Melanoma
Conditions
Brief summary
Treatment of subjects who have metastatic melanoma that expresses an activated mutant form of the BRAF oncogene (V600E) with a combination of the specific BRAF inhibitor, Vemurafenib, and the Cytotoxic T Lymphocyte Antigen 4 (CTLA-4) inhibitor mAb Ipilimumab will be safe and feasible and will show preliminary evidence of anti-tumor efficacy and survival in comparison to historical results following treatment with either agent alone.
Interventions
DRUGIpilimumab (BMS-734016)
Injection, intravenous (i.v.), cohort 1: 3 mg/kg, Escalate to cohort 2: 10 mg/kg, Escalate to cohort 3: at Recommended Phase 2 Dose (RP2D), De-escalate cohort 1A: 3 mg/kg, De-escalate cohort -1B: 10 mg/kg, (every three week) Q3wk, upto 2 yrs
DRUGVemurafenib
tablets, oral, cohort 1: 960 mg Twice daily (BID) x 28 days after date, cohort 2: 960 mg BID x 28 days after date, cohort 3: at Recommended Phase 2 Dose (RP2D) x 14 days after date, De-escalate cohort 1A: 720 mg BID x 28 days after date, De-escalate cohort -1B: 720 mg BID x 28 days after date , Up to 2 yrs
Sponsors
Roche-Genentech
Bristol-Myers Squibb
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com. Inclusion Criteria: * Metastatic melanoma with activating V600 BRAF mutation * Measurable Tumor * Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0-1
Exclusion criteria
* Autoimmune disease * Active Brain Metastasis (must be stable after radiation for at least one month) * Prior therapy with immune stimulating agents
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| During the Lead In Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Vemurafenib Alone | From first vemurafenib dose to day prior to first ipilimumab dose (28 days); Patients who never progressed from Lead-in to combination treatment (720 mg Alone): first dose to last dose + 90 days (approximately 2 years) | AEs graded using National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0. AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Grade (Gr) 1=Mild, Gr 2=Moderate, Gr 3=Severe, Gr 4= Potentially Life-threatening or disabling, Gr 5=Death. Related=relationship to study drug reported as certain, probable, possible, or missing. Immune-related AEs (irAEs) characterized by potential association with inflammation and considered by investigator as drug related. Lead In Period: between the first vemurafenib dose and the day prior to the first ipilimumab dose. |
| During the Combination Treatment Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Concurrent Ipilimumab and Vemurafenib | Combination drugs: Day 1 to last dose of drug + 90 days (approximately 2 years) | AEs graded using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0. AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Grade (Gr) 1=Mild, Gr 2=Moderate, Gr 3=Severe, Gr 4= Potentially Life-threatening or disabling, Gr 5=Death. Related=relationship to study drug reported as certain, probable, possible, or missing. AEs: onset on or after ipilimumab start and within 90 days of last dose. Immune-related AEs (irAEs) characterized by potential association with inflammation and considered by investigator as drug related. Day 1=first dose of ipilimumab. |
| Number of Participants With Hepatic Dose Limiting Toxicities (DLT) in Participants Treated With Concurrent Ipilimumab and Vemurafenib | Day 1 to last dose of drug + 90 (approximately 2 years) | DLT defined as a \>= Grade 3 drug-related AE during induction with ipilimumab in combination with vemurafenib excluding: Grade 3 AE of tumor flare (defined as local pain, irritation, or rash localized at sites of known or suspected tumor); Grade 3 cutaneous squamous cell carcinoma; Grade 3 photosensitivity that resolved to a Grade 1 or baseline within 15 days; Grade 3 immune-mediated events of the skin (rash, pruritis) or endocrine systems (hypothyroidism, hyperthyroidism, hypopituitarism, adrenal insufficiency, hypogonadism and cushingoid) that resolved to a Grade 1 or baseline within 28 days; a transient (resolving within 6 hours of onset) Grade 3 infusion-related AE. Hepatic=elevated aspartate aminotransferase and alanine aminotransferase. Maximum tolerable dose (MTD) was defined as the maximum dose of combination treatment that could be given to 6 subjects such that no more than 2 subjects experience DLT. Day 1=first day of concurrent therapy with ipilimumab and vemurafenib. |
Countries
United States
Participant flow
Recruitment details
Study started Nov 2011; Primary Endpoint April 2013; Completed safety follow-up December 2013. Dose-limiting toxicities observed early in dose escalation (Phase I) part of the study. The combination of drugs was not well tolerated, and a maximum tolerable dose was not attained so the study was closed to enrollment and Phase II part was not started.
