SBP): ≤ 90 mmHg with decrease from baseline of ≥ 20 mmHg; Diastolic blood pressure (DBP) : ≤ 50 mmHg with decrease from baseline of ≥ 15 mmHg; Heart rate: ≤ 50 bpm with decrease from baseline of ≥ 15 bpm; Weight: ≥ 20% decrease from baseline; Body temperature [°C]: ≤ 36 °C. Number of participants with clinically notable abnormalities in vital signs was reported. | Safety Analysis Set | Posted | Count of Participants | Participants | Screening (Days -28 to -1), Cycle 1 Days 1, 8, 15 and 22, Day 1 of each subsequent cycle, the end of treatment visit and the 30-day safety follow-up visit, approximately up to 6 months. Each cycle was 28 days. |
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| Secondary | Notable or Abnormal Changes From Baseline of 12-lead Electrocardiograms (ECGs) | 12-lead ECGs were obtained using an internationally recognized 12-lead cardiograph. Clinically notable ECG values: QT [millisecond (ms)] and QT interval (ms) corrected for heart rate using Fridericia's formula (QTcF) intervals (ms): increase from baseline > 30 ms; increase from baseline > 60 ms, new > 450 ms, new > 480 ms, new > 500 ms. Heart rate (beats/min): increase from baseline > 25% to a value > 100 bpm, decrease from baseline > 25% and to a value < 50 bpm. Number of participants with clinically notable values was reported. | Safety Analysis Set | Posted | Count of Participants | Participants | Screening (Days -28 to -1), Cycle 1 Day 8, 15 and 22, Day 1 of each subsequent even cycle, and the end of treatment visit, approximately up to 6 months. Each cycle was 28 days. |
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| Secondary | Occurrence of Targeted Treatment Emergent Adverse Events (TEAEs) of Special Interest | Adverse event of special interest (AESI) were as follows: Cutaneous non-squamous cell carcinoma, cutaneous squamous cell carcinoma, melanomas, facial paresis, uveitis-type events, QT prolongation, non-cutaneous malignancies with RAS mutation. Number of participants with at least one event of any AESI is presented. | Safety Analysis Set | Posted | Number | participants | Cycle 1 Day 1 through safety follow-up visit (30 days after end of treatment [EOT] visit or 7 days after end EOT visit/last dose if EOT not performed), approximately up to 6 months. |
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| Secondary | Plasma Pharmacokinetics (PK) of Encorafenib: Area Under the Curve (AUC) After Single and Repeated Administration of Encorafenib | All enrolled participants (n=3) received at least two doses of Encorafenib, did all the planned PK blood collection with associated bioanalytical results and were therefore included in the PK Set. The Area under the curve of Encorafenib was assessed after single and repeated administrations. AUC0-tlast = area under the concentration curve from time 0 to time of last measurable concentration | Pharmacokinetics Set | Posted | Mean | Standard Deviation | h*ng/mL | First day of treatment (Cycle 1 Day 1) and at steady state after 1 month treatment (Cycle 2 Day 1). Each cycle was 28 days. |
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| Secondary | Plasma Pharmacokinetics (PK) of Encorafenib Metabolite (LHY746): Area Under the Curve (AUC) After Single and Repeated Administration of Encorafenib Metabolite (LHY746) | All enrolled participants (n=3) received at least two doses of Encorafenib, did all the planned PK blood collection with associated bioanalytical results and were therefore included in the PK Set. The Area under the curve of Encorafenib metabolite (LHY746) was assessed after single and repeated administrations. AUC0-tlast = area under the concentration curve from time 0 to time of last measurable concentration | Pharmacokinetic Set | Posted | Mean | Standard Deviation | h*ng/mL | First day of treatment (Cycle 1 Day 1) and at steady state after 1 month treatment (Cycle 2 Day 1). Each cycle was 28 days. |
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| Secondary | Plasma Pharmacokinetics (PK) of Encorafenib: Maximum Concentration (Cmax) After Single and Repeated Administration of Encorafenib | All enrolled participants (n=3) received at least two doses of encorafenib, did all the planned PK blood collection with associated bioanalytical results and were therefore included in the PK Set. The Maximum Concentration of encorafenib was assessed after single and repeated administrations. | Pharmacokinetic Set | Posted | Mean | Standard Deviation | (ng/mL) | First day of treatment (Cycle 1 Day 1) and at steady state after 1 month treatment (Cycle 2 Day 1). Each cycle was 28 days. |
