Malignant Melanoma
Conditions
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.
Interventions
DRUGvemurafenib
960 mg b.i.d. continuous oral dosing
Sponsors
Hoffmann-La Roche
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Best Overall Response (BOR) Assessed by an Independent Review Committee Using Response Evaluation Criteria In Solid Tumors (RECIST 1.1) | From first treatment through September 27, 2010 | 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
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response Assessed by an Independent Review Committee Using Response Evaluation Criteria In Solid Tumors (RECIST 1.1) | From first treatment through September 27, 2010 | 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) | From first treatment through September 27, 2010 | 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) | From first treatment through September 27, 2010 | 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 | From first treatment through September 27, 2010 | 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 | From first treatment through September 27, 2010 | 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. |
| Best Overall Response (BOR) Assessed by the Investigator Using Response Evaluation Criteria In Solid Tumors (RECIST 1.1) | From first treatment through September 27, 2010 | 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. |
| Vemurafenib Plasma Level Area Under the Curve From 0 to 8 Hours (AUC0-8h) on Day 15 of Cycle 1 | Pre-dose to 8 hours post-dose 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 | Pre-dose Cycle 1 Day 1 to 4 hours post-dose Cycle 10 Day 1 | 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) | Pre-dose Cycle 1 Day 1 to pre-dose Cycle 6 Day 1 | 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 | From first treatment through September 27, 2010 | 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). |
| Maximum Plasma Concentration (Cmax) of Vemurafenib on Day 15 of Cycle 1 | Pre-dose to 8 hours post-dose 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). |
Countries
Australia, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Vemurafenib 960 mg Patients received vemurafenib 960 mg (four 240 mg tablets) bid (bis in die, twice daily) orally until disease progression, unacceptable toxicity, withdrawal of consent, or another reason as determined by the investigator. | 132 |
| Total | 132 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 40 |
| Overall Study | Disease progression | 7 |
| Overall Study | Withdrawal of consent | 1 |
Baseline characteristics
| Characteristic | Vemurafenib 960 mg |
|---|---|
| Age, Continuous | 50.3 years STANDARD_DEVIATION 14.7 |
| Sex: Female, Male Female | 51 Participants |
| Sex: Female, Male Male | 81 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 131 / 132 |
| serious Total, serious adverse events | 67 / 132 |
Outcome results
Primary
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.
Time frame: From first treatment through September 27, 2010
Population: Intent-to-treat population: All enrolled patients who received at least one, or a partial dose of vemurafenib.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vemurafenib 960 mg | Best Overall Response (BOR) Assessed by an Independent Review Committee Using Response Evaluation Criteria In Solid Tumors (RECIST 1.1) | 52.3 Percentage of participants |
Secondary
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.
Time frame: From first treatment through September 27, 2010
Population: Intent-to-treat population: All enrolled patients who received at least one, or a partial dose of vemurafenib.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vemurafenib 960 mg | Best Overall Response (BOR) Assessed by the Investigator Using Response Evaluation Criteria In Solid Tumors (RECIST 1.1) | 54.5 Percentage of participants |
Secondary
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 frame: From first treatment through September 27, 2010
Population: Intent-to-treat population: All enrolled patients who received at least one, or a partial dose of vemurafenib.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vemurafenib 960 mg | Duration of Response Assessed by an Independent Review Committee Using Response Evaluation Criteria In Solid Tumors (RECIST 1.1) | 6.5 Months |
Secondary
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.
Time frame: From first treatment through September 27, 2010
Population: Intent-to-treat population: All enrolled patients who received at least one, or a partial dose of vemurafenib.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Vemurafenib 960 mg | 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 | Improvement in performance status | 83.3 Percentage of participants |
| Vemurafenib 960 mg | 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 | Improvement in oxygen saturation requirement | 4.5 Percentage of participants |
| Vemurafenib 960 mg | 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 | Decrease in use of narcotic pain analgesics | 3.0 Percentage of participants |
Secondary
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).
Time frame: Pre-dose to 8 hours post-dose on Day 15 of Cycle 1
Population: Pharmacokinetic population: All patients who received all doses of vemurafenib without dose reduction up to and including Day 15 and who provided at least one of the pharmacokinetic assessments up to and including 8 hours after the first daily dose on Day 15.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vemurafenib 960 mg | Maximum Plasma Concentration (Cmax) of Vemurafenib on Day 15 of Cycle 1 | 56.73 μg/mL | Standard Deviation 21.76 |
Secondary
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.
Time frame: From first treatment through September 27, 2010
Population: Intent-to-treat population: All enrolled patients who received at least one, or a partial dose of vemurafenib.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vemurafenib 960 mg | Overall Survival | NA Months |
Secondary
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).
Time frame: From first treatment through September 27, 2010
Population: Intent-to-treat population: All enrolled patients who received at least one, or a partial dose of vemurafenib.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vemurafenib 960 mg | Percentage of Patients With Adverse Event | 100.0 Percentage of participants |
Secondary
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.