Pre-assignment details
18 participants enrolled; 12 treated with study drug and 6 participants were not treated because they no longer met study criteria. Two of the 12 only received vemurafenib while the other 10 received the combination of vemurafenib and ipilimumab.
Participants by arm
| Arm | Count |
|---|---|
| 3 mg/kg Ipilimumab + 960 mg Vemurafenib Lead In Period: 28 Days of 960 mg vemurafenib orally twice daily (starting Day -27 or -13).
Combination Treatment (Induction of ipilimumab) Period: 3 milligrams per kilogram body weight (mg/kg) ipilimumab intravenously once every 3 weeks for 4 weeks (Week 1, Week 4, Week 7, Week 10) starting on Day 1, plus 960 mg vemurafenib orally twice daily throughout combination treatment. | 6 |
| 3 mg/kg Ipilimumab + 720 mg Vemurafenib Lead In Period: 28 Days of 720 mg vemurafenib orally twice daily (starting Day -27 or -13).
Combination Treatment (Induction of ipilimumab) Period: 3 milligrams per kilogram body weight (mg/kg) ipilimumab intravenously once every 3 weeks for 4 weeks (Week 1, Week 4, Week 7, Week 10) starting on Day 1 plus 720 mg vemurafenib orally twice daily throughout combination treatment. | 4 |
| 720 mg Vemurafenib These participants were receiving 720 mg vemurafenib in the Lead in Period prior to starting ipilimumab but after the dose limiting toxicities (DLTs) were identified, ipilimumab was not started. Due to disease stabilization, they continued on 720 mg vemurafenib alone orally twice daily. | 2 |
| Total | 12 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Combination Treatment (or Intended) | Adverse Event | 1 | 0 | 0 |
| Combination Treatment (or Intended) | Disease Progression | 3 | 1 | 1 |
| Combination Treatment (or Intended) | Dose-limiting toxicity | 0 | 1 | 0 |
| Combination Treatment (or Intended) | Drug Toxicity | 0 | 1 | 0 |
| Combination Treatment (or Intended) | Withdrawal by Subject | 2 | 1 | 1 |
Baseline characteristics
| Characteristic | 3 mg/kg Ipilimumab + 960 mg Vemurafenib | 3 mg/kg Ipilimumab + 720 mg Vemurafenib | 720 mg Vemurafenib | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 3 Participants | 0 Participants | 1 Participants | 4 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 4 Participants | 1 Participants | 8 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 5 Participants | 4 Participants | 2 Participants | 11 Participants |
| Region of Enrollment United States | 6 participants | 4 participants | 2 participants | 12 participants |
| Sex: Female, Male Female | 3 Participants | 2 Participants | 1 Participants | 6 Participants |
| Sex: Female, Male Male | 3 Participants | 2 Participants | 1 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 6 / 6 | 4 / 4 | 2 / 2 | 6 / 6 | 4 / 4 |
| serious Total, serious adverse events | 2 / 6 | 1 / 4 | 1 / 2 | 5 / 6 | 2 / 4 |
Outcome results
Primary
During the Combination Treatment Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Concurrent Ipilimumab and Vemurafenib
AEs graded using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0. AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Grade (Gr) 1=Mild, Gr 2=Moderate, Gr 3=Severe, Gr 4= Potentially Life-threatening or disabling, Gr 5=Death. Related=relationship to study drug reported as certain, probable, possible, or missing. AEs: onset on or after ipilimumab start and within 90 days of last dose. Immune-related AEs (irAEs) characterized by potential association with inflammation and considered by investigator as drug related. Day 1=first dose of ipilimumab.