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| Secondary | Plasma Pharmacokinetics (PK) of Encorafenib Metabolite (LHY746): Maximum Concentration (Cmax) After Single and Repeated Administration of Encorafenib | All enrolled participants (n=3) received at least two doses of encorafenib, did all the planned PK blood collection with associated bioanalytical results and were therefore included in the PK Set. The Maximum Concentration of encorafenib metabolite (LHY746) was assessed after single and repeated administrations. | Pharmacokinetic Set | Posted | Mean | Standard Deviation | ng/mL | First day of treatment (Cycle 1 Day 1) and at steady state after 1 month treatment (Cycle 2 Day 1). Each cycle was 28 days. |
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| Secondary | Plasma Pharmacokinetics (PK) of Encorafenib: Minimum Concentration (Cmin) After Single and Repeated Administration of Encorafenib | All enrolled participants (n=3) received at least two doses of encorafenib, did all the planned PK blood collection with associated bioanalytical results and were therefore included in the PK Set. The Minimum concentration of encorafenib was assessed after single and repeated administrations. | pharmacokinetic set | Posted | Mean | Standard Deviation | ng/mL | First day of treatment (Cycle 1 Day 1) and at steady state after 1 month treatment (Cycle 2 Day 1). Each cycle was 28 days. |
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| Secondary | Plasma Pharmacokinetics (PK) of Encorafenib Metabolite (LHY746): Minimum Concentration (Cmin) After Single and Repeated Administration of Encorafenib | All enrolled participants (n=3) received at least two doses of encorafenib, did all the planned PK blood collection with associated bioanalytical results and were therefore included in the PK Set. The Minimum concentration of encorafenib metabolite (LHY746) was assessed after single and repeated administrations. | Pharmacokinetic Set | Posted | Mean | Standard Deviation | ng/mL | First day of treatment (Cycle 1 Day 1) and at steady state after 1 month treatment (Cycle 2 Day 1). Each cycle was 28 days. |
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| Secondary | Plasma Pharmacokinetics (PK) of Encorafenib: Time Taken to Reach Maximum Concentration (Tmax) After Single and Repeated Administration of Encorafenib | All enrolled participants (n=3) received at least two doses of encorafenib, did all the planned PK blood collection with associated bioanalytical results and were therefore included in the PK Set. The time taken to reach maximum concentration of Encorafenib was assessed after single and repeated administrations. | Pharmacokinetic Set | Posted | Median | Full Range | hours | First day of treatment (Cycle 1 Day 1) and at steady state after 1 month treatment (Cycle 2 Day 1). Each cycle was 28 days. |
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| Secondary | Plasma Pharmacokinetics (PK) of Encorafenib Metabolite (LHY746): Time Taken to Reach Maximum Concentration (Tmax) After Single and Repeated Administration of Encorafenib Metabolite (LHY746) | All enrolled participants (n=3) received at least two doses of encorafenib, did all the planned PK blood collection with associated bioanalytical results and were therefore included in the PK Set. The time taken to reach maximum concentration of Encorafenib Metabolite (LHY746) was assessed after single and repeated administrations. | Pharmacokinetic Set | Posted | Median | Full Range | hours | First day of treatment (Cycle 1 Day 1) and at steady state after 1 month treatment (Cycle 2 Day 1). Each cycle was 28 days. |
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| Secondary | Plasma Pharmacokinetics (PK) of Encorafenib: ARAUC After Single and Repeated Administration of Encorafenib | All enrolled participants (n=3) received at least two doses of Encorafenib, did all the planned PK blood collection with associated bioanalytical results and were therefore included in the PK Set. The ARAUC of Encorafenib was assessed after single and repeated administrations. ARAUC = Observed accumulation ratio based on AUC0-6 | Pharmacokinetics Set | Posted | Geometric Mean | Geometric Coefficient of Variation | ratio | at steady state after 1 month treatment (Cycle 2 Day 1). Each cycle was 28 days. |
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| Secondary | Plasma Pharmacokinetics (PK) of Encorafenib Metabolite (LHY746): ARAUC After Single and Repeated Administration of Encorafenib Metabolite (LHY746) | All enrolled participants (n=3) received at least two doses of encorafenib, did all the planned PK blood collection with associated bioanalytical results and were therefore included in the PK Set. The ARAUC of encorafenib metabolite (LHY746) was assessed after single and repeated administrations. ARAUC = Observed accumulation ratio based on AUC0-6 | Pharmacokinetics Set | Posted | Geometric Mean | Geometric Coefficient of Variation | ratio | at steady state after 1 month treatment (Cycle 2 Day 1). Each cycle was 28 days. |
