Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Label indication ZELBORAF ® is a kinase inhibitor indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test. ( 1.1 , 2.1 ) ZELBORAF ® is indicated for the treatment of patients with Erdheim- Chester Disease with BRAF V600 mutation. FDA label
Also known as Vemurafenib, Zelboraf, Vemurafenib (All Groups), PLX4032
RO5185426 · 22 trials · 10 indications
Progression-free survival was defined as the time from randomization to the first occurrence of disease progression, as determined by the investigator using Response Evaluation Criteria in Solid Tumors v1.1, or death from any cause, whichever came first. Disease progression was defined as: (1) at least a 20% increase in the sum (the increase in the sum must be at least 5 mm) of diameters of target lesions, taking as reference the smallest sum during the study; (2) unequivocal progression of existing non-target lesions; or (3) the appearance of 1 or more new lesions.
DFS was defined as the time from randomization until the date of the first local, regional, or distant melanoma recurrence, occurrence of new primary melanoma, or death from any cause.
The intensity of AEs were graded on a 5-point scale (Grade 1 to 5) according to the NCI-CTCAE version 4.0, where Grade 1 indicates "Mild" severity and Grade 5 indicates "Death". The CTCAE defines Grades 3 and 4 as follows: Grade 3 means "Severe"; Inability to work or perform normal daily activity; treatment or medical intervention is indicated in order to improve the overall well-being or symptoms; delaying the onset of treatment is not putting the survival of the participant at direct risk. Grade 4 means "Life-threatening, Disabling"; based on extreme limitation in activity; significant medical intervention/therapy required; and hospitalization probable.
An AE was considered as any unfavorable and unintended sign, symptom, or disease associated with the use of the study drug, whether or not considered related to the study drug. Pre existing conditions that worsened during the study and laboratory or clinical tests that resulted in a change in treatment or discontinuation from study drug were reported as adverse events. Percentage of participants with dose interruption or discontinuation due to AE was presented.
AEs of special interest included cutaneous squamous cell carcinoma (SCC), rash, photosensitivity, liver injury, arthralgia, fatigue, gastrointestinal (GI) polyps, pancreatitis, potentiation of radiation toxicity, prolongation of cardiac repolarization or arrhythmia, non-cutaneous SCC and other primary malignancies (other than cutaneous SCC or new primary melanoma).
Exposure excluding treatment interruptions: Duration during which participants actually took vemurafenib. Any time without dose-taken due to adverse events, non-compliance or any other reasons was not counted. Exposure including treatment interruptions: date of last dose - date of first dose + 1; duration during which participants actually took vemurafenib as well as duration on which medication was not taken were included in this calculation.
Exposure excluding treatment interruptions: Duration during which participants actually took vemurafenib. Any time without dose-taken due to adverse events, non-compliance or any other reasons was not counted. Exposure including treatment interruptions: date of last dose - date of first dose + 1; duration during which participants actually took vemurafenib as well as duration on which medication was not taken were included in this calculation. Average total dose per day: total actual dose taken divided by total actual days on treatment.
Dose intensity was defined as (total actual doses taken/total planned doses) \*100, where total planned doses = prescribed doses \* planned days on treatment, where planned days on treatment were defined as the interval between date of first dose and date of last dose.
An Overall survival event was defined as death due to any cause. The number of participants with overall survival events is reported.
per CTCAE v5.0 within first 6 months from the start of the treatment to account delayed toxicities of the treatments
ERK phosphorylation and tumor size measured at baseline before first dose of Vemurafenib and again after 56 days of Vemurafenib. We will test whether correlation between percent change in ERK phosphorylation and percent change in tumor size is different from 0 with a t-test.
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.
BORR assessed by IRC is defined as percentage of participants who were responders \[with best overall response (BOR) documented as confirmed complete response (CR) or partial response (PR)\]. The RECIST v1.1 criteria modified for independent review of body and brain lesions was based on current radiology practices. The modifications to RECIST v1.1 included allowing target lesions in the brain to be \>=5 mm by contrast-enhanced magnetic resonance imaging scan (in traditional RECIST v1.1 this is \>=10 mm), allowing up to 5 target lesions in the brain (in traditional RECIST v1.1 only 2 target lesions), and examining the lesions within the brain and outside the brain separately for analytical purposes. CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (\<) 10 millimeters (mm), PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Best overall response rate was assessed by the investigators according to the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Best overall response rate: the percentage of participants with best objective response of complete response (CR) or partial response (PR) (calculated as the number of participants with best response CR or PR divided by the total number of efficacy-evaluable participants). CR: disappearance of all target lesions with reduction in target/non-target pathological lymph nodes to \< 10 millimeters (mm). PR: ≥ 30% decrease in the sum of diameters of target lesions, compared to the baseline sum diameters.