Time frame: Combination drugs: Day 1 to last dose of drug + 90 days (approximately 2 years)
Population: All participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 960 mg Vemurafenib Lead in Period | During the Combination Treatment Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Concurrent Ipilimumab and Vemurafenib | Deaths | 4 participants |
| 960 mg Vemurafenib Lead in Period | During the Combination Treatment Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Concurrent Ipilimumab and Vemurafenib | Deaths due to disease progression | 4 participants |
| 960 mg Vemurafenib Lead in Period | During the Combination Treatment Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Concurrent Ipilimumab and Vemurafenib | Grade 3 SAEs | 3 participants |
| 960 mg Vemurafenib Lead in Period | During the Combination Treatment Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Concurrent Ipilimumab and Vemurafenib | Grade 4 SAEs | 0 participants |
| 960 mg Vemurafenib Lead in Period | During the Combination Treatment Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Concurrent Ipilimumab and Vemurafenib | Grade 5 SAEs | 2 participants |
| 960 mg Vemurafenib Lead in Period | During the Combination Treatment Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Concurrent Ipilimumab and Vemurafenib | Drug Related Grade 3 SAEs | 5 participants |
| 960 mg Vemurafenib Lead in Period | During the Combination Treatment Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Concurrent Ipilimumab and Vemurafenib | Drug Related Grade 4 SAEs | 0 participants |
| 960 mg Vemurafenib Lead in Period | During the Combination Treatment Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Concurrent Ipilimumab and Vemurafenib | AEs Leading to Study Drug Discontinuation | 2 participants |
| 960 mg Vemurafenib Lead in Period | During the Combination Treatment Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Concurrent Ipilimumab and Vemurafenib | Grade 1 irAEs | 1 participants |
| 960 mg Vemurafenib Lead in Period | During the Combination Treatment Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Concurrent Ipilimumab and Vemurafenib | Grade 2 irAEs | 1 participants |
| 960 mg Vemurafenib Lead in Period | During the Combination Treatment Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Concurrent Ipilimumab and Vemurafenib | Grade 3 irAEs | 4 participants |
| 960 mg Vemurafenib Lead in Period | During the Combination Treatment Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Concurrent Ipilimumab and Vemurafenib | Grade 4 irAEs | 0 participants |
| 960 mg Vemurafenib Lead in Period | During the Combination Treatment Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Concurrent Ipilimumab and Vemurafenib | Grade 1 AEs | 0 participants |
| 960 mg Vemurafenib Lead in Period | During the Combination Treatment Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Concurrent Ipilimumab and Vemurafenib | Grade 2 AEs | 1 participants |
| 960 mg Vemurafenib Lead in Period | During the Combination Treatment Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Concurrent Ipilimumab and Vemurafenib | Grade 3 AEs | 3 participants |
| 960 mg Vemurafenib Lead in Period | During the Combination Treatment Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Concurrent Ipilimumab and Vemurafenib | Grade 4 AEs | 0 participants |
| 960 mg Vemurafenib Lead in Period | During the Combination Treatment Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Concurrent Ipilimumab and Vemurafenib | Grade 5 AEs | 2 participants |
| 960 mg Vemurafenib Lead in Period | During the Combination Treatment Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Concurrent Ipilimumab and Vemurafenib | Drug Related Grade 1 AEs | 0 participants |
| 960 mg Vemurafenib Lead in Period | During the Combination Treatment Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Concurrent Ipilimumab and Vemurafenib | Drug Related Grade 2 AEs | 1 participants |
| 960 mg Vemurafenib Lead in Period | During the Combination Treatment Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Concurrent Ipilimumab and Vemurafenib | Drug Related Grade 3 AEs | 5 participants |
| 960 mg Vemurafenib Lead in Period | During the Combination Treatment Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Concurrent Ipilimumab and Vemurafenib | Drug Related Grade 4 AEs | 0 participants |
| 720 mg Vemurafenib Lead in Period | During the Combination Treatment Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Concurrent Ipilimumab and Vemurafenib | Grade 3 irAEs | 2 participants |