Time frame: From first treatment through September 27, 2010
Population: Intent-to-treat population: All enrolled patients who received at least one, or a partial dose of vemurafenib.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vemurafenib 960 mg | Progression Free Survival (PFS) Assessed by an Independent Review Committee Using Response Evaluation Criteria In Solid Tumors (RECIST 1.1) | 6.1 Months |
Secondary
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.
Time frame: Pre-dose Cycle 1 Day 1 to pre-dose Cycle 6 Day 1
Population: Electrocardiogram (ECG) evaluable population: All treated patients who had a baseline ECG and at least one ECG during treatment.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Vemurafenib 960 mg | Time-matched Change From Baseline in the Study Specific Corrected QT Interval (QTcP) | Cycle 1 Day 15 at 2 hours post-dose, n=109 | 12.8 ms |
| Vemurafenib 960 mg | Time-matched Change From Baseline in the Study Specific Corrected QT Interval (QTcP) | Cycle 6 Day 1 at pre-dose, n=85 | 15.1 ms |
Secondary
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.
Time frame: From first treatment through September 27, 2010
Population: Intent-to-treat population: All enrolled patients who received at least one, or a partial dose of vemurafenib.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vemurafenib 960 mg | Time to Response Assessed by an Independent Review Committee Using Response Evaluation Criteria In Solid Tumors (RECIST 1.1) | 1.38 Months |
Secondary
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.
Time frame: Pre-dose to 8 hours post-dose on Day 15 of Cycle 1
Population: Pharmacokinetic population: All patients who received all doses of vemurafenib without dose reduction up to and including Day 15 and who provided at least one of the pharmacokinetic assessments up to and including 8 hours after the first daily dose on Day 15.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vemurafenib 960 mg | Vemurafenib Plasma Level Area Under the Curve From 0 to 8 Hours (AUC0-8h) on Day 15 of Cycle 1 | 380.16 μg⋅h/mL | Standard Deviation 143.56 |
Secondary
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 frame: Pre-dose Cycle 1 Day 1 to 4 hours post-dose Cycle 10 Day 1
Population: Pharmacokinetic population: All patients who received all doses of vemurafenib without dose reduction up to and including Day 15 and who provided at least one of the pharmacokinetic assessments up to and including 8 hours after the first daily dose on Day 15.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Vemurafenib 960 mg | Vemurafenib Plasma Levels at Various Treatment Cycles | Pre-dose Cycle 1 Day 15, n=108 | 47.55 μg/mL | Standard Deviation 23.14 |
| Vemurafenib 960 mg | Vemurafenib Plasma Levels at Various Treatment Cycles | Pre-dose Cycle 2 Day 1, n=122 | 41.12 μg/mL | Standard Deviation 23.39 |
| Vemurafenib 960 mg | Vemurafenib Plasma Levels at Various Treatment Cycles | Pre-dose Cycle 3 Day 1, n=109 | 45.20 μg/mL | Standard Deviation 21.33 |
| Vemurafenib 960 mg | Vemurafenib Plasma Levels at Various Treatment Cycles | Pre-dose Cycle 4 Day 1, n=109 | 50.31 μg/mL | Standard Deviation 19.52 |
| Vemurafenib 960 mg | Vemurafenib Plasma Levels at Various Treatment Cycles | Pre-dose Cycle 6 Day 1, n=96 | 50.38 μg/mL | Standard Deviation 19.54 |
| Vemurafenib 960 mg | Vemurafenib Plasma Levels at Various Treatment Cycles | Pre-dose Cycle 8 Day 1, n=71 | 50.42 μg/mL | Standard Deviation 22.06 |
| Vemurafenib 960 mg | Vemurafenib Plasma Levels at Various Treatment Cycles | Pre-dose Cycle 10 Day 1, n=50 | 50.78 μg/mL | Standard Deviation 20.19 |
| Vemurafenib 960 mg | Vemurafenib Plasma Levels at Various Treatment Cycles | 4 hours post-dose Cycle 2 Day 22, n=93 | 48.38 μg/mL | Standard Deviation 20 |
| Vemurafenib 960 mg | Vemurafenib Plasma Levels at Various Treatment Cycles | 4 hours post-dose Cycle 3 Day 43, n=78 | 50.79 μg/mL | Standard Deviation 19.2 |
| Vemurafenib 960 mg | Vemurafenib Plasma Levels at Various Treatment Cycles | 4 hours post-dose Cycle 4 Day 1, n=75 | 55.76 μg/mL | Standard Deviation 20.57 |
| Vemurafenib 960 mg | Vemurafenib Plasma Levels at Various Treatment Cycles | 4 hours post-dose Cycle 6 Day 1, n=58 | 58.92 μg/mL | Standard Deviation 20.12 |
| Vemurafenib 960 mg | Vemurafenib Plasma Levels at Various Treatment Cycles | 4 hours post-dose Cycle 8 Day 1, n=43 | 58.95 μg/mL | Standard Deviation 20.98 |
| Vemurafenib 960 mg | Vemurafenib Plasma Levels at Various Treatment Cycles | 4 hours post-dose Cycle 10 Day 1, n=27 | 63.27 μg/mL | Standard Deviation 21.52 |