A Study of Vemurafenib in Participants With BRAF V600 Mutation-Positive Cancers

An Open-label, Phase II Study of Vemurafenib in Patients With BRAF V600 Mutation-positive Cancers

This open-label, multi-center study will assess the efficacy and safety of vemurafenib in participants with BRAF V600 mutation-positive cancers (solid tumors and multiple myeloma, except melanoma and papillary thyroid cancer) and for whom vemurafenib is deemed the best treatment option in the opinion of the investigator. Participants will receive twice daily oral doses of 960 mg vemurafenib until disease progression, unacceptable toxicity, or withdrawal of consent. The safety and efficacy of vemurafenib in combination with cetuximab in a subset of participants with colorectal cancer will also be assessed.

Study Overview

• Status: Completed
• Conditions: Multiple Myeloma, Neoplasms
• Intervention / Treatment: Drug: vemurafenib; Drug: vemurafenib; Drug: cetuximab

• Study Type: Interventional
• Enrollment (Actual): 208
• Phase: Phase 2

Contacts and Locations

Study Locations

• China
  • Tianjin, China, 300060
    • Tianjin cancer hospital
• France
  • Bordeaux, France, 33076
    • Institut Bergonie; Oncologie
  • Caen, France, 14076
    • Centre Francois Baclesse; Oncologie
  • Dijon, France, 21000
    • Centre Georges Francois Leclerc
  • Lyon, France, 69373
    • Centre Leon Berard; Departement Oncologie Medicale
  • Marseille Cedex 09, France, 13273
    • Institut Paoli-Calmettes; Oncologie Medicale 1
  • Saint Herblain, France, 44805
    • Centre René Gauducheau
  • Toulouse, France, 31059
    • Institut Claudius Regaud; Departement Oncologie Medicale
  • VILLEJUIF Cedex, France, 94805
    • Institut Gustave Roussy; Sitep
• Germany
  • Essen, Germany, 45122
    • Universitätsklinikum Essen; Innere Klinik und Poliklinik für Tumorforschung
  • Köln, Germany, 50937
    • Klinik der Uni zu Koeln; Klinik I für Innere Medizin; Onkologie
  • Mannheim, Germany, 68167
    • Universitätsklinikum Mannheim, Tagestherapiezentrum, Interdisziplinäres Tumorzentrum
• Spain
  • Barcelona, Spain, 08003
    • Hospital del Mar; Servicio de Oncologia
  • Barcelona, Spain, 08035
    • Hospital Univ Vall d'Hebron; Servicio de Oncologia
  • Madrid, Spain, 28007
    • Hospital General Universitario Gregorio Marañon; Servicio de Oncologia
  • Madrid, Spain, 28050
    • Centro Integral Oncologico Clara Campal (CIOCC); Dirección Médica
  • Madrid, Spain, 28040
    • Fundacion Jimenez Diaz; Servicio de Oncologia
  • Salamanca, Spain, 37007
    • Hospital Clinico Universitario de Salamanca; Servicio de Oncologia
  • Valencia, Spain, 46010
    • Hospital Clinico Universitario de Valencia; Servicio de Onco-hematologia
  • Asturias
    • Oviedo, Asturias, Spain, 33011
      • Hospital Univ. Central de Asturias; Servicio de Oncologia
• United Kingdom
  • Aberdeen, United Kingdom, AB25 2ZN
    • Aberdeen Royal Infirmary
  • London, United Kingdom, SW3 5PT
    • The Royal Marsden Hospital; Dept of Medicine
  • Sutton, United Kingdom, SM2 5PT
    • The Royal Marsden Hospital
• United States
  • Arizona
    • Tucson, Arizona, United States, 85704
      • Arizona Oncology
  • Colorado
    • Aurora, Colorado, United States, 80012
      • Rocky Mountain Cancer Centers, LLP
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center
    • Boston, Massachusetts, United States, 02215
      • Dana-Farber Cancer Institute
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital;Oncology
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Karmanos Cancer Institute
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University
  • New York
    • New York, New York, United States
      • Memorial Sloan-Kettering Cancer Center
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt
  • Texas
    • Houston, Texas, United States, 77030
      • University of Texas M.D. Anderson Cancer Center
  • Washington
    • Yakima, Washington, United States, 98902
      • Yakima Valley Memorial Hospital/North Star Lodge

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
• Must have recovered from all side effects of their most recent systemic or local treatment
• Adequate hematological, renal and liver function

For solid tumors only:

