Multiple Myeloma, Neoplasms
Conditions
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.
Interventions
DRUGcetuximab
Escalating doses administered on Day 1 and then once weekly by intravenous infusion.
DRUGvemurafenib
Escalating doses given orally twice a day starting on Day 2
Sponsors
Hoffmann-La Roche
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
16 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Confirmed Best Overall Response Rate (BORR) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) | 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) | 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 | 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) | 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. |
| Percentage of Participants With Confirmed Clinical Benefit | 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 Survival (OS) | 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 | 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 | 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 | 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. |
| Progression Free Survival (PFS) | 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. |
Countries
China, France, Germany, Spain, United Kingdom, United States
Participant flow
Pre-assignment details
One participant with breast cancer was screened shortly after Cohort 5 (Breast Cancer) had been closed. This participant was allowed to enter the study in Cohort 7: Other BRAF V600-positive tumors. For analysis purposes Cohort 7 was split into sub-cohorts for indications with sufficient participants.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1: Non-Small Cell Lung Cancer (NSCLC) - Vemurafenib Participants with NSCLC were treated with vemurafenib monotherapy. | 62 |
| Cohort 2: Ovarian Cancer - Vemurafenib Participants with ovarian cancer were treated with vemurafenib monotherapy. | 4 |
| Cohort 3a: Colorectal Cancer - Vemurafenib Participants with colorectal cancer were treated with vemurafenib monotherapy. | 10 |
| Cohort 3b: Colorectal Cancer - Vemurafenib + Cetuximab Participants with colorectal cancer were treated with vemurafenib and cetuximab combination therapy. | 27 |
| Cohort 4: Cholangiocarcinoma - Vemurafenib Participants with cholangiocarcinoma were treated with vemurafenib monotherapy. | 9 |
| Cohort 6: Multiple Myeloma - Vemurafenib Participants with multiple myeloma were treated with vemurafenib monotherapy. | 9 |
| Cohort 7a: ECD/LCH - Vemurafenib Participants with Erdheim-Chester disease (ECD) or Langerhans cell histiocytosis (LCH) were treated with vemurafenib monotherapy. | 26 |
| Cohort 7b: Anaplastic Thyroid Cancer - Vemurafenib Participants with anaplastic thyroid cancer were treated with vemurafenib monotherapy. | 12 |
| Cohort 7c: Advanced Stage Astrocytoma - Vemurafenib Participants with advanced stage astrocytoma were treated with vemurafenib monotherapy. | 12 |
| Cohort 7d: Early Stage Astrocytoma - Vemurafenib Participants with early stage astrocytoma were treated with vemurafenib monotherapy. | 9 |
| Cohort 7: Other BRAF V600-positive Tumors - Vemurafenib Participants with other BRAF V600-positive tumors were treated with vemurafenib monotherapy. | 28 |
| Total | 208 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Death | 34 | 2 | 5 | 24 | 4 | 4 | 1 | 9 | 5 | 6 | 17 |
| Overall Study | Lost to Follow-up | 0 | 0 | 3 | 0 | 1 | 1 | 2 | 0 | 1 | 1 | 1 |
| Overall Study | Other | 16 | 2 | 1 | 2 | 1 | 3 | 17 | 1 | 2 | 2 | 5 |
| Overall Study | Withdrawal by Subject | 12 | 0 | 1 | 1 | 3 | 1 | 6 | 2 | 4 | 0 | 5 |
Baseline characteristics
| Characteristic | Cohort 1: Non-Small Cell Lung Cancer (NSCLC) - Vemurafenib | Cohort 2: Ovarian Cancer - Vemurafenib | Cohort 3a: Colorectal Cancer - Vemurafenib | Cohort 3b: Colorectal Cancer - Vemurafenib + Cetuximab | Cohort 4: Cholangiocarcinoma - Vemurafenib | Cohort 6: Multiple Myeloma - Vemurafenib | Cohort 7a: ECD/LCH - Vemurafenib | Cohort 7b: Anaplastic Thyroid Cancer - Vemurafenib | Cohort 7c: Advanced Stage Astrocytoma - Vemurafenib | Cohort 7d: Early Stage Astrocytoma - Vemurafenib | Cohort 7: Other BRAF V600-positive Tumors - Vemurafenib | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 65.4 years STANDARD_DEVIATION 10.2 | 45.8 years STANDARD_DEVIATION 5.3 | 57.3 years STANDARD_DEVIATION 5.4 | 64.3 years STANDARD_DEVIATION 8.8 | 53.2 years STANDARD_DEVIATION 9.7 | 62.1 years STANDARD_DEVIATION 4.3 | 60.8 years STANDARD_DEVIATION 13.3 | 66.8 years STANDARD_DEVIATION 9.2 | 41.6 years STANDARD_DEVIATION 12.2 | 34.3 years STANDARD_DEVIATION 20.7 | 53.7 years STANDARD_DEVIATION 17.5 | 59.0 years STANDARD_DEVIATION 14.5 |
| Sex: Female, Male Female | 27 Participants | 4 Participants | 5 Participants | 18 Participants | 5 Participants | 3 Participants | 14 Participants | 3 Participants | 8 Participants | 9 Participants | 15 Participants | 111 Participants |
| Sex: Female, Male Male | 35 Participants | 0 Participants | 5 Participants | 9 Participants | 4 Participants | 6 Participants | 12 Participants | 9 Participants | 4 Participants | 0 Participants | 13 Participants | 97 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 26 / 27 | 177 / 181 |
| serious Total, serious adverse events | 11 / 27 | 91 / 181 |
Outcome results
Primary
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.