| 720 mg Vemurafenib Lead in Period | During the Combination Treatment Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Concurrent Ipilimumab and Vemurafenib | Deaths | 1 participants |
| 720 mg Vemurafenib Lead in Period | During the Combination Treatment Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Concurrent Ipilimumab and Vemurafenib | Drug Related Grade 2 AEs | 2 participants |
| 720 mg Vemurafenib Lead in Period | During the Combination Treatment Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Concurrent Ipilimumab and Vemurafenib | Deaths due to disease progression | 1 participants |
| 720 mg Vemurafenib Lead in Period | During the Combination Treatment Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Concurrent Ipilimumab and Vemurafenib | Grade 4 irAEs | 0 participants |
| 720 mg Vemurafenib Lead in Period | During the Combination Treatment Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Concurrent Ipilimumab and Vemurafenib | Grade 3 SAEs | 2 participants |
| 720 mg Vemurafenib Lead in Period | During the Combination Treatment Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Concurrent Ipilimumab and Vemurafenib | Grade 5 AEs | 0 participants |
| 720 mg Vemurafenib Lead in Period | During the Combination Treatment Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Concurrent Ipilimumab and Vemurafenib | Grade 4 SAEs | 0 participants |
| 720 mg Vemurafenib Lead in Period | During the Combination Treatment Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Concurrent Ipilimumab and Vemurafenib | Grade 1 AEs | 0 participants |
| 720 mg Vemurafenib Lead in Period | During the Combination Treatment Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Concurrent Ipilimumab and Vemurafenib | Grade 5 SAEs | 0 participants |
| 720 mg Vemurafenib Lead in Period | During the Combination Treatment Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Concurrent Ipilimumab and Vemurafenib | Drug Related Grade 4 AEs | 0 participants |
| 720 mg Vemurafenib Lead in Period | During the Combination Treatment Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Concurrent Ipilimumab and Vemurafenib | Drug Related Grade 3 SAEs | 2 participants |
| 720 mg Vemurafenib Lead in Period | During the Combination Treatment Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Concurrent Ipilimumab and Vemurafenib | Grade 2 AEs | 2 participants |
| 720 mg Vemurafenib Lead in Period | During the Combination Treatment Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Concurrent Ipilimumab and Vemurafenib | Drug Related Grade 4 SAEs | 0 participants |
| 720 mg Vemurafenib Lead in Period | During the Combination Treatment Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Concurrent Ipilimumab and Vemurafenib | Drug Related Grade 1 AEs | 0 participants |
| 720 mg Vemurafenib Lead in Period | During the Combination Treatment Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Concurrent Ipilimumab and Vemurafenib | AEs Leading to Study Drug Discontinuation | 1 participants |
| 720 mg Vemurafenib Lead in Period | During the Combination Treatment Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Concurrent Ipilimumab and Vemurafenib | Grade 3 AEs | 2 participants |
| 720 mg Vemurafenib Lead in Period | During the Combination Treatment Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Concurrent Ipilimumab and Vemurafenib | Grade 1 irAEs | 0 participants |
| 720 mg Vemurafenib Lead in Period | During the Combination Treatment Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Concurrent Ipilimumab and Vemurafenib | Drug Related Grade 3 AEs | 2 participants |
| 720 mg Vemurafenib Lead in Period | During the Combination Treatment Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Concurrent Ipilimumab and Vemurafenib | Grade 2 irAEs | 2 participants |
| 720 mg Vemurafenib Lead in Period | During the Combination Treatment Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Concurrent Ipilimumab and Vemurafenib | Grade 4 AEs | 0 participants |
Primary
During the Lead In Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Vemurafenib Alone
AEs graded using National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0. AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Grade (Gr) 1=Mild, Gr 2=Moderate, Gr 3=Severe, Gr 4= Potentially Life-threatening or disabling, Gr 5=Death. Related=relationship to study drug reported as certain, probable, possible, or missing. Immune-related AEs (irAEs) characterized by potential association with inflammation and considered by investigator as drug related. Lead In Period: between the first vemurafenib dose and the day prior to the first ipilimumab dose.