• Histologically confirmed cancers (excluding melanoma and papillary thyroid cancer) with a BRAF V600 mutation and that are resistant to standard therapy or for which standard or curative therapy does not exist
• Measurable disease according to Response Evaluation Criteria In Solid Tumors (RECIST)

For multiple myeloma only:

• Confirmed diagnosis of multiple myeloma with a BRAF V600 mutation
• Must have received at least one prior systemic therapy for the treatment of multiple myeloma
• Treated with local radiotherapy
• Must have relapsed and/or refractory multiple myeloma with measurable disease

Exclusion Criteria:

• Melanoma, papillary thyroid cancer or hematological malignancies (with the exception of multiple myeloma)
• Uncontrolled concurrent malignancy
• Multiple myeloma: solitary bone or solitary extramedullary plasmacytoma as the only evidence of plasma cell dyscrasia
• Active or untreated central nervous system (CNS) metastases
• History of or known carcinomatous meningitis
• Concurrent administration of any anti-cancer therapies other than those administered in this study
• Other severe, acute, or chronic medical or psychiatric condition or laboratory abnormality that would, in the investigator's opinion, contraindicate participation in this study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

7

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1: Non-Small Cell Lung Cancer (NSCLC) - vemurafenib; Participants with NSCLC will be treated with vemurafenib monotherapy.	Drug: vemurafenib; Escalating doses given orally twice a day starting on Day 2; Other Names: Zelboraf; Drug: vemurafenib; 960 mg vemurafenib orally twice a day until disease progression, unacceptable toxicity, or withdrawal of consent.; Other Names: Zelboraf
Experimental: Cohort 2: Ovarian Cancer - vemurafenib; Participants with ovarian cancer will be treated with vemurafenib monotherapy.	Drug: vemurafenib; Escalating doses given orally twice a day starting on Day 2; Other Names: Zelboraf; Drug: vemurafenib; 960 mg vemurafenib orally twice a day until disease progression, unacceptable toxicity, or withdrawal of consent.; Other Names: Zelboraf
Experimental: Cohort 3a: Colorectal Cancer - vemurafenib; Participants with colorectal cancer will be treated with vemurafenib monotherapy.	Drug: vemurafenib; Escalating doses given orally twice a day starting on Day 2; Other Names: Zelboraf; Drug: vemurafenib; 960 mg vemurafenib orally twice a day until disease progression, unacceptable toxicity, or withdrawal of consent.; Other Names: Zelboraf
Experimental: Cohort 3b: Colorectal Cancer - vemurafenib + cetuximab; Participants with colorectal cancer will be treated with vemurafenib and cetuximab combination therapy.	Drug: vemurafenib; Escalating doses given orally twice a day starting on Day 2; Other Names: Zelboraf; Drug: vemurafenib; 960 mg vemurafenib orally twice a day until disease progression, unacceptable toxicity, or withdrawal of consent.; Other Names: Zelboraf; Drug: cetuximab; Escalating doses administered on Day 1 and then once weekly by intravenous infusion.
Experimental: Cohort 4: Cholangiocarcinoma - vemurafenib; Participants with cholangiocarcinoma will be treated with vemurafenib monotherapy.	Drug: vemurafenib; Escalating doses given orally twice a day starting on Day 2; Other Names: Zelboraf; Drug: vemurafenib; 960 mg vemurafenib orally twice a day until disease progression, unacceptable toxicity, or withdrawal of consent.; Other Names: Zelboraf
Experimental: Cohort 6: Multiple Myeloma - vemurafenib; Participants with multiple myeloma will be treated with vemurafenib monotherapy.	Drug: vemurafenib; Escalating doses given orally twice a day starting on Day 2; Other Names: Zelboraf; Drug: vemurafenib; 960 mg vemurafenib orally twice a day until disease progression, unacceptable toxicity, or withdrawal of consent.; Other Names: Zelboraf
Experimental: Cohort 7: Other Solid Tumors - vemurafenib; Participants with Erdheim-Chester disease (ECD), Langerhans cell histiocytosis (LCH), anaplastic thyroid cancer, advanced stage astrocytoma, early stage astrocytoma and other BRAF V600-positive tumors will be treated with vemurafenib monotherapy. Subcohorts will be analyzed separately if 7 or more participants are enrolled for each indication.	Drug: vemurafenib; Escalating doses given orally twice a day starting on Day 2; Other Names: Zelboraf; Drug: vemurafenib; 960 mg vemurafenib orally twice a day until disease progression, unacceptable toxicity, or withdrawal of consent.; Other Names: Zelboraf

