Back to resultsA Study of Vemurafenib in Previously Treated Patients With Metastatic Melanoma
Primary Purpose
Malignant Melanoma
Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
vemurafenib
Sponsored by
About this trial
This is an interventional treatment trial for Malignant Melanoma
Eligibility Criteria
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
Sites / Locations
- UCLA - School of Medicine; Division of Hematology/Oncology
- University of Colorado
- Moffitt Cancer Center
- Massachusetts General Hospital;Hematology/ Oncology
- Dana Farber Cancer Inst. ; Dept. of Medical Oncology
- Beth Israel Deaconess Medical Center
- New York University Medical Center
- Hospital of the Uni of Pennsylvania; Section of Hematology/Oncology
- University of Pittsburgh
- Vanderbilt-Ingram Cancer Ctr
- Texas Oncology-Baylor Sammons Cancer Center
- University of Texas M.D. Anderson Cancer Center
- Calvary Mater Newcastle; Melanoma Clinic
- Westmead Hospital; Medical Oncology and Pallative Care
- Peter Maccallum Cancer Institute; Medical Oncology
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Single arm
Arm Description
Outcomes
Primary Outcome Measures
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.
Secondary Outcome Measures
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.
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.
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.
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.
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.
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.
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).
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.
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.
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.
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).
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT00949702
Brief Title
A Study of Vemurafenib in Previously Treated Patients With Metastatic Melanoma
Official Title
An Open-label Multicenter Study on the Efficacy of Continuous Oral Dosing of Vemurafenib on Tumour Response in Previously Treated Patients With Metastatic Melanoma
Study Type
Interventional
2. Study Status
Record Verification Date
June 2017
Overall Recruitment Status
Completed
Study Start Date
September 30, 2009 (Actual)
Primary Completion Date
September 27, 2010 (Actual)
Study Completion Date
June 3, 2014 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Hoffmann-La Roche
4. Oversight
5. Study Description
Brief Summary
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Malignant Melanoma
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
132 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Single arm
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
vemurafenib
Intervention Description
960 mg b.i.d. continuous oral dosing
Primary Outcome Measure Information:
Title
Best Overall Response (BOR) Assessed by an Independent Review Committee Using Response Evaluation Criteria In Solid Tumors (RECIST 1.1)
Description
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.
Time Frame
From first treatment through September 27, 2010
Secondary Outcome Measure Information:
Title
Best Overall Response (BOR) Assessed by the Investigator Using Response Evaluation Criteria In Solid Tumors (RECIST 1.1)
Description
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.
Time Frame
From first treatment through September 27, 2010
Title
Duration of Response Assessed by an Independent Review Committee Using Response Evaluation Criteria In Solid Tumors (RECIST 1.1)
Description
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.
Time Frame
From first treatment through September 27, 2010
Title
Time to Response Assessed by an Independent Review Committee Using Response Evaluation Criteria In Solid Tumors (RECIST 1.1)
Description
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.
Time Frame
From first treatment through September 27, 2010
Title
Progression Free Survival (PFS) Assessed by an Independent Review Committee Using Response Evaluation Criteria In Solid Tumors (RECIST 1.1)
Description
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.
Time Frame
From first treatment through September 27, 2010
Title
Overall Survival
Description
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.
Time Frame
From first treatment through September 27, 2010
Title
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
Description
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.
Time Frame
From first treatment through September 27, 2010
Title
Maximum Plasma Concentration (Cmax) of Vemurafenib on Day 15 of Cycle 1
Description
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).
Time Frame
Pre-dose to 8 hours post-dose on Day 15 of Cycle 1
Title
Vemurafenib Plasma Level Area Under the Curve From 0 to 8 Hours (AUC0-8h) on Day 15 of Cycle 1
Description
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.
Time Frame
Pre-dose to 8 hours post-dose on Day 15 of Cycle 1
Title
Vemurafenib Plasma Levels at Various Treatment Cycles
Description
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.
Time Frame
Pre-dose Cycle 1 Day 1 to 4 hours post-dose Cycle 10 Day 1
Title
Time-matched Change From Baseline in the Study Specific Corrected QT Interval (QTcP)
Description
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.
Time Frame
Pre-dose Cycle 1 Day 1 to pre-dose Cycle 6 Day 1
Title
Percentage of Patients With Adverse Event
Description
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).