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| Secondary | Plasma Pharmacokinetics (PK) of Encorafenib Metabolite (LHY746): MRAUC After Single and Repeated Administration of Encorafenib Metabolite (LHY746) | All enrolled participants (n=3) received at least two doses of encorafenib, did all the planned PK blood collection with associated bioanalytical results and were therefore included in the PK Set. The MRAUC of encorafenib metabolite (LHY746) was assessed after single and repeated administrations. MRAUC = Metabolite Parent ratio based on AUC0-6 | Pharmacokinetics Set | Posted | Geometric Mean | Geometric Coefficient of Variation | ratio | First day of treatment (Cycle 1 Day 1) and at steady state after 1 month treatment (Cycle 2 Day 1). Each cycle was 28 days. |
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|
|
| 0 |
| 3 |
| 2 |
| 3 |
| 3 |
| 3 |
| Dysplastic naevus | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA 25.0 | Systematic Assessment |
|
| Nausea | Gastrointestinal disorders | MedDRA 25.0 | Systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | MedDRA 25.0 | Systematic Assessment |
|
| Neutrophil count increased | Investigations | MedDRA 25.0 | Systematic Assessment |
|
| Blood cholesterol increased | Investigations | MedDRA 25.0 | Systematic Assessment |
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| Blood glucose increased | Investigations | MedDRA 25.0 | Systematic Assessment |
|
| C-reactive protein increased | Investigations | MedDRA 25.0 | Systematic Assessment |
|
| Coagulation time prolonged | Investigations | MedDRA 25.0 | Systematic Assessment |
|
| Lipase increased | Investigations | MedDRA 25.0 | Systematic Assessment |
|
| Platelet count increased | Investigations | MedDRA 25.0 | Systematic Assessment |
|
| Urinary occult blood | Investigations | MedDRA 25.0 | Systematic Assessment |
|
| White blood cell count increased | Investigations | MedDRA 25.0 | Systematic Assessment |
|
| Proteinuria | Renal and urinary disorders | MedDRA 25.0 | Systematic Assessment |
|
| Diabetic nephropathy | Renal and urinary disorders | MedDRA 25.0 | Systematic Assessment |
|
| Hyperkeratosis | Skin and subcutaneous tissue disorders | MedDRA 25.0 | Systematic Assessment |
|
| Palmar-plantar erythrodysaesthesia syndrome | Skin and subcutaneous tissue disorders | MedDRA 25.0 | Systematic Assessment |
|
| Pigmentation disorder | Skin and subcutaneous tissue disorders | MedDRA 25.0 | Systematic Assessment |
|
| Rash | Skin and subcutaneous tissue disorders | MedDRA 25.0 | Systematic Assessment |
|
| Rash pruritic | Skin and subcutaneous tissue disorders | MedDRA 25.0 | Systematic Assessment |
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| Skin hyperpigmentation | Skin and subcutaneous tissue disorders | MedDRA 25.0 | Systematic Assessment |
|
| Leukocytosis | Blood and lymphatic system disorders | MedDRA 25.0 | Systematic Assessment |
|
| Anaemia | Blood and lymphatic system disorders | MedDRA 25.0 | Systematic Assessment |
|
| Subcutaneous abscess | Infections and infestations | MedDRA 25.0 | Systematic Assessment |
|
| Postoperative wound complication | Injury, poisoning and procedural complications | MedDRA 25.0 | Systematic Assessment |
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| Diabetes mellitus | Metabolism and nutrition disorders | MedDRA 25.0 | Systematic Assessment |
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| Hyperlipidaemia | Metabolism and nutrition disorders | MedDRA 25.0 | Systematic Assessment |
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| Hypokalaemia | Metabolism and nutrition disorders | MedDRA 25.0 | Systematic Assessment |
|
| Periarthritis | Musculoskeletal and connective tissue disorders | MedDRA 25.0 | Systematic Assessment |
|
| Neuritis | Nervous system disorders | MedDRA 25.0 | Systematic Assessment |
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| Dysphonia | Respiratory, thoracic and mediastinal disorders | MedDRA 25.0 | Systematic Assessment |
|
| Hypertension | Vascular disorders | MedDRA 25.0 | Systematic Assessment |
|
Except for the release of SAE of study drug/product defects of the institution, institution and/or investigator shall promptly notify sponsor of the content to be released before releasing other research information and obtain sponsor's consent. If there is no response from sponsor within 60 working days after issuance or specific reason for disagreement and modification suggestions are not listed in the response, it shall be deemed that sponsor agrees.