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Confirmed Best Overall Response Rate (BORR)	Confirmed BORR: percentage of participants with an objective response (OR) (complete response [CR], partial response [PR], stringent CR [sCR] or very good PR [VGPR]) on 2 occasions >/= 4 weeks apart as assessed by the Investigator using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. or International Myeloma Working Group (IMWG) criteria. RECIST v1.1: CR: disappearance of all target lesions; PR: >/= 30% decrease in the sum of diameters of target lesions. IMWG: CR: negative immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas and </= 5% plasma cells in bone marrow; PR: >/= 50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by >/= 90% or to <200 mg per 24 hours. VGPR: serum and urine M-protein detectable by immunofixation but not on electrophoresis or >/= 90% reduction in serum M-protein plus urine M-protein level < 100 mg per 24 hour; sCR: CR plus normal free light chain (FLC) ratio and no clonal cells in bone marrow.	Up to approximately 3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Confirmed Clinical Benefit	Included were participants with confirmed PR or CR or Stable Disease (SD) that had lasted at least 6 months according to RECIST v1.1 or confirmed CR, PR, VGPR, sCR or SD for at least 6 months according to IMWG criteria. RECIST v1.1: PR: >/= 30% decrease in the sum of diameters of target lesions; CR: disappearance of all target lesions; SD: not meeting criteria for CR, PR or progressive disease (PD). IMWG: CR: negative immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas and </= 5% plasma cells in bone marrow; PR: >/= 50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by >/= 90% or to <200 mg per 24 hours. VGPR: serum and urine M-protein detectable by immunofixation but not on electrophoresis or >/= 90% reduction in serum M-protein plus urine M-protein level < 100 mg per 24 hour; sCR: CR plus normal FLC ratio and no clonal cells in bone marrow; SD: not meeting criteria for CR, VGPR, PR or PD.	Up to approximately 3 years
Overall Response Rate (ORR)	ORR: percentage of participants with an objective response (OR) (CR, PR, sCR or VGPR) on 2 occasions >/= 4 weeks apart as assessed by the Investigator using RECIST v1.1. or IMWG criteria. RECIST v1.1: CR: disappearance of all target lesions; PR: >/= 30% decrease in the sum of diameters of target lesions. IMWG: CR: negative immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas and </= 5% plasma cells in bone marrow; PR: >/= 50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by >/= 90% or to <200 mg per 24 hours. VGPR: serum and urine M-protein detectable by immunofixation but not on electrophoresis or >/= 90% reduction in serum M-protein plus urine M-protein level < 100 mg per 24 hour; sCR: CR plus normal FLC ratio and no clonal cells in bone marrow.	Up to approximately 3 years
Duration of Response (DOR)	DOR was defined as the period from the date of initial PR or CR for solid tumors according to RECISTv1.1 and CR, PR, VGPR or sCR for multiple myeloma according to IMWG criteria, until the date of PD or death from any cause. RECIST v1.1: PD: At least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 mm. IMWG: PD: increase of >/= 25% from lowest response value in serum or urine M-protein or bone marrow plasma cell percentage or development of new or increase in size of bone lesions or soft tissue plasmacytomas.	Up to approximately 3 years
Time to Response	Time to response was defined as the time from the first day of study treatment to the date of first CR, or PR for solid tumors according to RECISTv1.1 and CR, PR, VGPR or sCR for multiple myeloma according to IMWG criteria. RECIST v1.1: CR: disappearance of all target lesions; PR: at least a 30% decrease in the sum of diameters of target lesions. IMWG criteria: CR: negative immunofixation on serum and urine and disappearance of any soft tissue plasmacytomas and </= 5% plasma cells in bone marrow; PR: >/= 50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by >/= 90% or to < 200 mg per 24 hours. VGPR: serum and urine M-protein detectable by immunofixation but not on electrophoresis or >/= 90% reduction in serum M-protein plus urine M-protein level < 100 mg per 24 hour; sCR: CR plus normal FLC ratio and no clonal cells in bone marrow.	Up to approximately 3 years
Time to Tumor Progression (TTP)	TTP was defined as time from the first day of study treatment to the first occurrence of progressive disease (PD). RECIST v1.1: PD: at least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 mm. IMWG: PD: increase of >/= 25% from lowest response value in serum or urine M-protein or bone marrow plasma cell percentage or development of new or increase in size of bone lesions or soft tissue plasmacytomas.	Up to approximately 3 years
Progression Free Survival (PFS)	PFS was defined as the time from the first day of study treatment, until the first documented PD or death from any cause, whichever occurs first. RECIST v1.1: PD: at least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 mm. IMWG criteria: PD: increase of >/= 25% from lowest response value in serum or urine M-protein or bone marrow plasma cell percentage or development of new or increase in size of bone lesions or soft tissue plasmacytomas.	Up to approximately 3 years
Overall Survival (OS)	OS was defined as time between the first day of study treatment and date of death of any cause.	Up to approximately 3 years
Maximum Tolerated Dose for Vemurafenib in Combination With Cetuximab	Cohort 3b included participants with colorectal cancer treated with escalating doses of vemurafenib and cetuximab. The escalating doses were as follows: Dose Level 1: 720 milligrams (mg) of vemurafenib orally twice daily starting on Day 2 of Cycle 1 and 300 milligrams per square meter (mg/m^2) loading dose of cetuximab by infusion and then 200 mg/m^2 weekly; Dose Level 2: 720 mg of vemurafenib twice daily starting on Day 2 of Cycle 1 and 400 mg/m^2 loading dose of cetuximab and then 250 mg/m^2 weekly; Dose Level 3: 960 mg of vemurafenib twice daily starting on Day 2 of Cycle 1 and 400 mg/m^2 loading dose of cetuximab and then 250 mg/m^2 weekly. Reported here are the maximum tolerated doses for each vemurafenib and cetuximab.	Up to approximately 3 years
Number of Dose-limiting Toxicities of Vemurafenib in Combination With Cetuximab	Cohort 3b included participants with colorectal cancer treated with escalating doses of vemurafenib and cetuximab. The escalating doses were as follows: Dose Level 1: 720 milligrams (mg) of vemurafenib orally twice daily starting on Day 2 of Cycle 1 and 300 milligrams per square meter (mg/m^2) loading dose of cetuximab by infusion and then 200 mg/m^2 weekly; Dose Level 2: 720 mg of vemurafenib twice daily starting on Day 2 of Cycle 1 and 400 mg/m^2 loading dose of cetuximab and then 250 mg/m^2 weekly; Dose Level 3: 960 mg of vemurafenib twice daily starting on Day 2 of Cycle 1 and 400 mg/m^2 loading dose of cetuximab and then 250 mg/m^2 weekly. Reported here are type and number of dose limited toxicities observed.	Up to 28 days
Safety: Percentage of Participants With Adverse Event	An adverse event is any untoward medical occurrence in a subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.	Up to approximately 3 years