Time Frame
From first treatment through September 27, 2010
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Clinical Trials
Organizational Affiliation
Hoffmann-La Roche
Official's Role
Study Director
Facility Information:
Facility Name
UCLA - School of Medicine; Division of Hematology/Oncology
City
Los Angeles
State/Province
California
ZIP/Postal Code
90095-6984
Country
United States
Facility Name
University of Colorado
City
Denver
State/Province
Colorado
ZIP/Postal Code
80262
Country
United States
Facility Name
Moffitt Cancer Center
City
Tampa
State/Province
Florida
ZIP/Postal Code
33612
Country
United States
Facility Name
Massachusetts General Hospital;Hematology/ Oncology
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States
Facility Name
Dana Farber Cancer Inst. ; Dept. of Medical Oncology
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Facility Name
Beth Israel Deaconess Medical Center
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02215
Country
United States
Facility Name
New York University Medical Center
City
New York
State/Province
New York
ZIP/Postal Code
10036
Country
United States
Facility Name
Hospital of the Uni of Pennsylvania; Section of Hematology/Oncology
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104-4283
Country
United States
Facility Name
University of Pittsburgh
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15213
Country
United States
Facility Name
Vanderbilt-Ingram Cancer Ctr
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37232
Country
United States
Facility Name
Texas Oncology-Baylor Sammons Cancer Center
City
Dallas
State/Province
Texas
ZIP/Postal Code
75246
Country
United States
Facility Name
University of Texas M.D. Anderson Cancer Center
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
Calvary Mater Newcastle; Melanoma Clinic
City
Newcastle
State/Province
New South Wales
ZIP/Postal Code
2298
Country
Australia
Facility Name
Westmead Hospital; Medical Oncology and Pallative Care
City
Westmead
State/Province
New South Wales
ZIP/Postal Code
2145
Country
Australia
Facility Name
Peter Maccallum Cancer Institute; Medical Oncology
City
Melbourne
State/Province
Victoria
ZIP/Postal Code
3000
Country
Australia
12. IPD Sharing Statement
Citations:
PubMed Identifier
32746839
Citation
Ascierto PA, Ribas A, Larkin J, McArthur GA, Lewis KD, Hauschild A, Flaherty KT, McKenna E, Zhu Q, Mun Y, Dreno B. Impact of initial treatment and prognostic factors on postprogression survival in BRAF-mutated metastatic melanoma treated with dacarbazine or vemurafenib +/- cobimetinib: a pooled analysis of four clinical trials. J Transl Med. 2020 Aug 3;18(1):294. doi: 10.1186/s12967-020-02458-x.
Results Reference
derived
PubMed Identifier
24983357
Citation
Frederick DT, Salas Fragomeni RA, Schalck A, Ferreiro-Neira I, Hoff T, Cooper ZA, Haq R, Panka DJ, Kwong LN, Davies MA, Cusack JC, Flaherty KT, Fisher DE, Mier JW, Wargo JA, Sullivan RJ. Clinical profiling of BCL-2 family members in the setting of BRAF inhibition offers a rationale for targeting de novo resistance using BH3 mimetics. PLoS One. 2014 Jul 1;9(7):e101286. doi: 10.1371/journal.pone.0101286. eCollection 2014.
Results Reference
derived
PubMed Identifier
23457002
Citation
Lacouture ME, Duvic M, Hauschild A, Prieto VG, Robert C, Schadendorf D, Kim CC, McCormack CJ, Myskowski PL, Spleiss O, Trunzer K, Su F, Nelson B, Nolop KB, Grippo JF, Lee RJ, Klimek MJ, Troy JL, Joe AK. Analysis of dermatologic events in vemurafenib-treated patients with melanoma. Oncologist. 2013;18(3):314-22. doi: 10.1634/theoncologist.2012-0333. Epub 2013 Mar 1.
Results Reference
derived
PubMed Identifier
22356324
Citation
Sosman JA, Kim KB, Schuchter L, Gonzalez R, Pavlick AC, Weber JS, McArthur GA, Hutson TE, Moschos SJ, Flaherty KT, Hersey P, Kefford R, Lawrence D, Puzanov I, Lewis KD, Amaravadi RK, Chmielowski B, Lawrence HJ, Shyr Y, Ye F, Li J, Nolop KB, Lee RJ, Joe AK, Ribas A. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med. 2012 Feb 23;366(8):707-14. doi: 10.1056/NEJMoa1112302.
Results Reference
derived
PubMed Identifier
22256804
Citation
Su F, Viros A, Milagre C, Trunzer K, Bollag G, Spleiss O, Reis-Filho JS, Kong X, Koya RC, Flaherty KT, Chapman PB, Kim MJ, Hayward R, Martin M, Yang H, Wang Q, Hilton H, Hang JS, Noe J, Lambros M, Geyer F, Dhomen N, Niculescu-Duvaz I, Zambon A, Niculescu-Duvaz D, Preece N, Robert L, Otte NJ, Mok S, Kee D, Ma Y, Zhang C, Habets G, Burton EA, Wong B, Nguyen H, Kockx M, Andries L, Lestini B, Nolop KB, Lee RJ, Joe AK, Troy JL, Gonzalez R, Hutson TE, Puzanov I, Chmielowski B, Springer CJ, McArthur GA, Sosman JA, Lo RS, Ribas A, Marais R. RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N Engl J Med. 2012 Jan 19;366(3):207-15. doi: 10.1056/NEJMoa1105358.
Results Reference
derived
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A Study of Vemurafenib in Previously Treated Patients With Metastatic Melanoma
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