| D009369 | Neoplasms |
| D009380 | Neoplasms, Nerve Tissue |
| D018326 | Nevi and Melanomas |
| D012878 | Skin Neoplasms |
| D009371 | Neoplasms by Site |
| D012871 | Skin Diseases |
| D017437 | Skin and Connective Tissue Diseases |
| Title | Measurements |
|---|---|
|
| TEAEs Related Grade 3+ |
|
| Serious TEAE Overall |
|
| Serious TEAE Related |
|
| Serious TEAE Grade 3+ |
|
| Serious TEAE Related Grade 3+ |
|
| Serious TEAE Leading to Death |
|
| TEAE by severity grade Grade 1 |
|
| TEAE by severity grade Grade 2 |
|
| TEAE by severity grade Grade 3 |
|
| TEAE leading to discontinuation of encorafenib regardless of causality Overall |
|
| TEAEs leading to encorafenib dose modification (interruption or reduction) Overall |
|
| TEAEs leading to encorafenib dose modification (interruption or reduction) Related |
|
| TEAEs leading to encorafenib dose modification (interruption or reduction) Grade 3+ |
|
| TEAEs leading to encorafenib dose modification (interruption or reduction) Related Grade 3+ |
|
| TEAEs leading to encorafenib drug interruption Overall |
|
| TEAEs leading to encorafenib drug interruption Related |
|
| TEAEs leading to encorafenib drug interruption Grade 3+ |
|
| TEAEs leading to encorafenib drug interruption Related Grade 3+ |
|
| TEAEs leading to encorafenib dose reduction Overall |
|
| TEAE action taken with encorafenib Dose not Change |
|
| TEAE action taken with encorafenib Dose Reduced |
|
| TEAE action taken with encorafenib Drug Interrupted |
|
| Title | Measurements |
|---|---|
|
| Leukocytes (10^9/L) (Low) |
|
| Leukocytes (10^9/L) (High) |
|
| Lymphocytes (10^9/L) (Low) |
|
| Lymphocytes (10^9/L) (High) |
|
| Neutrophils (10^9/L) (Low) |
|
| Title | Measurements |
|---|---|
|
| Aspartate Aminotransferase (IU/L) (High) |
|
| Bilirubin (umol/L) (High) |
|
| Calcium Corrected (mmol/L) (Low) |
|
| Calcium Corrected (mmol/L) (High) |
|
| Creatine Kinase (IU/L) (High) |
|
| Creatinine (umol/L) (High) |
|
| Gamma Glutamyl Transferase (IU/L) (High) |
|
| Glucose (mmol/L) (Low) |
|
| Glucose (mmol/L) (High) |
|
| Lipase (IU/L) (High) |
|
| Amylase (IU/L) (High) |
|
| Magnesium (mmol/L) (Low) |
|
| Magnesium (mmol/L) (High) |
|
| Phosphate (mmol/L) (Low) |
|
| Potassium (mmol/L) (Low) |
|
| Potassium (mmol/L) (High) |
|
| Sodium (mmol/L) (Low) |
|
| Sodium (mmol/L) (High) |
|
| Urate (umol/L) (High) |
|
| Grade 3 |
|
| Grade 4 |
|
| Prothrombin International Normalized Ratio (RATIO) |
|
| Cloudy |
|
| Cycle 1 Day 15 |
|
| Cycle 1 Day 22 |
|
| Cycle 2 Day 1 |
|
| Cycle 3 Day 1 |
|
| Cycle 4 Day 1 |
|
|
| Clinically notable elevated values: Weight: increase from baseline of ≥ 10% |
|
| Clinically notable elevated values: Body temperature [C]: ≥ 37.5 C |
|
| Clinically notable low values: SBP: ≤ 90 mmHg with decrease from baseline of ≥ 20 mmHg |
|
| Clinically notable low values: DBP: ≤ 50 mmHg with decrease from baseline of ≥ 15 mmHg |
|
| Clinically notable low values: Pulse rate: ≤ 50 bpm with decrease from baseline of ≥ 15 bpm |
|
| Clinically notable low values: Weight: ≥ 20% decrease from baseline |
|
| Clinically notable low values: Body temperature [C]: ≤ 36 C |
|
| Title | Measurements |
|---|---|
|
| QT Interval : New > 480 ms |
|
| QT Interval : New > 500 ms |
|
| QTcF Interval : Increase from baseline > 30 ms |
|
| QTcF Interval : Increase from baseline > 60 ms |
|
| QTcF Interval : New > 450 ms |
|
| QTcF Interval : New > 480 ms |
|
| QTcF Interval : New > 500 ms |
|
| Heart rate : Increase from baseline > 25% to a value > 100 bpm |
|
| Heart rate : Decrease from baseline > 25% and to a value < 50 bpm |
|