An Adverse Event (AE) is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. AEs will be graded according to the 'National Cancer Institute Common Terminology Criteria for Adverse Events' (NCI CTCAE, v4.0). However Laboratory data will be summarized by grade using the NCI CTCAE, v4.0 toxicity grade.
Serious Adverse Event (SAEs) is defined as those events that were fatal or immediately life-threatening, and those events that resulted in hospitalization; prolonged an existing hospitalization; resulted in disability; or was a congenital anomaly. Number of participants who died and the cause of death are also recorded.
AE:any unfavorable and unintended sign, symptom, or disease associated with use of study drug, regardless of relation to study drug. Pre-existing conditions that worsened and laboratory or clinical tests that resulted in change in treatment or discontinuation from study drug were reported as AEs. Serious AE: resulted in death, life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was congenital anomaly/birth defect or was medically significant. Grade-1:discomfort but no disruption of normal daily activity. Grade-2:discomfort sufficient to reduce or affect daily activity,no intervention indicated.Grade-3:inability to perform normal daily activity,intervention indicated.Grade-4:immediate threat to life or leading to permanent mental or physical condition that prevented performing normal daily activities.Grade 5: death. Any AE included participants with serious and non-serious AE.
BOR was defined as a complete response (CR) or partial response (PR) confirmed per Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. Patients who never received study treatment and treated patients without any post-baseline tumor assessments were considered as non-responders. CR: Disappearance of all target lesions, all non-target lesions, and no new lesion. Any pathological lymph nodes must have had reduction in the short axis to \<10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, no progression in non-target lesion, and no new lesion.
%F is the ratio of dose normalized AUCtau following vemurafenib oral dose to dose normalized AUC0-inf following IV dose. Time Frame: Vemurafenib oral dose (Day 21: Predose \[0 hour\]; 15 minutes after oral dose \[at the end of IV infusion\], at 30 and 45 minutes, and 1.15, 2.25, 3.25, 4.25, 6.25, 8.25, and 12 hours following oral administration of unlabeled vemurafenib); Vemurafenib IV dose (Day 21: Predose \[Hour 0\]; end of infusion \[infusion duration: 15 minutes\]; 5, 15 and 30 minutes post-infusion; 1, 2, 3, 4, 6, 8, 12 hours post-infusion of 14C-labeled vemurafenib).
Plasma PK samples were obtained from each participant for calculation of AUC from 0 to 8 hours, using the linear trapezoid rule. The value was averaged among all participants and expressed in hours by micrograms per milliliter (h\*μg/mL).
Plasma PK samples were obtained from each participant for calculation of AUC from 0 to 8 hours, using the linear trapezoid rule. The value was averaged among all participants and expressed in h\*μg/mL.
Plasma PK samples were obtained from each participant for calculation of AUC from 0 to 12 hours, using the linear trapezoid rule. The value was averaged among all participants and expressed in h\*μg/mL.
Plasma PK samples were obtained from each participant for calculation of AUC from 0 to 12 hours, using the linear trapezoid rule. The value was averaged among all participants and expressed in h\*μg/mL.
Plasma PK samples were obtained from each participant, and the maximum observed post-dose concentration was recorded. The value was averaged among all participants and expressed in micrograms per milliliter (μg/mL).
Plasma PK samples were obtained from each participant, and the maximum observed post-dose concentration was recorded. The value was averaged among all participants and expressed in μg/mL.
Plasma PK samples were obtained from each participant, and the time of maximum post-dose concentration was recorded. The median value was derived from all participants and expressed in hours.
Plasma PK samples were obtained from each participant, and the time of maximum post-dose concentration was recorded. The median value was derived from all participants and expressed in hours.
Plasma PK samples were obtained from each participant for calculation of AUC from 0 to 168 hours, using the linear trapezoid rule. The value was averaged among all participants and expressed in h\*μg/mL.
Plasma PK samples were obtained from each participant for calculation of t1/2, defined as the time elapsed for plasma concentrations to drop by half. The value was averaged among all participants and expressed in hours.
