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

• ClinicalTrials.gov Identifier: NCT01524978
• Recruitment Status: Completed
• First Posted: February 2, 2012
• Results First Posted: November 20, 2017
• Last Update Posted: November 20, 2017
• Sponsor: Hoffmann-La Roche
• Information provided by (Responsible Party): Hoffmann-La Roche

Tracking Information

• First Submitted Date: January 27, 2012
• First Posted Date: February 2, 2012
• Results First Submitted Date: August 22, 2017
• Results First Posted Date: November 20, 2017
• Last Update Posted Date: November 20, 2017
• Actual Study Start Date: April 12, 2012
• Actual Primary Completion Date: October 28, 2016 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 17, 2017)

Confirmed Best Overall Response Rate (BORR) [ Time Frame: Up to approximately 3 years ]

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.

• Original Primary Outcome Measures (submitted: January 31, 2012): Tumor Response Rate [ Time Frame: Week 8 ]

Current Secondary Outcome Measures (submitted: October 17, 2017)

• Percentage of Participants With Confirmed Clinical Benefit [ Time Frame: Up to approximately 3 years ]
  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.
• Overall Response Rate (ORR) [ Time Frame: Up to approximately 3 years ]
  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.
• Duration of Response (DOR) [ Time Frame: Up to approximately 3 years ]
  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.
• Time to Response [ Time Frame: Up to approximately 3 years ]
  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.
• Time to Tumor Progression (TTP) [ Time Frame: Up to approximately 3 years ]
  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.
• Progression Free Survival (PFS) [ Time Frame: Up to approximately 3 years ]
  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.
• Overall Survival (OS) [ Time Frame: Up to approximately 3 years ]
  OS was defined as time between the first day of study treatment and date of death of any cause.
• Maximum Tolerated Dose for Vemurafenib in Combination With Cetuximab [ Time Frame: Up to approximately 3 years ]
  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.
• Number of Dose-limiting Toxicities of Vemurafenib in Combination With Cetuximab [ Time Frame: Up to 28 days ]
  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.
• Safety: Percentage of Participants With Adverse Event [ Time Frame: Up to approximately 3 years ]
  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.

Original Secondary Outcome Measures (submitted: January 31, 2012)

• Safety: Incidence of adverse events [ Time Frame: Approximately 3 years ]
• Overall Response Rate (ORR) [ Time Frame: Approximately 3 years ]
• Tumor Response Rate [ Time Frame: Approximately 3 years ]
• Duration of Response (DOR) [ Time Frame: Approximately 3 years ]
• Time to Response [ Time Frame: Approximately 3 years ]
• Time to Tumor Progression (TTP) [ Time Frame: Approximately 3 years ]
• Progression free Survival (PFS) [ Time Frame: Approximately 3 years ]
• Overall Survival (OS) [ Time Frame: Approximately 3 years ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of Vemurafenib in Participants With BRAF V600 Mutation-Positive Cancers
• Official Title: An Open-label, Phase II Study of Vemurafenib in Patients With BRAF V600 Mutation-positive Cancers
• Brief Summary: 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Multiple Myeloma, Neoplasms

Intervention

• Drug: cetuximab
  Escalating doses administered on Day 1 and then once weekly by intravenous infusion.
• Drug: vemurafenib
  Escalating doses given orally twice a day starting on Day 2
  Other Name: Zelboraf
• Drug: vemurafenib
  960 mg vemurafenib orally twice a day until disease progression, unacceptable toxicity, or withdrawal of consent.
  Other Name: Zelboraf

Study Arms

• Experimental: Cohort 1: Non-Small Cell Lung Cancer (NSCLC) - vemurafenib
  Participants with NSCLC will be treated with vemurafenib monotherapy.
  Intervention: Drug: vemurafenib
• Experimental: Cohort 2: Ovarian Cancer - vemurafenib
  Participants with ovarian cancer will be treated with vemurafenib monotherapy.
  Intervention: Drug: vemurafenib
• Experimental: Cohort 3a: Colorectal Cancer - vemurafenib
  Participants with colorectal cancer will be treated with vemurafenib monotherapy.
  Intervention: Drug: vemurafenib
• Experimental: Cohort 3b: Colorectal Cancer - vemurafenib + cetuximab
  Participants with colorectal cancer will be treated with vemurafenib and cetuximab combination therapy.
  Interventions:

  • Drug: cetuximab
  • Drug: vemurafenib
• Experimental: Cohort 4: Cholangiocarcinoma - vemurafenib
  Participants with cholangiocarcinoma will be treated with vemurafenib monotherapy.
  Intervention: Drug: vemurafenib
• Experimental: Cohort 6: Multiple Myeloma - vemurafenib
  Participants with multiple myeloma will be treated with vemurafenib monotherapy.
  Intervention: Drug: vemurafenib
• 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.
  Intervention: Drug: vemurafenib

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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: November 2, 2015): 208
• Original Estimated Enrollment (submitted: January 31, 2012): 101
• Actual Study Completion Date: October 28, 2016
• Actual Primary Completion Date: October 28, 2016 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 16 Years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: China, France, Germany, Spain, United Kingdom, United States

Administrative Information

• NCT Number: NCT01524978
• Other Study ID Numbers: MO28072; 2011-004426-10 ( EudraCT Number )
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Hoffmann-La Roche
• Original Responsible Party: Disclosures Group, Hoffmann-La Roche
• Current Study Sponsor: Hoffmann-La Roche
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Clinical Trials; Hoffmann-La Roche

• PRS Account: Hoffmann-La Roche
• Verification Date: October 2017