Time frame: Up to approximately 3 years
Population: ITT population included all participants enrolled in the study irrespective of whether they had received study drug or not.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1: Non-Small Cell Lung Cancer (NSCLC) - Vemurafenib | Confirmed Best Overall Response Rate (BORR) | 37.1 percentage of participants |
| Cohort 2: Ovarian Cancer - Vemurafenib | Confirmed Best Overall Response Rate (BORR) | 50.0 percentage of participants |
| Cohort 3a: Colorectal Cancer - Vemurafenib | Confirmed Best Overall Response Rate (BORR) | 0 percentage of participants |
| Cohort 3b: Colorectal Cancer - Vemurafenib + Cetuximab | Confirmed Best Overall Response Rate (BORR) | 7.4 percentage of participants |
| Cohort 4: Cholangiocarcinoma - Vemurafenib | Confirmed Best Overall Response Rate (BORR) | 22.2 percentage of participants |
| Cohort 6: Multiple Myeloma - Vemurafenib | Confirmed Best Overall Response Rate (BORR) | 22.2 percentage of participants |
| Cohort 7a: ECD/LCH - Vemurafenib | Confirmed Best Overall Response Rate (BORR) | 61.5 percentage of participants |
| Cohort 7b: Anaplastic Thyroid Cancer - Vemurafenib | Confirmed Best Overall Response Rate (BORR) | 25.0 percentage of participants |
| Cohort 7c: Advanced Stage Astrocytoma - Vemurafenib | Confirmed Best Overall Response Rate (BORR) | 16.7 percentage of participants |
| Cohort 7d: Early Stage Astrocytoma - Vemurafenib | Confirmed Best Overall Response Rate (BORR) | 33.3 percentage of participants |
| Cohort 7: Other BRAF V600-positive Tumors - Vemurafenib | Confirmed Best Overall Response Rate (BORR) | 17.9 percentage of participants |
Secondary
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.
Time frame: Up to approximately 3 years
Population: ITT population included all participants enrolled in the study irrespective of whether they had received study medication or not.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1: Non-Small Cell Lung Cancer (NSCLC) - Vemurafenib | Duration of Response (DOR) | 7.16 months |
| Cohort 2: Ovarian Cancer - Vemurafenib | Duration of Response (DOR) | 8.16 months |
| Cohort 3a: Colorectal Cancer - Vemurafenib | Duration of Response (DOR) | NA months |
| Cohort 3b: Colorectal Cancer - Vemurafenib + Cetuximab | Duration of Response (DOR) | 6.54 months |
| Cohort 4: Cholangiocarcinoma - Vemurafenib | Duration of Response (DOR) | 12.86 months |
| Cohort 6: Multiple Myeloma - Vemurafenib | Duration of Response (DOR) | NA months |
| Cohort 7a: ECD/LCH - Vemurafenib | Duration of Response (DOR) | NA months |
| Cohort 7b: Anaplastic Thyroid Cancer - Vemurafenib | Duration of Response (DOR) | 9.95 months |
| Cohort 7c: Advanced Stage Astrocytoma - Vemurafenib | Duration of Response (DOR) | NA months |
| Cohort 7d: Early Stage Astrocytoma - Vemurafenib | Duration of Response (DOR) | 3.42 months |
| Cohort 7: Other BRAF V600-positive Tumors - Vemurafenib | Duration of Response (DOR) | 9.92 months |
Secondary
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.