Plasma PK samples were obtained from each participant, and the concentration immediately prior to drug administration was recorded. The value was averaged among all participants and expressed in μg/mL.
Plasma PK samples were obtained from each participant, and the concentration immediately prior to drug administration was recorded. The value was averaged among all participants and expressed in μg/mL.
Plasma PK samples were obtained from each participant, and the concentration immediately prior to drug administration was recorded. The value was averaged among all participants and expressed in μg/mL.
Plasma PK samples were obtained from each participant for calculation of AUC from 0 to 8 hours, using the linear trapezoid rule. The AUC on Day 21 was divided by the AUC for Day 1. The resulting value was averaged among all participants and expressed as the accumulation ratio.
Plasma PK samples were obtained from each participant and the kel was estimated. The value was averaged among all participants and expressed in inverse hours (h\^-1).
AUClast is the area under the vemurafenib plasma concentration versus time curve from time zero to the time of last measured concentration of vemurafenib (Tlast). Area under the curve (AUC) is a measure of the plasma concentration of a drug over time. AUClast is presented in micrograms times (\*) hour per milliliter (mcg\*h/mL).
AUC(0-inf) is the AUC from time zero (pre-dose) to extrapolated infinite time (0-inf). AUC is a measure of the plasma concentration of a drug over time. AUC(0-inf) is presented in mcg\*h/mL.
Cmax is the maximum observed plasma vemurafenib concentration, presented in microgram per milliliter (mcg/mL).
AUClast = Area under the plasma-concentration time curve from time zero to the last measurable plasma concentration which is presented in hour\*nanogram per milliliter (hour\*ng/mL). Hour 0 (H0) signified pre-dose sampling.
Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population PK modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.
Pharmacokinetic (PK) analyses was performed after the completion of Period A and Period B of this study for all participants.
PK analyses was performed after the completion of Period A and Period B of this study for all participants.
PK analyses was performed after the completion of Period A and Period B of this study for all participants.
Single dose Pre-dose concentration is referred as Cmin here. PK analyses was performed after the completion of Period A and Period B of this study for all participants.
PK analyses was performed after the completion of Period A and Period B of this study for all participants.
T1/2 is the time required for the concentration of the drug to reach half of its original value. PK analyses was performed after the completion of Period A and Period B of this study for all participants.
Apparent first-order terminal elimination rate constant (kel), was calculated as the negative slope of the linear regression of the terminal phase in plasma vemurafenib concentration-time profile using specific appropriate time points. PK analyses was performed after the completion of Period A and Period B of this study for all participants.
Collection of samples continued until the recovery criterion was met (radioactivity recovered from urine and feces ≤ 1 % of the radioactivity in the administered dose between any two successive 48-hour interval assessments). 14C-labeled RO5185426 given was equivalent to ≤1 millisieverts (mSv).
Collection of samples continued until the recovery criterion was met (radioactivity recovered from urine and feces ≤ 1 % of the radioactivity in the administered dose between any two successive 48-hour interval assessments).
Collection of samples continued until the recovery criterion was met (radioactivity recovered from urine and feces ≤ 1 % of the radioactivity in the administered dose between any two successive 48-hour interval assessments). 14C-labeled RO5185426 given was equivalent to ≤1mSv.
Collection of samples continued until the recovery criterion was met (radioactivity recovered from urine and feces ≤ 1 % of the radioactivity in the administered dose between any two successive 48-hour interval assessments).
Collection of samples continued until the recovery criterion was met (radioactivity recovered from urine and feces ≤ 1 % of the radioactivity in the administered dose between any two successive 48-hour interval assessments).
Urinary and fecal samples were analyze for the percentage dose recovered as total radioactivity. The radioactivity was determined on a Packard liquid scintillation counter. Collection of samples continued until the recovery criterion was met (radioactivity recovered from urine and feces ≤ 1 % of the radioactivity in the administered dose between any two successive 48-hour interval assessments).
Collection of samples continued until the recovery criterion was met (radioactivity recovered from urine and feces ≤ 1 % of the radioactivity in the administered dose between any two successive 48-hour interval assessments). Plasma samples were pooled over three time intervals for this analysis based on available radioactive counts (4 + 6 hours, 12 + 24 hours, and 36 + 48 hours). Radioactivity was measured in terms of region of interest by high performance liquid chromatography. The radiolabelled components in each chromatogram were evaluated to determine retention times and peak area values. Data for 14C-labeled RO5185426 and 14C-labeled metabolite (mono-hydroxy) are reported.