Time frame: From first vemurafenib dose to day prior to first ipilimumab dose (28 days); Patients who never progressed from Lead-in to combination treatment (720 mg Alone): first dose to last dose + 90 days (approximately 2 years)
Population: All participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 960 mg Vemurafenib Lead in Period | During the Lead In Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Vemurafenib Alone | Drug Related Grade 3 SAEs | 2 participants |
| 960 mg Vemurafenib Lead in Period | During the Lead In Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Vemurafenib Alone | AEs Leading to Study Drug Discontinuation | 0 participants |
| 960 mg Vemurafenib Lead in Period | During the Lead In Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Vemurafenib Alone | Drug Related Grade 4 AEs | 0 participants |
| 960 mg Vemurafenib Lead in Period | During the Lead In Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Vemurafenib Alone | Grade 3 AEs | 4 participants |
| 960 mg Vemurafenib Lead in Period | During the Lead In Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Vemurafenib Alone | Grade 1 irAEs | 2 participants |
| 960 mg Vemurafenib Lead in Period | During the Lead In Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Vemurafenib Alone | Drug Related Grade 3 AEs | 3 participants |
| 960 mg Vemurafenib Lead in Period | During the Lead In Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Vemurafenib Alone | Grade 2 AEs | 2 participants |
| 960 mg Vemurafenib Lead in Period | During the Lead In Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Vemurafenib Alone | Drug Related Grade 4 SAEs | 0 participants |
| 960 mg Vemurafenib Lead in Period | During the Lead In Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Vemurafenib Alone | Grade 1 AEs | 0 participants |
| 960 mg Vemurafenib Lead in Period | During the Lead In Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Vemurafenib Alone | Grade 3 irAEs | 2 participants |
| 960 mg Vemurafenib Lead in Period | During the Lead In Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Vemurafenib Alone | Grade 3 SAEs | 2 participants |
| 960 mg Vemurafenib Lead in Period | During the Lead In Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Vemurafenib Alone | Grade 4 irAEs | 0 participants |
| 960 mg Vemurafenib Lead in Period | During the Lead In Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Vemurafenib Alone | Deaths | 0 participants |
| 960 mg Vemurafenib Lead in Period | During the Lead In Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Vemurafenib Alone | Grade 2 irAEs | 1 participants |
| 960 mg Vemurafenib Lead in Period | During the Lead In Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Vemurafenib Alone | Drug Related Grade 2 AEs | 2 participants |
| 960 mg Vemurafenib Lead in Period | During the Lead In Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Vemurafenib Alone | Drug Related Grade 1 AEs | 1 participants |
| 960 mg Vemurafenib Lead in Period | During the Lead In Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Vemurafenib Alone | Deaths due to disease progression | 0 participants |
| 960 mg Vemurafenib Lead in Period | During the Lead In Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Vemurafenib Alone | Grade 5 AEs | 0 participants |
| 960 mg Vemurafenib Lead in Period | During the Lead In Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Vemurafenib Alone | Grade 5 SAEs | 0 participants |
| 960 mg Vemurafenib Lead in Period | During the Lead In Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Vemurafenib Alone | Grade 4 SAEs | 0 participants |
| 960 mg Vemurafenib Lead in Period | During the Lead In Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Vemurafenib Alone | Grade 4 AEs | 0 participants |
| 720 mg Vemurafenib Lead in Period | During the Lead In Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Vemurafenib Alone | Drug Related Grade 2 AEs | 2 participants |
| 720 mg Vemurafenib Lead in Period | During the Lead In Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Vemurafenib Alone | Deaths | 0 participants |