Time frame: Up to approximately 3 years
Population: All participants from Cohort 3b who received at least one dose of study medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 3b: Colorectal Cancer - Vemurafenib + Cetuximab | Maximum Tolerated Dose for Vemurafenib in Combination With Cetuximab | vemurafenib | 960 milligrams (mg) |
| Cohort 3b: Colorectal Cancer - Vemurafenib + Cetuximab | Maximum Tolerated Dose for Vemurafenib in Combination With Cetuximab | cetuximab | 400 milligrams (mg) |
Secondary
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.
Time frame: Up to 28 days
Population: All participants from Cohort 3b who received at least one dose of study medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 3b: Colorectal Cancer - Vemurafenib + Cetuximab | Number of Dose-limiting Toxicities of Vemurafenib in Combination With Cetuximab | Grade 3 amylase increased | 1 dose-limiting toxicities |
| Cohort 3b: Colorectal Cancer - Vemurafenib + Cetuximab | Number of Dose-limiting Toxicities of Vemurafenib in Combination With Cetuximab | Grade 4 lipase increased | 1 dose-limiting toxicities |
Secondary
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.
Time frame: Up to approximately 3 years
Population: ITT population included all participants enrolled in the study irrespective of whether they had received study medication or not.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1: Non-Small Cell Lung Cancer (NSCLC) - Vemurafenib | Overall Response Rate (ORR) | VGPR | NA percentage of participants |
| Cohort 1: Non-Small Cell Lung Cancer (NSCLC) - Vemurafenib | Overall Response Rate (ORR) | sCR | NA percentage of participants |
| Cohort 1: Non-Small Cell Lung Cancer (NSCLC) - Vemurafenib | Overall Response Rate (ORR) | CR | 0 percentage of participants |
| Cohort 1: Non-Small Cell Lung Cancer (NSCLC) - Vemurafenib | Overall Response Rate (ORR) | PR | 37.1 percentage of participants |
| Cohort 2: Ovarian Cancer - Vemurafenib | Overall Response Rate (ORR) | PR | 50.0 percentage of participants |
| Cohort 2: Ovarian Cancer - Vemurafenib | Overall Response Rate (ORR) | VGPR | NA percentage of participants |
| Cohort 2: Ovarian Cancer - Vemurafenib | Overall Response Rate (ORR) | sCR | NA percentage of participants |
| Cohort 2: Ovarian Cancer - Vemurafenib | Overall Response Rate (ORR) | CR | 0 percentage of participants |
| Cohort 3a: Colorectal Cancer - Vemurafenib | Overall Response Rate (ORR) | VGPR | NA percentage of participants |
| Cohort 3a: Colorectal Cancer - Vemurafenib | Overall Response Rate (ORR) | sCR | NA percentage of participants |
| Cohort 3a: Colorectal Cancer - Vemurafenib | Overall Response Rate (ORR) | PR | 0 percentage of participants |
| Cohort 3a: Colorectal Cancer - Vemurafenib | Overall Response Rate (ORR) | CR | 0 percentage of participants |
| Cohort 3b: Colorectal Cancer - Vemurafenib + Cetuximab | Overall Response Rate (ORR) | VGPR | NA percentage of participants |
| Cohort 3b: Colorectal Cancer - Vemurafenib + Cetuximab | Overall Response Rate (ORR) | CR | 0 percentage of participants |
| Cohort 3b: Colorectal Cancer - Vemurafenib + Cetuximab | Overall Response Rate (ORR) | sCR | NA percentage of participants |
| Cohort 3b: Colorectal Cancer - Vemurafenib + Cetuximab | Overall Response Rate (ORR) | PR | 7.4 percentage of participants |
| Cohort 4: Cholangiocarcinoma - Vemurafenib | Overall Response Rate (ORR) | sCR | NA percentage of participants |
| Cohort 4: Cholangiocarcinoma - Vemurafenib | Overall Response Rate (ORR) | VGPR | NA percentage of participants |
| Cohort 4: Cholangiocarcinoma - Vemurafenib | Overall Response Rate (ORR) | PR | 22.2 percentage of participants |
| Cohort 4: Cholangiocarcinoma - Vemurafenib | Overall Response Rate (ORR) | CR | 0 percentage of participants |
| Cohort 6: Multiple Myeloma - Vemurafenib | Overall Response Rate (ORR) | sCR | 0 percentage of participants |
| Cohort 6: Multiple Myeloma - Vemurafenib | Overall Response Rate (ORR) | CR | 0 percentage of participants |
