A Study of Vemurafenib in Previously Treated Patients With Metastatic Melanoma

Study Overview
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Brief Summary
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This open-label single arm study will assess the efficacy, safety and tolerability of Vemurafenib in previously treated patients with metastatic melanoma. Patients will receive oral Vemurafenib [RG7204; PLEXXIKON: PLX4032] at a dose of 960 mg b.i.d. continuously until disease progression or withdrawal from study and will be assessed at regular intervals for tumour response and tolerability. Target sample size is <100 patients.

Official Title
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An Open-label Multicenter Study on the Efficacy of Continuous Oral Dosing of Vemurafenib on Tumour Response in Previously Treated Patients With Metastatic Melanoma

Conditions
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Malignant Melanoma

Intervention / Treatment
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* Drug: vemurafenib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: adult patients >/=18 years of age histologically confirmed metastatic melanoma (Stage IV, AJCC) patients must have completed and failed at least one prior standard of care regimen (e.g. DTIC, temozolomide, etc.) BRAF V600E positive mutation (by Roche CoDx BRAF mutation assay) measurable disease by RECIST criteria negative pregnancy test and, for fertile men and women, effective contraception during treatment and for 6 months after completion Exclusion Criteria: active CNS metastases on CT/MRI within 28 days prior to enrollment history of or known carcinomatous meningitis previous treatment with BRAF (sorafenib allowed) or MEK inhibitor cardiac dysrhythmias >2 NCI CTCAE or treatment with drugs with dysrhythmic potential uncontrolled hypertension(>150/100mmHg) despite optimal medical therapy infectious disease including HIV, HBV and HCV

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single arm<br> | Drug: vemurafenib<br>* 960 mg b.i.d. continuous oral dosing<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Overall Response (BOR) Assessed by an Independent Review Committee Using Response Evaluation Criteria In Solid Tumors (RECIST 1.1) | BOR was defined as a complete response (CR) or partial response (PR) confirmed per Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. Patients who never received study treatment and treated patients without any post-baseline tumor assessments were considered as non-responders. CR: Disappearance of all target lesions, all non-target lesions, and no new lesion. Any pathological lymph nodes must have had reduction in the short axis to <10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, no progression in non-target lesion, and no new lesion. | From first treatment through September 27, 2010 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Overall Response (BOR) Assessed by the Investigator Using Response Evaluation Criteria In Solid Tumors (RECIST 1.1) | BOR was defined as a complete response (CR) or partial response (PR) confirmed per Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. Patients who never received study treatment and treated patients without any post-baseline tumor assessments were considered as non-responders. CR: Disappearance of all target lesions, all non-target lesions, and no new lesion. Any pathological lymph nodes must have had reduction in the short axis to <10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, no progression in non-target lesion, and no new lesion. | From first treatment through September 27, 2010 | 
| Duration of Response Assessed by an Independent Review Committee Using Response Evaluation Criteria In Solid Tumors (RECIST 1.1) | Duration of response was defined as the time interval between the date of the earliest qualifying response and the date of disease progression (PD) or death, only for those patients whose best overall response was complete response or partial response. PD: At least 20% increase in the sum of diameters of target lesions compared to Nadir (smallest sum of diameters on-study), unequivocal progression of existing non-target lesions, or presence of new lesion. For patients who were alive without progression, duration of response was censored on the date of the last evaluable tumor assessment. | From first treatment through September 27, 2010 | 
| Time to Response Assessed by an Independent Review Committee Using Response Evaluation Criteria In Solid Tumors (RECIST 1.1) | Time to response was defined as the interval between the date of the first treatment and the date of the first documentation of confirmed complete response (CR) or partial response (PR), whichever occurred first. | From first treatment through September 27, 2010 | 
| Progression Free Survival (PFS) Assessed by an Independent Review Committee Using Response Evaluation Criteria In Solid Tumors (RECIST 1.1) | PFS was defined the time interval between the date of the first treatment and the date of progression or death from any cause, whichever occurred first. Deaths that occurred in patients without disease progression were considered to be a PFS event on the date of death. Patients who neither progressed nor died were censored on the date of the last evaluable tumor assessment prior to the data cutoff date. | From first treatment through September 27, 2010 | 
| Overall Survival | Overall survival was defined as the time from the date of the first treatment to the date of death, regardless of the cause of death. For patients who were alive at the time of analysis, overall survival was censored at the last date the patient was known to be alive prior to the data cutoff date. | From first treatment through September 27, 2010 | 
| Improvement in Physical Symptoms (Improvement in Physician's Assessment of Global Performance Status and Oxygen Saturation Requirements, and Decrease in Total Dose and Frequency of Narcotic Pain Analgesics) During Treatment in Comparison to Baseline | Three parameters were measured. (1) Improvement in the Physician's Assessment of Global Performance status on a 7-point scale (1=very much better to 7=very much worse). (2) Improvement in oxygen saturation requirements, defined as a clinically meaningful increase in oxygen saturation requirement (from a baseline value < 95% to ≥ 95% saturation using a pulse oximeter). (3) A decrease in total dose and frequency of narcotic pain analgesics. The percentage of patients showing improvement (1 and 2) or a decrease (3) are reported. | From first treatment through September 27, 2010 | 
| Maximum Plasma Concentration (Cmax) of Vemurafenib on Day 15 of Cycle 1 | Blood samples for assessing the concentration of vemurafenib in plasma were drawn before the morning dose and at 2, 4, 6, and 8 hours post-dose on Day 15 of Cycle 1. Pharmacokinetic parameters were estimated by non-compartmental analysis (Win Non-Lin). | Pre-dose to 8 hours post-dose on Day 15 of Cycle 1 | 
| Vemurafenib Plasma Level Area Under the Curve From 0 to 8 Hours (AUC0-8h) on Day 15 of Cycle 1 | Blood samples for assessing the concentration of vemurafenib in plasma were drawn before the morning dose and at 2, 4, 6, and 8 hours post-dose on Day 15 of Cycle 1. Pharmacokinetic parameters were estimated by non-compartmental analysis (Win Non-Lin). AUC0-8h was calculated using the linear trapezoidal rule. | Pre-dose to 8 hours post-dose on Day 15 of Cycle 1 | 
| Vemurafenib Plasma Levels at Various Treatment Cycles | Blood samples for assessing the concentration of vemurafenib in plasma were drawn before the morning dose and 4 hours post-dose at Day 1 of Cycles 1, 2, 3, 4, 6, 8, and 10. Each Cycle was 3 weeks in duration. | Pre-dose Cycle 1 Day 1 to 4 hours post-dose Cycle 10 Day 1 | 
| Time-matched Change From Baseline in the Study Specific Corrected QT Interval (QTcP) | Three electrocardiograms (ECG) were obtained pre-dose and 2, 4, 6, and 8 hours post-dose at Days 1 and 15 of Cycle 1 and again pre-dose and 4 hours post-dose at various Cycles throughout treatment. Five baseline triplicate ECGs were obtained before the start of treatment at the same time points used during treatment. Reported is the largest mean time-matched QTcP change from baseline. QTcP=QT/(60/heart rate)^β (β=mean [calculated separately for males and females] log-transformed QT versus log-transformed RR regression slopes using all available pre-treatment (baseline) ECG values. | Pre-dose Cycle 1 Day 1 to pre-dose Cycle 6 Day 1 | 
| Percentage of Patients With Adverse Event | The intensity of adverse events was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events v 4.0 (CTCAE) on a 5-point scale (Grade 1 to 5: Mild, Moderate, Severe, Life-threatening, and Death). | From first treatment through September 27, 2010 |