Collection of samples for radioactivity continued until the recovery criterion was met (radioactivity recovered from urine and feces ≤ 1 % of the radioactivity in the administered dose between any two successive 48 hour interval assessments). Plasma samples were pooled over three time intervals for this analysis based on available radioactive counts (4 + 6 hours, 12 + 24 hours, and 36 + 48 hours). The concentrations were measured in nanogram equivalent per gram which was calculated based on ratio of dosed radioactivity and the last dose of RO5185426. The concentration values represented the drug portion of the last dose. Data for 14C-labeled RO5185426 and 14C-labeled metabolite (mono-hydroxy) are reported.
Collection of samples continued until the recovery criterion was met (radioactivity recovered from urine and feces ≤ 1 % of the radioactivity in the administered dose between any two successive 48-hour interval assessments). Fecal samples were pooled over two time intervals for this analysis (0-24 + 24-48 hours, 48-72 + 72-96 hours). Radioactivity was measured in terms of region of interest by high performance liquid chromatography. The radiolabelled components in each chromatogram were evaluated to determine retention times and peak area values. Data for 14C-labeled RO5185426 and 14C-labeled metabolites (glucosylation, mono-hydroxy, and glucuronide) are reported.
Collection of samples continued until the recovery criterion was met (radioactivity recovered from urine and feces ≤ 1 % of the radioactivity in the administered dose between any two successive 48-hour interval assessments). Fecal samples were pooled over 2 time intervals (0-24 + 24-48 hours, 48-72 + 72-96 hours) for measurement of 14C-labeled RO5185426 and 14C-labeled metabolites (glucosylation, mono-hydroxy, glucuronide) levels.
Collection of samples continued until the recovery criterion was met (radioactivity recovered from urine and feces ≤ 1 % of the radioactivity in the administered dose between any two successive 48-hour interval assessments). Urine samples were pooled over period of 96 hours (pool of 0-6 + 6-12 + 12-24 + 24-48 + 48-72 + 72-96 hour samples), Radioactivity was measured in terms of region of interest by high performance liquid chromatography. The radiolabelled components in each chromatogram were evaluated to determine retention times and peak area values. Data for 14C-labeled RO5185426 and 14C-labeled metabolites (2 unknown metabolites, glucosylation, mono-hydroxy) are reported.
Collection of samples continued until the recovery criterion was met (radioactivity recovered from urine and feces ≤ 1 % of the radioactivity in the administered dose between any two successive 48-hour interval assessments). Urine samples were pooled over period of 96 hours (pool of 0-6 + 6-12 + 12-24 + 24-48 + 48-72 + 72-96 hour samples). Data for parent drug (RO5185426) and metabolites (2 unknown metabolites, glucosylation, mono-hydroxy) are reported.
Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed.
Time measured for vemurafenib plasma concentrations to decrease by one-half (t1/2) was calculated as 0.693 divided by apparent first-order terminal elimination rate constant (0.693/kel).
Accumulation ratio was calculated as, AUC(0-8) on Day 15 divided by AUC(0-8) on Day 1.
AUC (0-8 hour) was defined as the area under the plasma concentration-time curve from time equals zero (0) to 8 hours post-dose. AUC (0-24 hour) was defined as the area under the plasma concentration-time curve from time equals 0 to 24 hours post-dose. AUC (0-8 hour) and AUC (0-24 hour) were computed using the linear trapezoidal rule.
AUC (0-8 hour) was defined as the area under the plasma concentration-time curve from time equals 0 to 8 hours post-dose. AUC (0-24 hour) was defined as the area under the plasma concentration-time curve from time equals 0 to 24 hours post-dose. AUC (0-8 hour) and AUC (0-24 hour) were computed using the linear trapezoidal rule.
AUC (0-8 hour) was defined as the area under the plasma concentration-time curve from time equals zero (0) to 8 hours post-dose. AUC (0-24 hour) was defined as the area under the plasma concentration-time curve from time equals 0 to 24 hours post-dose. AUC (0-8 hour) and AUC (0-24 hour) were computed using the linear trapezoidal rule.
AUC (0-8 hour) was defined as the area under the plasma concentration-time curve from time equals zero (0) to 8 hours post-dose. AUC (0-24 hour) was defined as the area under the plasma concentration-time curve from time equals 0 to 24 hours post-dose. AUC (0-8 hour) and AUC (0-24 hour) were computed using the linear trapezoidal rule.
