Ph I Ipilimumab Vemurafenib Combo in Patients With v-Raf Murine Sarcoma Viral Oncogene Homolog B1 (BRAF)

NCT01400451 | Terminated Phase 1 Results

• 2 other identifiers: CA184-161 ST2011-000906-22
• Study Type: interventional
• Target: 18
• Locations: 1 country
• Sites: 4

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.

Conditions

Melanoma

Outcome Measures

Primary Outcomes (3)

• 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.

  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)

• 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.

  Combination drugs: Day 1 to last dose of drug + 90 days (approximately 2 years)

• 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.

  Day 1 to last dose of drug + 90 (approximately 2 years)

Study Arms (1)

Ipilimumab + Vemurafenib

EXPERIMENTAL

Drug: Ipilimumab (BMS-734016); Drug: Vemurafenib

Interventions

Ipilimumab (BMS-734016) DRUG

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

Also known as: Yervoy®, Ipilimumab, BMS-734016

Ipilimumab + Vemurafenib

Vemurafenib DRUG

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

Ipilimumab + Vemurafenib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Metastatic melanoma with activating V600 BRAF mutation
• Measurable Tumor
• Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0-1

You may not qualify if:

• Autoimmune disease
• Active Brain Metastasis (must be stable after radiation for at least one month)
• Prior therapy with immune stimulating agents

Sponsors & Collaborators

• Bristol-Myers Squibb: lead
• Roche-Genentech: collaborator

Study Sites (4)

University Of California Los Angeles

Los Angeles, California, 90095, United States

Location

Dana Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Dana Farber Cancer Inst

Boston, Massachusetts, 02215, United States

Location

Memorial Sloan-Kettering Cancer Center

New York, New York, 10065, United States

Location

Related Publications (3)

• Ackerman A, Klein O, McDermott DF, Wang W, Ibrahim N, Lawrence DP, Gunturi A, Flaherty KT, Hodi FS, Kefford R, Menzies AM, Atkins MB, Long GV, Sullivan RJ. Outcomes of patients with metastatic melanoma treated with immunotherapy prior to or after BRAF inhibitors. Cancer. 2014 Jun 1;120(11):1695-701. doi: 10.1002/cncr.28620. Epub 2014 Feb 27.

  PMID: 24577748 DERIVED

• Ludlow SP, Pasikhova Y. Cumulative dermatologic toxicity with ipilimumab and vemurafenib responsive to corticosteroids. Melanoma Res. 2013 Dec;23(6):496-7. doi: 10.1097/CMR.0000000000000018.

  PMID: 24025700 DERIVED

• Mandala M, Voit C. Targeting BRAF in melanoma: biological and clinical challenges. Crit Rev Oncol Hematol. 2013 Sep;87(3):239-55. doi: 10.1016/j.critrevonc.2013.01.003. Epub 2013 Feb 15.

  PMID: 23415641 DERIVED

Related Links

• BMS clinical trial educational resource
• Investigator Inquiry form

MeSH Terms

Conditions

Melanoma

Interventions

Ipilimumab; Vemurafenib

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Sulfonamides; Amides; Organic Chemicals; Sulfones; Sulfur Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Limitations and Caveats

In Phase 1 of the study, MTD was not reached because more than 2 of 6 treated participants experienced DLTs with the combination therapy. Enrollments in Phase 1 were terminated and Phase 2 was not started so only overall safety was summarized.

Results Point of Contact

• Title: Bristol-Myers Squibb Study Director
• Organization: Bristol-Myers Squibb

Clinical.Trials@bms.com

Study Officials

• Bristol-Myers Squibb

  Bristol-Myers Squibb

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 21, 2011
• First Posted: July 22, 2011
• Study Start: November 1, 2011
• Primary Completion: April 1, 2013
• Study Completion: December 1, 2013
• Last Updated: January 1, 2015
• Results First Posted: May 19, 2014

Record last verified: 2014-12

Locations

US (4)