| Cohort 6: Multiple Myeloma - Vemurafenib | Overall Response Rate (ORR) | PR | 11.1 percentage of participants |
| Cohort 6: Multiple Myeloma - Vemurafenib | Overall Response Rate (ORR) | VGPR | 11.1 percentage of participants |
| Cohort 7a: ECD/LCH - Vemurafenib | Overall Response Rate (ORR) | VGPR | NA percentage of participants |
| Cohort 7a: ECD/LCH - Vemurafenib | Overall Response Rate (ORR) | sCR | NA percentage of participants |
| Cohort 7a: ECD/LCH - Vemurafenib | Overall Response Rate (ORR) | CR | 7.7 percentage of participants |
| Cohort 7a: ECD/LCH - Vemurafenib | Overall Response Rate (ORR) | PR | 53.8 percentage of participants |
| Cohort 7b: Anaplastic Thyroid Cancer - Vemurafenib | Overall Response Rate (ORR) | PR | 16.7 percentage of participants |
| Cohort 7b: Anaplastic Thyroid Cancer - Vemurafenib | Overall Response Rate (ORR) | VGPR | NA percentage of participants |
| Cohort 7b: Anaplastic Thyroid Cancer - Vemurafenib | Overall Response Rate (ORR) | sCR | NA percentage of participants |
| Cohort 7b: Anaplastic Thyroid Cancer - Vemurafenib | Overall Response Rate (ORR) | CR | 8.3 percentage of participants |
| Cohort 7c: Advanced Stage Astrocytoma - Vemurafenib | Overall Response Rate (ORR) | CR | 8.3 percentage of participants |
| Cohort 7c: Advanced Stage Astrocytoma - Vemurafenib | Overall Response Rate (ORR) | sCR | NA percentage of participants |
| Cohort 7c: Advanced Stage Astrocytoma - Vemurafenib | Overall Response Rate (ORR) | VGPR | NA percentage of participants |
| Cohort 7c: Advanced Stage Astrocytoma - Vemurafenib | Overall Response Rate (ORR) | PR | 8.3 percentage of participants |
| Cohort 7d: Early Stage Astrocytoma - Vemurafenib | Overall Response Rate (ORR) | VGPR | NA percentage of participants |
| Cohort 7d: Early Stage Astrocytoma - Vemurafenib | Overall Response Rate (ORR) | PR | 33.3 percentage of participants |
| Cohort 7d: Early Stage Astrocytoma - Vemurafenib | Overall Response Rate (ORR) | CR | 0 percentage of participants |
| Cohort 7d: Early Stage Astrocytoma - Vemurafenib | Overall Response Rate (ORR) | sCR | NA percentage of participants |
| Cohort 7: Other BRAF V600-positive Tumors - Vemurafenib | Overall Response Rate (ORR) | PR | 14.3 percentage of participants |
| Cohort 7: Other BRAF V600-positive Tumors - Vemurafenib | Overall Response Rate (ORR) | sCR | NA percentage of participants |
| Cohort 7: Other BRAF V600-positive Tumors - Vemurafenib | Overall Response Rate (ORR) | VGPR | NA percentage of participants |
| Cohort 7: Other BRAF V600-positive Tumors - Vemurafenib | Overall Response Rate (ORR) | CR | 3.6 percentage of participants |
Secondary
Overall Survival (OS)
OS was defined as time between the first day of study treatment and date of death of any cause.
Time frame: Up to approximately 3 years
Population: ITT population included all participants enrolled in the study irrespective of whether they had received study medication or not.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1: Non-Small Cell Lung Cancer (NSCLC) - Vemurafenib | Overall Survival (OS) | 15.38 months |
| Cohort 2: Ovarian Cancer - Vemurafenib | Overall Survival (OS) | NA months |
| Cohort 3a: Colorectal Cancer - Vemurafenib | Overall Survival (OS) | 9.30 months |
| Cohort 3b: Colorectal Cancer - Vemurafenib + Cetuximab | Overall Survival (OS) | 7.16 months |
| Cohort 4: Cholangiocarcinoma - Vemurafenib | Overall Survival (OS) | 17.94 months |
| Cohort 6: Multiple Myeloma - Vemurafenib | Overall Survival (OS) | 24.54 months |
| Cohort 7a: ECD/LCH - Vemurafenib | Overall Survival (OS) | NA months |
| Cohort 7b: Anaplastic Thyroid Cancer - Vemurafenib | Overall Survival (OS) | 5.88 months |
| Cohort 7c: Advanced Stage Astrocytoma - Vemurafenib | Overall Survival (OS) | 40.11 months |
| Cohort 7d: Early Stage Astrocytoma - Vemurafenib | Overall Survival (OS) | 12.75 months |
| Cohort 7: Other BRAF V600-positive Tumors - Vemurafenib | Overall Survival (OS) | 11.56 months |
Secondary
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.