Accumulation ratio is the ratio of AUC (0-8 hour) on Day 15 / AUC (0-8 hour) on Day 1.
Accumulation ratio is the ratio of AUC (0-8 hour) on Day 15 / AUC (0-8 hour) on Day 1.
AUC (0-8 hour) was defined as the area under the plasma concentration-time curve from time equals zero (0) to 8 hours post-dose. AUC (0-24 hour) was defined as the area under the plasma concentration-time curve from time equals 0 to 24 hours post-dose. AUC (0-8 hour) and AUC (0-24 hour) were computed using the linear trapezoidal rule.
AUC (0-8 hour) was defined as the area under the plasma concentration-time curve from time equals 0 to 8 hours post-dose. AUC (0-24 hour) was defined as the area under the plasma concentration-time curve from time equals 0 to 24 hours post-dose. AUC (0-8 hour) and AUC (0-24 hour) were computed using the linear trapezoidal rule.
BOR of confirmed /unconfirmed (total) response was defined as CR or PR recorded from baseline until disease progression/recurrence according to Response Evaluation Criteria In Solid Tumors (RECIST) v 1.0 criteria. For target lesions (TLs), CR was defined as the disappearance of all TLs, and PR was defined as at least a 30 percent (%) decrease in the sum of longest diameters of the TLs, taking as a reference the baseline (BL) sum of longest diameters. For non-target lesions (NTLs), CR was defined as the disappearance of all NTLs and normalization of tumor marker levels. Confirmed responses were those which were confirmed by repeat assessments performed no less than four weeks after the criteria for response are first met. Percentage of participants with best overall response rate was calculated as the (number of participants with CR or PR) divided by (total number of participants in the cohort), and then multiplied by 100. The 95% Cl was determined using the Pearson-Clopper method.
BOR of CR or PR was recorded from baseline until disease progression/recurrence according to RECIST v 1.0 criteria. For TLs, CR was defined as the disappearance of all TLs, and PR was defined as at least a 30% decrease in the sum of longest diameters of the TLs, taking as a reference the BL sum of longest diameters. For NTLs, CR was defined as the disappearance of all NTLs and normalization of tumor marker levels. Confirmed responses were those which were confirmed by repeat assessments performed no less than four weeks after the criteria for response are first met Percentage of participants with best overall response rate was calculated as the (number of participants with CR or PR) divided by (total number of participants in the cohort), and then multiplied by 100. The 95% Cl was determined using the Pearson-Clopper method.
BOR of CR or PR was recorded from baseline until disease progression/recurrence according to RECIST v 1.0 criteria. For TLs, CR was defined as the disappearance of all TLs, and PR was defined as at least a 30% decrease in the sum of longest diameters of the TLs, taking as a reference the BL sum of longest diameters. For NTLs, CR was defined as the disappearance of all NTLs and normalization of tumor marker levels. Percentage of participants with best overall response rate was calculated as the (number of participants with CR or PR) divided by (total number of participants in the cohort), and then multiplied by 100. The 95% Cl was determined using the Pearson-Clopper method.
BOR of CR or PR was recorded from baseline until disease progression/recurrence according to RECIST v 1.0 criteria. For TLs, CR was defined as the disappearance of all TLs, and PR was defined as at least a 30% decrease in the sum of longest diameters of the TLs, taking as a reference the BL sum of longest diameters. For NTLs, CR was defined as the disappearance of all NTLs and normalization of tumor marker levels. Percentage of participants with best overall response rate was calculated as the (number of participants with CR or PR) divided by (total number of participants in the cohort), and then multiplied by 100. The 95% Cl was determined using the Pearson-Clopper method.
