Phase II Safety Study of Vemurafenib Followed by Ipilimumab in Subjects With V600 BRAF Mutated Advanced Melanoma

A Single Arm Open-Label Phase II Study of Vemurafenib Followed by Ipilimumab in Subjects With Previously Untreated V600 BRAF Mutated Advanced Melanoma

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01673854

Enrollment

Registered

2012-08-28

Start date

2012-09-13

Completion date

2015-05-12

Last updated

2018-07-24

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Melanoma

Brief summary

The purpose of this study is to assess the safety profile of vemurafenib, 960 mg, administered for 6 weeks, followed by ipilimumab monotherapy in patients with BRAF V600 mutated advanced/metastatic melanoma.

Interventions

DRUGIpilimumab

BIOLOGICALVemurafenib

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Healthy volunteers

Inclusion criteria

For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com Key Inclusion Criteria: * Men and women 18 years of age and older * Histologic diagnosis of malignant melanoma tested positive for the BRAF V600 mutation * Previously untreated unresectable Stage III or Stage IV melanoma * Complete set of brain/neck, chest, abdomen/pelvis axial radiographs taken within 28 days of first dose of study drug * Measurable melanoma by physical or radiographic examination * Brain metastases stable after radiation for at least 1 month and off corticosteroid therapy for ≥30 days prior to enrollment * Eastern Cooperative Oncology Group performance status of 0 or 1 * Adequate hematologic parameters and renal and hepatic function Key

Exclusion criteria

* Primary ocular melanoma * Active brain metastases with symptoms or requiring corticosteroid treatment * Any other malignancy from which the patient has been disease-free for less than 2 years, with the exception of adequately treated and cured basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the cervix * History of or current active autoimmune diseases, including but not limited to inflammatory bowel diseases, rheumatoid arthritis, autoimmune thyroiditis, autoimmune hepatitis, systemic sclerosis, systemic lupus erythematosus, autoimmune vasculitis, autoimmune neuropathies * History of or current immunodeficiency disease, splenectomy, or splenic irradiation * Prior anticancer therapy or investigational products \<4 weeks prior to enrollment * Prior therapy with a BRAF or MEK inhibitor and prior investigational anticancer immunotherapies; * Prior therapies with immunosuppressive agents within the past 2 years * Concomitant therapy with any anticancer or potent immunosuppressive agent, surgery, radiotherapy, other investigational anticancer therapies, or chronic use of systemic corticosteroids

Design outcomes

Primary

Measure	Time frame	Description
Percentage of Participants Who Received Ipilimumab and Who Had Grade 3-4 Drug-related Skin Adverse Events (AEs)	From the first dose date of Vem1 to the last dose of ipilimumab (to a maximum of 3 years) + 90 days or to the first dose date of Vem2, whichever occurred first	AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. Drug-related=having certain, probable, possible, or unknown relationship to study drug. Grading criteria for AEs: Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Life-threatening or disabling, Grade 5=Death.

Secondary

Measure	Time frame	Description
Percentage of Participants Who Received Ipilimumab and Who Had Grade 3-4 Drug-related Gastrointestinal Adverse Events (AEs)	From the first dose date of Vem1 to the last dose of ipilimumab (to a maximum of 3 years) + 90 days or to the first dose date of Vem2, whichever occurred first	AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. Drug-related=having certain, probable, possible, or unknown relationship to study drug. Grading criteria for AEs: Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Life-threatening or disabling, Grade 5=Death.
Percentage of Participants Who Received Ipilimumab and Who Had Grade 3-4 Drug-related Hepatobiliary Adverse Events	From the first dose date of Vem1 to the last dose of ipilimumab (to a maximum of 3 years) + 90 days or to the first dose date of Vem2, whichever occurred first	AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. Drug-related=having certain, probable, possible, or unknown relationship to study drug. Grading criteria for AEs: Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Life-threatening or disabling, Grade 5=Death.

Other

Measure	Time frame	Description
Number of Participants Who Died, Who Died Due to Related Adverse Events (AEs), and With Related AEs, Serious Adverse Events (SAEs), Related SAEs, Discontinuations Due to AEs and Related AEs, Immune-related (ir) AEs, and Serious irAEs	From the first dose date of Vem1 to the last dose of ipilimumab (to a maximum of 3 years) + 90 days or to the first dose date of Vem2, whichever occurred first	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. Related=having certain, probable, possible, or unknown relationship to study drug.
Number of Participants With Adverse Events (AEs) Grade 3-4, Related AEs Grade 3-4, Related Serious Adverse Events (SAEs) Grade 3-4, Immune-related (ir) AEs Grade 3-4, and Serious irAEs Grade 3-4	From the first dose date of Vem1 to the last dose of ipilimumab (to a maximum of 3 years) + 90 days or to the first dose date of Vem2, whichever occurred first	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. Related=having certain, probable, possible, or unknown relationship to study drug. Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Life-threatening or disabling, Grade 5=Death.