| 720 mg Vemurafenib Lead in Period | During the Lead In Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Vemurafenib Alone | Deaths due to disease progression | 0 participants |
| 720 mg Vemurafenib Lead in Period | During the Lead In Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Vemurafenib Alone | Grade 3 SAEs | 1 participants |
| 720 mg Vemurafenib Lead in Period | During the Lead In Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Vemurafenib Alone | Drug Related Grade 3 SAEs | 1 participants |
| 720 mg Vemurafenib Lead in Period | During the Lead In Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Vemurafenib Alone | Drug Related Grade 4 SAEs | 0 participants |
| 720 mg Vemurafenib Lead in Period | During the Lead In Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Vemurafenib Alone | Grade 4 SAEs | 0 participants |
| 720 mg Vemurafenib Lead in Period | During the Lead In Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Vemurafenib Alone | Grade 5 SAEs | 0 participants |
| 720 mg Vemurafenib Lead in Period | During the Lead In Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Vemurafenib Alone | AEs Leading to Study Drug Discontinuation | 0 participants |
| 720 mg Vemurafenib Lead in Period | During the Lead In Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Vemurafenib Alone | Grade 1 irAEs | 3 participants |
| 720 mg Vemurafenib Lead in Period | During the Lead In Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Vemurafenib Alone | Grade 2 irAEs | 0 participants |
| 720 mg Vemurafenib Lead in Period | During the Lead In Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Vemurafenib Alone | Grade 3 irAEs | 0 participants |
| 720 mg Vemurafenib Lead in Period | During the Lead In Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Vemurafenib Alone | Grade 4 irAEs | 0 participants |
| 720 mg Vemurafenib Lead in Period | During the Lead In Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Vemurafenib Alone | Grade 1 AEs | 1 participants |
| 720 mg Vemurafenib Lead in Period | During the Lead In Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Vemurafenib Alone | Grade 2 AEs | 2 participants |
| 720 mg Vemurafenib Lead in Period | During the Lead In Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Vemurafenib Alone | Grade 3 AEs | 1 participants |
| 720 mg Vemurafenib Lead in Period | During the Lead In Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Vemurafenib Alone | Grade 4 AEs | 0 participants |
| 720 mg Vemurafenib Lead in Period | During the Lead In Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Vemurafenib Alone | Grade 5 AEs | 0 participants |
| 720 mg Vemurafenib Lead in Period | During the Lead In Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Vemurafenib Alone | Drug Related Grade 1 AEs | 1 participants |
| 720 mg Vemurafenib Lead in Period | During the Lead In Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Vemurafenib Alone | Drug Related Grade 3 AEs | 1 participants |
| 720 mg Vemurafenib Lead in Period | During the Lead In Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Vemurafenib Alone | Drug Related Grade 4 AEs | 0 participants |
| 720 mg Vemurafenib Alone | During the Lead In Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Vemurafenib Alone | AEs Leading to Study Drug Discontinuation | 0 participants |
| 720 mg Vemurafenib Alone | During the Lead In Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Vemurafenib Alone | Drug Related Grade 3 SAEs | 1 participants |
| 720 mg Vemurafenib Alone | During the Lead In Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Vemurafenib Alone | Grade 3 AEs | 2 participants |
| 720 mg Vemurafenib Alone | During the Lead In Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Vemurafenib Alone | Grade 5 SAEs | 0 participants |
| 720 mg Vemurafenib Alone | During the Lead In Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Vemurafenib Alone | Drug Related Grade 4 AEs | 0 participants |
| 720 mg Vemurafenib Alone | During the Lead In Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Vemurafenib Alone | Grade 4 AEs | 0 participants |