| Arm | Type | Description |
|---|---|---|
| Placebo + Vemurafenib | ACTIVE_COMPARATOR | Participants will receive placebo orally once daily on Days 1-21 of each 28-day cycle plus vemurafenib 960 milligrams (mg) orally twice a day on Days 1-28 of each 28-day cycle until disease progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs earliest. |
| Cobimetinib + Vemurafenib | EXPERIMENTAL | Participants will receive cobimetinib 60 mg orally once daily on Days 1-21 of each 28-day cycle plus vemurafenib 960 mg orally twice a day on Days 1-28 of each 28-day cycle until disease progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs earliest. |
| Cohort 1 Vemurafenib | EXPERIMENTAL | Participants with completely resected Stage IIC, IIIA, or IIIB cutaneous melanoma) received vemurafenib, 960 milligrams (mg) twice daily, in 28-day cycles, for up to 52 weeks |
| Cohort 1 Placebo | PLACEBO_COMPARATOR | Participants with completely resected Stage IIC, IIIA, or IIIB cutaneous melanoma) received vemurafenib-matching placebo twice daily, in 28-day cycles, for up to 52 weeks |
| Cohort 2 Vemurafenib | EXPERIMENTAL | Participants with Stage IIIC cutaneous melanoma received vemurafenib, 960 mg twice daily, in 28-day cycles, for up to 52 weeks |
| Cohort 2 Placebo | PLACEBO_COMPARATOR | Participants with Stage IIIC cutaneous melanoma received vemurafenib-matching placebo twice daily, in 28-day cycles, for up to 52 weeks |
| Vemurafenib | EXPERIMENTAL | Participants will receive vemurafenib at a dose of 960 milligrams (mg) twice daily (bid) until the development of progressive disease, unacceptable toxicity, consent withdrawal, protocol violations endangering participant's safety, death, or study termination by the Sponsor, whichever occurs first. |
| Dacarbazine | ACTIVE_COMPARATOR | - |
| Vemurafenib plus Obinutuzumab | EXPERIMENTAL | Patients assigned to the study arm will receive vemurafenib orally twice daily (b.i.d.) continuously in cycles of 4 weeks (28 days) for a total of 4 cycles. Obinutuzumab will be administered concomitantly with vemurafenib starting at cycle 2 of treatment in cycles of 4 weeks. Obinutuzumab infusions will be administered on days 1, 8 and 15 during the cycle 2 and every 4 weeks during the cycle 3 and 4 of treatment. |
| Standard treatment of Cladribine plus Rituximab | ACTIVE_COMPARATOR | Patients assigned to the SOC arm will receive cladribine IV on days 1-5 concurrently with rituximab IV per week for 8 times, i.e., weekly x8 from day 1. |
| Vemurafenib - (Presurgery) | EXPERIMENTAL | All Groups: Vemurafenib 960 mg by mouth 2 times a day for 56 days prior to surgery (patients not planned for surgical resection will have a core biopsy at day 56 +/- 7 days). |
| Vemurafenib (Post Surgery) - Group A | EXPERIMENTAL | Vemurafenib 960 mg by mouth two times a day 2 weeks post-surgery, or if patients have not sufficiently recovered at that point, as soon as their condition permits. Patients in Group A restaged 8 weeks after resuming drug. If patients in Group A demonstrate either stable or regressing disease, they will continue on vemurafenib with restaging occurring every 8 weeks until no longer benefitting from the drug. |
| Post Surgery - Group B | NO_INTERVENTION | Post Surgery - Group B: Patients discontinue vemurafenib after surgery but will be restaged with CT neck 8 weeks after surgery. |
| Vemurafenib - Group C | EXPERIMENTAL | Patients not scheduled for surgical resection undergo a CT scan and core biopsy at day 56, Vemurafenib 960 mg by mouth twice a day unless there is evidence of progressive disease on day 56 CT scan. Patients evaluated for resectability after each CT scan is performed. If scheduled for resection, patient continues vemurafenib until surgery and follows same treatment schema as patients in Groups A and B. |
| Cohort 1: Non-Small Cell Lung Cancer (NSCLC) - vemurafenib | EXPERIMENTAL | Participants with NSCLC will be treated with vemurafenib monotherapy. |
| Cohort 2: Ovarian Cancer - vemurafenib | EXPERIMENTAL | Participants with ovarian cancer will be treated with vemurafenib monotherapy. |
| Cohort 3a: Colorectal Cancer - vemurafenib | EXPERIMENTAL | Participants with colorectal cancer will be treated with vemurafenib monotherapy. |
| Cohort 3b: Colorectal Cancer - vemurafenib + cetuximab | EXPERIMENTAL | Participants with colorectal cancer will be treated with vemurafenib and cetuximab combination therapy. |