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche

Publications and helpful links

General Publications

• Kaley T, Touat M, Subbiah V, Hollebecque A, Rodon J, Lockhart AC, Keedy V, Bielle F, Hofheinz RD, Joly F, Blay JY, Chau I, Puzanov I, Raje NS, Wolf J, DeAngelis LM, Makrutzki M, Riehl T, Pitcher B, Baselga J, Hyman DM. BRAF Inhibition in BRAFV600-Mutant Gliomas: Results From the VE-BASKET Study. J Clin Oncol. 2018 Dec 10;36(35):3477-3484. doi: 10.1200/JCO.2018.78.9990. Epub 2018 Oct 23.
• Hyman DM, Puzanov I, Subbiah V, Faris JE, Chau I, Blay JY, Wolf J, Raje NS, Diamond EL, Hollebecque A, Gervais R, Elez-Fernandez ME, Italiano A, Hofheinz RD, Hidalgo M, Chan E, Schuler M, Lasserre SF, Makrutzki M, Sirzen F, Veronese ML, Tabernero J, Baselga J. Vemurafenib in Multiple Nonmelanoma Cancers with BRAF V600 Mutations. N Engl J Med. 2015 Aug 20;373(8):726-36. doi: 10.1056/NEJMoa1502309. Erratum In: N Engl J Med. 2018 Oct 18;379(16):1585.

Helpful Links

• Trialreach Entry

Study record dates

Study Major Dates

• Study Start (Actual): April 12, 2012
• Primary Completion (Actual): October 28, 2016
• Study Completion (Actual): October 28, 2016

Study Registration Dates

• First Submitted: January 27, 2012
• First Submitted That Met QC Criteria: January 31, 2012
• First Posted (Estimate): February 2, 2012

Study Record Updates

• Last Update Posted (Actual): November 20, 2017
• Last Update Submitted That Met QC Criteria: October 17, 2017
• Last Verified: October 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Neoplasms, Plasma Cell; Multiple Myeloma; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Immunological; Protein Kinase Inhibitors; Cetuximab; Vemurafenib
• Other Study ID Numbers: MO28072; 2011-004426-10 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No