Countries

United States

Participant flow

Pre-assignment details

A total of 70 patients were enrolled, and 46 received treatment.

Participants by arm

Arm	Count
Vemurafenib, 960 mg + Ipilimumab, 10 mg/kg Participants received vemurafenib, 960 mg, twice daily for 6 weeks (Vem1 Phase). After a washout period of 3-10 days, patients received ipilimumab, 10 mg/kg, every 3 weeks for a maximum of 4 doses. At Week 24, participants received ipilimumab, 10 mg/kg, every 12 weeks until disease progression or unacceptable toxicity. Patients who did not progress or have unacceptable toxicity in the Vem1 Phase were retreated with vemurafenib (Vem 2 Phase) at the last dose level identified at the end of the Vem1 Phase until disease progression or unacceptable toxicity.	46
Total	46

Arm

Count

Vemurafenib, 960 mg + Ipilimumab, 10 mg/kg

Participants received vemurafenib, 960 mg, twice daily for 6 weeks (Vem1 Phase). After a washout period of 3-10 days, patients received ipilimumab, 10 mg/kg, every 3 weeks for a maximum of 4 doses. At Week 24, participants received ipilimumab, 10 mg/kg, every 12 weeks until disease progression or unacceptable toxicity. Patients who did not progress or have unacceptable toxicity in the Vem1 Phase were retreated with vemurafenib (Vem 2 Phase) at the last dose level identified at the end of the Vem1 Phase until disease progression or unacceptable toxicity.

Total

Withdrawals & dropouts

Period	Reason	FG000
Ipilimumab Phase (Ipilimumab, 10 mg/kg)	Administrative Reason by Sponsor	2
Ipilimumab Phase (Ipilimumab, 10 mg/kg)	Adverse event unrelated to study drug	1
Ipilimumab Phase (Ipilimumab, 10 mg/kg)	Death	1
Ipilimumab Phase (Ipilimumab, 10 mg/kg)	Disease progression	7
Ipilimumab Phase (Ipilimumab, 10 mg/kg)	Maximum clinical benefit	1
Ipilimumab Phase (Ipilimumab, 10 mg/kg)	Not identified	2
Ipilimumab Phase (Ipilimumab, 10 mg/kg)	Not reported	7
Ipilimumab Phase (Ipilimumab, 10 mg/kg)	Study drug toxicity	6
Vem 2 Phase (Vemurafenib Retreatment)	Adverse event unrelated to study drug	1
Vem 2 Phase (Vemurafenib Retreatment)	Death	1
Vem 2 Phase (Vemurafenib Retreatment)	Disease progression	12
Vem 2 Phase (Vemurafenib Retreatment)	Study drug toxicity	5

Baseline characteristics

Characteristic	Vemurafenib, 960 mg + Ipilimumab, 10 mg/kg
Age, Continuous	57.5 Years
Disease Stage at Study Entry III	8 Participants
Disease Stage at Study Entry IV	38 Participants
Eastern Cooperative Oncology Group (ECOG) Performance Status 0	35 Participants
Eastern Cooperative Oncology Group (ECOG) Performance Status 1	11 Participants
M-Stage at Study Entry M0	6 Participants
M-Stage at Study Entry M1A	8 Participants
M-Stage at Study Entry M1B	8 Participants
M-Stage at Study Entry M1C	24 Participants
Number of Disease Sites 1	2 Participants
Number of Disease Sites 2	8 Participants
Number of Disease Sites 3	7 Participants
Number of Disease Sites 4	4 Participants
Number of Disease Sites 5 or more	25 Participants
Race/Ethnicity, Customized Other	4 Participants
Race/Ethnicity, Customized White	42 Participants
Sex: Female, Male Female	9 Participants
Sex: Female, Male Male	37 Participants
Time from Diagnosis of Advanced /Metastatic Melanoma to First Vem1 Phase Dose	1.86 Months

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	— / —
other Total, other adverse events	44 / 46
serious Total, serious adverse events	34 / 46

Outcome results

Primary

Percentage of Participants Who Received Ipilimumab and Who Had Grade 3-4 Drug-related Skin Adverse Events (AEs)

AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. Drug-related=having certain, probable, possible, or unknown relationship to study drug. Grading criteria for AEs: Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Life-threatening or disabling, Grade 5=Death.