| Cohort 4: Cholangiocarcinoma - vemurafenib | EXPERIMENTAL | Participants with cholangiocarcinoma will be treated with vemurafenib monotherapy. |
| Cohort 6: Multiple Myeloma - vemurafenib | EXPERIMENTAL | Participants with multiple myeloma will be treated with vemurafenib monotherapy. |
| Cohort 7: Other Solid Tumors - vemurafenib | EXPERIMENTAL | 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. |
| Cohort 1: Previously Untreated Participants | EXPERIMENTAL | Participants who had not received previous treatment for brain metastases \[i.e., had never received brain stereotactic radiotherapy (SRT), whole-brain radiotherapy (WBRT), surgery, or any other treatment for their brain metastases\] received Vemurafenib 960 milligram (mg) tablet orally, twice daily (BID) from Day 1 until development of progressive disease within the brain or outside of the brain (whichever occurred first), unacceptable toxicity, consent withdrawal, protocol violation endangering participant's safety, death, reasons deemed by the investigator, or study termination by the Sponsor. |
| Cohort 2: Previously treated Participants | EXPERIMENTAL | Participants who were previously treated with brain SRT, WBRT, or surgery for their brain metastases and have progressed following this treatment, received Vemurafenib 960 milligram (mg) tablet orally, BID from Day 1 until development of progressive disease within the brain or outside of the brain (whichever occurred first), unacceptable toxicity, consent withdrawal, protocol violation endangering participant's safety, death, reasons deemed by the investigator, or study termination by the Sponsor. |
| Tyrosine Kinase Inhibitor (TKI) Naive | EXPERIMENTAL | Vemurafenib in participants naive to any prior systemic TKI therapy. |
| TKI Experienced | EXPERIMENTAL | Vemurafenib in participants previously treated with TKI therapy active against vascular endothelial growth factor receptor 2 (VEGFR). |
| Overall Trial | EXPERIMENTAL | Participants received vemurafenib 960 milligram (mg) orally two times a day for up to one year. Participants were treated until disease progression, unmanageable toxicity most probably attributable to vemurafenib, withdrawal of consent, and study termination by the sponsor |
| Single Arm | EXPERIMENTAL | - |
| Part 1: Vemurafenib+Itraconazole | EXPERIMENTAL | Part 1: Participants will receive vemurafenib orally BID up to Day 20 (Period A) followed by vemurafenib orally BID along with itraconazole orally once in the morning from Days 21 to 40 (Period B).\\nPart 2: Participants will receive vemurafenib orally BID up to Day 20 (Period A) followed by vemurafenib orally BID along with rifampin orally once in the morning from Days 21 to 40 (Period B). |
| Cohort 1: Participants with Normal Liver Function | ACTIVE_COMPARATOR | Participants with normal liver function (according to National Cancer Institute \[NCI\] liver dysfunction criteria) will receive vemurafenib 960 mg BID from Day 1 until the morning dose on Day 20 and then from Day 27 onward until disease progression, safety-related treatment termination, withdrawal of consent, death, or a decision by the Sponsor to terminate the study, whichever occurs first. |
| Cohort 2: Participants with Severe Liver Dysfunction | EXPERIMENTAL | Participants with severe liver dysfunction (according to NCI liver dysfunction criteria) will receive vemurafenib 720 mg BID from Day 1 until the morning dose on Day 20 and then from Day 27 onward until disease progression, safety-related treatment termination, withdrawal of consent, death, or a decision by the Sponsor to terminate the study, whichever occurs first. |
| Vemurafenib: Pharmacokinetic Cohort | EXPERIMENTAL | Participants will receive vemurafenib orally as 960 mg twice daily on Days 1 to 21 (morning dose only on Day 21), with a drug holiday from Days 22 to 27, and from Day 28 until progression, unacceptable toxicity, consent withdrawal, decision by the investigator or Sponsor, or protocol/eligibility violation. |
| Vemurafenib: Expansion Cohort | EXPERIMENTAL | Participants will receive vemurafenib orally as 960 mg twice daily from Day 1 until progression, unacceptable toxicity, consent withdrawal, decision by the investigator or Sponsor, or protocol/eligibility violation. |