Time frame: Up to approximately 3 years
Population: ITT population included all participants enrolled in the study irrespective of whether they had received study medication or not.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1: Non-Small Cell Lung Cancer (NSCLC) - Vemurafenib | Percentage of Participants With Confirmed Clinical Benefit | 48.4 percentage of participants |
| Cohort 2: Ovarian Cancer - Vemurafenib | Percentage of Participants With Confirmed Clinical Benefit | 50.0 percentage of participants |
| Cohort 3a: Colorectal Cancer - Vemurafenib | Percentage of Participants With Confirmed Clinical Benefit | 0 percentage of participants |
| Cohort 3b: Colorectal Cancer - Vemurafenib + Cetuximab | Percentage of Participants With Confirmed Clinical Benefit | 18.5 percentage of participants |
| Cohort 4: Cholangiocarcinoma - Vemurafenib | Percentage of Participants With Confirmed Clinical Benefit | 44.4 percentage of participants |
| Cohort 6: Multiple Myeloma - Vemurafenib | Percentage of Participants With Confirmed Clinical Benefit | 22.2 percentage of participants |
| Cohort 7a: ECD/LCH - Vemurafenib | Percentage of Participants With Confirmed Clinical Benefit | 76.9 percentage of participants |
| Cohort 7b: Anaplastic Thyroid Cancer - Vemurafenib | Percentage of Participants With Confirmed Clinical Benefit | 25.0 percentage of participants |
| Cohort 7c: Advanced Stage Astrocytoma - Vemurafenib | Percentage of Participants With Confirmed Clinical Benefit | 33.3 percentage of participants |
| Cohort 7d: Early Stage Astrocytoma - Vemurafenib | Percentage of Participants With Confirmed Clinical Benefit | 44.4 percentage of participants |
| Cohort 7: Other BRAF V600-positive Tumors - Vemurafenib | Percentage of Participants With Confirmed Clinical Benefit | 17.9 percentage of participants |
Secondary
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.
Time frame: Up to approximately 3 years
Population: ITT population included all participants enrolled in the study irrespective of whether they had received study medication or not.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1: Non-Small Cell Lung Cancer (NSCLC) - Vemurafenib | Progression Free Survival (PFS) | 6.51 months |
| Cohort 2: Ovarian Cancer - Vemurafenib | Progression Free Survival (PFS) | 6.44 months |
| Cohort 3a: Colorectal Cancer - Vemurafenib | Progression Free Survival (PFS) | 3.88 months |
| Cohort 3b: Colorectal Cancer - Vemurafenib + Cetuximab | Progression Free Survival (PFS) | 3.68 months |
| Cohort 4: Cholangiocarcinoma - Vemurafenib | Progression Free Survival (PFS) | 3.02 months |
| Cohort 6: Multiple Myeloma - Vemurafenib | Progression Free Survival (PFS) | 4.63 months |
| Cohort 7a: ECD/LCH - Vemurafenib | Progression Free Survival (PFS) | NA months |
| Cohort 7b: Anaplastic Thyroid Cancer - Vemurafenib | Progression Free Survival (PFS) | 2.83 months |
| Cohort 7c: Advanced Stage Astrocytoma - Vemurafenib | Progression Free Survival (PFS) | 9.59 months |
| Cohort 7d: Early Stage Astrocytoma - Vemurafenib | Progression Free Survival (PFS) | 5.26 months |
| Cohort 7: Other BRAF V600-positive Tumors - Vemurafenib | Progression Free Survival (PFS) | 3.12 months |
Secondary
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.
