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

Study Overview
=================
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.

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

Conditions
-----------------
Multiple Myeloma, Neoplasms

Intervention / Treatment
-----------------
* Drug: cetuximab
* Drug: vemurafenib
* Drug: vemurafenib


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 16 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1: Non-Small Cell Lung Cancer (NSCLC) - vemurafenib<br>Participants with NSCLC will be treated with vemurafenib monotherapy. | Drug: vemurafenib<br>* 960 mg vemurafenib orally twice a day until disease progression, unacceptable toxicity, or withdrawal of consent.<br>* Other names: Zelboraf;|
| Experimental: Cohort 2: Ovarian Cancer - vemurafenib<br>Participants with ovarian cancer will be treated with vemurafenib monotherapy. | Drug: vemurafenib<br>* 960 mg vemurafenib orally twice a day until disease progression, unacceptable toxicity, or withdrawal of consent.<br>* Other names: Zelboraf;|
| Experimental: Cohort 3a: Colorectal Cancer - vemurafenib<br>Participants with colorectal cancer will be treated with vemurafenib monotherapy. | Drug: vemurafenib<br>* 960 mg vemurafenib orally twice a day until disease progression, unacceptable toxicity, or withdrawal of consent.<br>* Other names: Zelboraf;|
| Experimental: Cohort 3b: Colorectal Cancer - vemurafenib + cetuximab<br>Participants with colorectal cancer will be treated with vemurafenib and cetuximab combination therapy. | Drug: cetuximab<br>* Escalating doses administered on Day 1 and then once weekly by intravenous infusion.<br>Drug: vemurafenib<br>* Escalating doses given orally twice a day starting on Day 2<br>* Other names: Zelboraf;|
| Experimental: Cohort 4: Cholangiocarcinoma - vemurafenib<br>Participants with cholangiocarcinoma will be treated with vemurafenib monotherapy. | Drug: vemurafenib<br>* 960 mg vemurafenib orally twice a day until disease progression, unacceptable toxicity, or withdrawal of consent.<br>* Other names: Zelboraf;|
| Experimental: Cohort 6: Multiple Myeloma - vemurafenib<br>Participants with multiple myeloma will be treated with vemurafenib monotherapy. | Drug: vemurafenib<br>* 960 mg vemurafenib orally twice a day until disease progression, unacceptable toxicity, or withdrawal of consent.<br>* Other names: Zelboraf;|
| Experimental: Cohort 7: Other Solid Tumors - vemurafenib<br>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<br>* 960 mg vemurafenib orally twice a day until disease progression, unacceptable toxicity, or withdrawal of consent.<br>* 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 |