| 720 mg Vemurafenib Alone | During the Lead In Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Vemurafenib Alone | Grade 4 SAEs | 0 participants |
| 720 mg Vemurafenib Alone | During the Lead In Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Vemurafenib Alone | Drug Related Grade 3 AEs | 2 participants |
| 720 mg Vemurafenib Alone | During the Lead In Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Vemurafenib Alone | Grade 5 AEs | 0 participants |
| 720 mg Vemurafenib Alone | During the Lead In Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Vemurafenib Alone | Grade 3 SAEs | 1 participants |
| 720 mg Vemurafenib Alone | During the Lead In Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Vemurafenib Alone | Deaths | 0 participants |
| 720 mg Vemurafenib Alone | During the Lead In Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Vemurafenib Alone | Drug Related Grade 1 AEs | 0 participants |
| 720 mg Vemurafenib Alone | During the Lead In Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Vemurafenib Alone | Grade 3 irAEs | 1 participants |
| 720 mg Vemurafenib Alone | During the Lead In Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Vemurafenib Alone | Deaths due to disease progression | 0 participants |
| 720 mg Vemurafenib Alone | During the Lead In Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Vemurafenib Alone | Grade 4 irAEs | 0 participants |
| 720 mg Vemurafenib Alone | During the Lead In Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Vemurafenib Alone | Grade 2 irAEs | 0 participants |
| 720 mg Vemurafenib Alone | During the Lead In Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Vemurafenib Alone | Drug Related Grade 4 SAEs | 0 participants |
| 720 mg Vemurafenib Alone | During the Lead In Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Vemurafenib Alone | Grade 1 AEs | 0 participants |
| 720 mg Vemurafenib Alone | During the Lead In Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Vemurafenib Alone | Grade 1 irAEs | 0 participants |
| 720 mg Vemurafenib Alone | During the Lead In Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Vemurafenib Alone | Drug Related Grade 2 AEs | 0 participants |
| 720 mg Vemurafenib Alone | During the Lead In Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Vemurafenib Alone | Grade 2 AEs | 0 participants |
Primary
Number of Participants With Hepatic Dose Limiting Toxicities (DLT) in Participants Treated With Concurrent Ipilimumab and Vemurafenib
DLT defined as a \>= Grade 3 drug-related AE during induction with ipilimumab in combination with vemurafenib excluding: Grade 3 AE of tumor flare (defined as local pain, irritation, or rash localized at sites of known or suspected tumor); Grade 3 cutaneous squamous cell carcinoma; Grade 3 photosensitivity that resolved to a Grade 1 or baseline within 15 days; Grade 3 immune-mediated events of the skin (rash, pruritis) or endocrine systems (hypothyroidism, hyperthyroidism, hypopituitarism, adrenal insufficiency, hypogonadism and cushingoid) that resolved to a Grade 1 or baseline within 28 days; a transient (resolving within 6 hours of onset) Grade 3 infusion-related AE. Hepatic=elevated aspartate aminotransferase and alanine aminotransferase. Maximum tolerable dose (MTD) was defined as the maximum dose of combination treatment that could be given to 6 subjects such that no more than 2 subjects experience DLT. Day 1=first day of concurrent therapy with ipilimumab and vemurafenib.
Time frame: Day 1 to last dose of drug + 90 (approximately 2 years)
Population: All participants who received at least one dose of concurrent study drugs.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 960 mg Vemurafenib Lead in Period | Number of Participants With Hepatic Dose Limiting Toxicities (DLT) in Participants Treated With Concurrent Ipilimumab and Vemurafenib | 4 participants |
| 720 mg Vemurafenib Lead in Period | Number of Participants With Hepatic Dose Limiting Toxicities (DLT) in Participants Treated With Concurrent Ipilimumab and Vemurafenib | 2 participants |