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Vemurafenib

Clinical Trials

This is a screening study to detect BRAF V600 mutation-positive patients for enrollment into clinical research studies of Zelboraf (vemurafenib). Tumor samples will be collected and analyzed from eligible patients with solid tumors (other than metastatic melanoma or papillary thyroid cancer) or multiple myeloma. All institutions with identified patients as defined by this screening protocol will have potential access to the separate vemurafenib protocol MO28072.

Formalin-fixed paraffin-embedded (FFPE) tumor samples

A Screening Study to Detect BRAF V600 Mutation-Positive Patients For Enrollment Into Clinical Research Studies of Zelboraf (Vemurafenib)

Screening Protocol to Detect BRAF V600 Mutation-Positive Patients for Enrollment Into Clinical Research Studies of Vemurafenib

Formalin-fixed paraffin-embedded (FFPEs) tumor samples (at least 5 serially-cut, unstained, 5 micrometer \[μm\] sections) were collected from eligible participants who consented to participate in the study. FFPE tumor samples were either from archived sections (from the initial diagnosis of cancer) or from fresh biopsies that were performed according to local standards. Tumor samples were then sent to a central laboratory to identify activating BRAF V600 mutations. Identification of mutations was done using bidirectional direct Sanger sequencing procedure.

FFPEs tumor samples (at least 5 serially-cut, unstained, 5 μm sections) were collected from eligible participants who consented to participate in the study. FFPE tumor samples were either from archived sections (from the initial diagnosis of cancer) or from fresh biopsies that were performed according to local standards. Tumor samples were then sent to a central laboratory to identify activating BRAF V600 mutations. Identification of mutations was done using bidirectional direct Sanger sequencing procedure. V600E, V600K, V600D, and V600R are the different types of BRAF V600 mutations.

Genentech, Inc.

Participants with solid tumors (other than metastatic melanoma or papillary thyroid cancer) or multiple myeloma who met the inclusion criteria and did not meet exclusion criteria of the study were enrolled and were evaluated for the presence of BRAF V600 mutations by collecting tumor samples or performing fresh biopsies according to local standards.

Participants With Confirmed Solid Tumors or Multiple Myeloma

Age, Continuous

Gender

All the participants who were enrolled and were evaluable for the BRAF V600 mutations were included in the analysis.

Medical Communications

Breast cancer (n=85)

Non-small cell lung carcinoma (n=65)

Colorectal cancer (n=74)

Ovarian cancer (n=66)

Prostate cancer (n=21)

Multiple myeloma (n=31)

Biliary tract cancer (n=16)

Other cancer (n=190)

Overall (n=540)

All the participants who were enrolled and were evaluable for the BRAF V600 mutations were included in the analysis. n is the number of participants with that type of cancer in the total population.

Percentage of Participants With BRAF V600 Mutation Positivity in Tumor Samples by Cancer Type

BRAF V600E

BRAF V600K

BRAF V600D

BRAF V600R

Other V600

Number of Participants Classified Based on Different Types of BRAF V600 Mutation Patterns in Tumor Samples

Overall Study

Cetuximab

Antineoplastic Agents, Immunological

Protein Kinase Inhibitors

Enzyme Inhibitors

Participants with NSCLC will be treated with vemurafenib monotherapy.

Participants with ovarian cancer will be treated with vemurafenib monotherapy.

Participants with colorectal cancer will be treated with vemurafenib monotherapy.

Participants with colorectal cancer will be treated with vemurafenib and cetuximab combination therapy.

Participants with cholangiocarcinoma will be treated with vemurafenib monotherapy.

Participants with multiple myeloma will be treated with vemurafenib monotherapy.

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.

Escalating doses administered on Day 1 and then once weekly by intravenous infusion.

cetuximab

Escalating doses given orally twice a day starting on Day 2

vemurafenib

960 mg vemurafenib orally twice a day until disease progression, unacceptable toxicity, or withdrawal of consent.

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.

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

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.

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.

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.

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 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.

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.

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.

OS was defined as time between the first day of study treatment and date of death of any cause.

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.

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.

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.

Hoffmann-La Roche

The safety population included all participants who received at least one dose of study medication.

Participants with colorectal cancer were treated with vemurafenib and cetuximab combination therapy.

Cohort 3b: Colorectal Cancer - Vemurafenib + Cetuximab

Participants with a variety of cancer types, who were treated with vemurafenib monotherapy, were combined into this arm.

Pooled Arm - Vemurafenib

Participants with NSCLC were treated with vemurafenib monotherapy.

Cohort 1: Non-Small Cell Lung Cancer (NSCLC) - Vemurafenib

Participants with ovarian cancer were treated with vemurafenib monotherapy.

Cohort 2: Ovarian Cancer - Vemurafenib

Participants with colorectal cancer were treated with vemurafenib monotherapy.

Cohort 3a: Colorectal Cancer - Vemurafenib

Participants with cholangiocarcinoma were treated with vemurafenib monotherapy.

Cohort 4: Cholangiocarcinoma - Vemurafenib

Participants with multiple myeloma were treated with vemurafenib monotherapy.

Cohort 6: Multiple Myeloma - Vemurafenib

Participants with Erdheim-Chester disease (ECD) or Langerhans cell histiocytosis (LCH) were treated with vemurafenib monotherapy.

Cohort 7a: ECD/LCH - Vemurafenib

Participants with anaplastic thyroid cancer were treated with vemurafenib monotherapy.

Cohort 7b: Anaplastic Thyroid Cancer - Vemurafenib

Participants with advanced stage astrocytoma were treated with vemurafenib monotherapy.

Cohort 7c: Advanced Stage Astrocytoma - Vemurafenib

Participants with early stage astrocytoma were treated with vemurafenib monotherapy.

Cohort 7d: Early Stage Astrocytoma - Vemurafenib

Participants with other BRAF V600-positive tumors were treated with vemurafenib monotherapy.

Cohort 7: Other BRAF V600-positive Tumors - Vemurafenib

Total

Sex: Female, Male

Intent-to-treat (ITT) population included all participants enrolled in the study irrespective of whether they had received study medication or not.

ITT population included all participants enrolled in the study irrespective of whether they had received study drug or not.

Confirmed Best Overall Response Rate (BORR)

ITT population included all participants enrolled in the study irrespective of whether they had received study medication or not.

Percentage of Participants With Confirmed Clinical Benefit

VGPR

Overall Response Rate (ORR)

Duration of Response (DOR)

Time to Response

Time to Tumor Progression (TTP)

Progression Free Survival (PFS)

Overall Survival (OS)

All participants from Cohort 3b who received at least one dose of study medication.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Screening Study to Detect BRAF V600 Mutation-Positive Patients For Enrollment Into Clinical Research Studies of Zelboraf (Vemurafenib)	NCT01804140	Multiple Myelom...		18 Years -	Genentech, Inc.
A Study of Vemurafenib in Participants With BRAF V600 Mutation-Positive Cancers	NCT01524978	Multiple Myelom...	cetuximab vemurafenib vemurafenib	16 Years -	Hoffmann-La Roche
A Screening Study to Detect BRAF V600 Mutation-Positive Patients For Enrollment Into Clinical Research Studies of Zelboraf (Vemurafenib)	NCT01804140	Multiple Myelom...		18 Years -	Genentech, Inc.

Spots Global Cancer Trial Database for multiple myeloma, neoplasms