Time frame: Up to approximately 3 years
Population: The safety population included all participants who received at least one dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1: Non-Small Cell Lung Cancer (NSCLC) - Vemurafenib | Safety: Percentage of Participants With Adverse Event | 100 percentage of participants |
| Cohort 2: Ovarian Cancer - Vemurafenib | Safety: Percentage of Participants With Adverse Event | 100 percentage of participants |
| Cohort 3a: Colorectal Cancer - Vemurafenib | Safety: Percentage of Participants With Adverse Event | 100 percentage of participants |
| Cohort 3b: Colorectal Cancer - Vemurafenib + Cetuximab | Safety: Percentage of Participants With Adverse Event | 100 percentage of participants |
| Cohort 4: Cholangiocarcinoma - Vemurafenib | Safety: Percentage of Participants With Adverse Event | 100 percentage of participants |
| Cohort 6: Multiple Myeloma - Vemurafenib | Safety: Percentage of Participants With Adverse Event | 100 percentage of participants |
| Cohort 7a: ECD/LCH - Vemurafenib | Safety: Percentage of Participants With Adverse Event | 100 percentage of participants |
| Cohort 7b: Anaplastic Thyroid Cancer - Vemurafenib | Safety: Percentage of Participants With Adverse Event | 91.7 percentage of participants |
| Cohort 7c: Advanced Stage Astrocytoma - Vemurafenib | Safety: Percentage of Participants With Adverse Event | 100 percentage of participants |
| Cohort 7d: Early Stage Astrocytoma - Vemurafenib | Safety: Percentage of Participants With Adverse Event | 100 percentage of participants |
| Cohort 7: Other BRAF V600-positive Tumors - Vemurafenib | Safety: Percentage of Participants With Adverse Event | 100 percentage of participants |
Secondary
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.
Time frame: Up to approximately 3 years
Population: ITT population included all participants enrolled in the study irrespective of whether they had received study medication or not.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1: Non-Small Cell Lung Cancer (NSCLC) - Vemurafenib | Time to Response | 7.26 months |
| Cohort 2: Ovarian Cancer - Vemurafenib | Time to Response | NA months |
| Cohort 3a: Colorectal Cancer - Vemurafenib | Time to Response | NA months |
| Cohort 3b: Colorectal Cancer - Vemurafenib + Cetuximab | Time to Response | NA months |
| Cohort 4: Cholangiocarcinoma - Vemurafenib | Time to Response | NA months |
| Cohort 6: Multiple Myeloma - Vemurafenib | Time to Response | 5.75 months |
| Cohort 7a: ECD/LCH - Vemurafenib | Time to Response | 5.49 months |
| Cohort 7b: Anaplastic Thyroid Cancer - Vemurafenib | Time to Response | NA months |
| Cohort 7c: Advanced Stage Astrocytoma - Vemurafenib | Time to Response | NA months |
| Cohort 7d: Early Stage Astrocytoma - Vemurafenib | Time to Response | NA months |
| Cohort 7: Other BRAF V600-positive Tumors - Vemurafenib | Time to Response | NA months |
Secondary
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.
Time frame: Up to approximately 3 years
Population: ITT population included all participants enrolled in the study irrespective of whether they had received study medication or not.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1: Non-Small Cell Lung Cancer (NSCLC) - Vemurafenib | Time to Tumor Progression (TTP) | 7.33 months |
| Cohort 2: Ovarian Cancer - Vemurafenib | Time to Tumor Progression (TTP) | 6.44 months |
| Cohort 3a: Colorectal Cancer - Vemurafenib | Time to Tumor Progression (TTP) | 3.88 months |
| Cohort 3b: Colorectal Cancer - Vemurafenib + Cetuximab | Time to Tumor Progression (TTP) | 3.68 months |
| Cohort 4: Cholangiocarcinoma - Vemurafenib | Time to Tumor Progression (TTP) | 3.02 months |
| Cohort 6: Multiple Myeloma - Vemurafenib | Time to Tumor Progression (TTP) | 4.63 months |
| Cohort 7a: ECD/LCH - Vemurafenib | Time to Tumor Progression (TTP) | NA months |
| Cohort 7b: Anaplastic Thyroid Cancer - Vemurafenib | Time to Tumor Progression (TTP) | 2.83 months |
| Cohort 7c: Advanced Stage Astrocytoma - Vemurafenib | Time to Tumor Progression (TTP) | 5.62 months |
| Cohort 7d: Early Stage Astrocytoma - Vemurafenib | Time to Tumor Progression (TTP) | 5.36 months |
| Cohort 7: Other BRAF V600-positive Tumors - Vemurafenib | Time to Tumor Progression (TTP) | 3.65 months |