| Vemurafenib + Rifampin | EXPERIMENTAL | There will be 3 intervention periods in the study: Period A (Days 1 to 7), Period B (Days 8 to 16), and Period C (Days 17 to 24). Participants, after an overnight fast of at least 10 hours, will receive vemurafenib at a dose of 960 milligrams (mg) as film-coated tablets orally alone on Day 1 (Period A); with rifampin (at a dose of 600 mg as capsules orally) on Day 17 (Period C); and rifampin alone at a dose of 600 mg as capsules orally once daily will be administered from Days 8 through 16 (Period B) and from Days 18 through 23 (Period C). |
| Vemurafenib + Digoxin | EXPERIMENTAL | Single oral dose of digoxin 0.25 mg tablet on Day 1 in Period A, followed by vemurafenib 960 mg tablet orally BID from Day 8 to Day 28 in Period B, and then single oral dose of digoxin 0.25 mg on Day 29, and vemurafenib 960 mg orally BID from Day 29 to Day 35 in Period C. |
| 1 | EXPERIMENTAL | - |
| 2 | EXPERIMENTAL | - |
| C | EXPERIMENTAL | - |
| 3 | EXPERIMENTAL | - |
| 4 | EXPERIMENTAL | - |
| PLX4032 | EXPERIMENTAL | Open-label, sequential dose escalation |
| Name | Type | Description |
|---|---|---|
| Placebo | DRUG | Placebo supplied as tablets |
| Vemurafenib | DRUG | Vemurafenib supplied as tablets |
| Cobimetinib | DRUG | Cobimetinib supplied as tablets |
| Dacarbazine | DRUG | 1000 mg/m2 intravenously every 3 weeks |
| Obinutuzumab | DRUG | Obinutuzumab will be administered concomitantly with vemurafenib starting at cycle 2 of treatment in cycles of 4 weeks. |
| Cladribine | DRUG | Cladribine IV on days 1-5 concurrently with rituximab. |
| Rituximab | DRUG | Rituximab on days 1-5 concurrently with rituximab. |
| Vemurafenib (All Groups) | DRUG | 960 mg by mouth 2 times a day 56 days prior to surgery (patients not planned for surgical resection will have a core biopsy at day 56. |
| Vemurafenib (Post Surgery) - Group A + C | DRUG | Group A: 960 mg by mouth twice a day 2 weeks post-surgery. Restaged 8 weeks after resuming drug. If patients demonstrate either stable or regressing disease, they will continue on vemurafenib with restaging occurring every 8 weeks until they are no longer benefitting from the drug. Group C: Patients not scheduled for surgical resection undergo a CT scan and core biopsy at day 56. Vemurafenib 960 mg by mouth twice a day, continued unless there is evidence of progressive disease on day 56 CT scan. Patients restaged every 8 weeks and continue vemurafenib until no longer benefitting from the drug. Patients evaluated for resectability after each CT scan is performed. If patient is scheduled for resection, then patient will continue vemurafenib until surgery and will follow the same treatment schema as patients in Groups A and B. |
| Post Surgery - Group B | OTHER | Patients who have had a complete surgical resection, and who do not have evidence of metastatic disease will discontinue vemurafenib after surgery. Patients restaged with CT neck 8 weeks after surgery. |
| cetuximab | DRUG | Escalating doses administered on Day 1 and then once weekly by intravenous infusion. |
| RO5185426 | DRUG | - |
| Itraconazole | DRUG | Itraconazole will be administered as a 200 mg oral solution QD during Part 1 only for 20 consecutive days. |
| Rifampin | DRUG | Rifampin will be administered as a 600 mg oral solution QD during Part 2 only for 20 consecutive days. |
| 14C-Labeled Vemurafenib | DRUG | IV infusion of 18.5 kilobecquerel (kBq) of 14C-labeled vemurafenib (3 milliliters \[mL\], which corresponds to a dose of 20 micrograms \[mcg\] of vemurafenib) on Day 21 (immediately after the morning oral dose of vemurafenib). |
| Digoxin | DRUG | Participants received single oral dose of digoxin 0.25 mg tablet on Day 1 and Day 29. |
| PLX4032 | DRUG | Oral capsules administered BID |
Inclusion Criteria: * Participants with histologically confirmed melanoma, either unresectable stage IIIc or stage IV metastatic melanoma, as defined by the American Joint Committee on Cancer 7th edition. Unresectability of stage IIIc disease must have confirmation from a surgical oncologist * Part...
RO5185426 is an investigational small molecule being studied for the treatment of malignant melanoma, including BRAF V600E mutation-positive metastatic melanoma and melanoma that has spread to the brain. It is being developed by Roche Holding AG and has been evaluated in Phase 2 clinical trials.
RO5185426 is being developed by Roche Holding AG, which trades on the OTC market under the ticker RHHBY. Roche sponsored the clinical trial program evaluating the drug in patients with malignant melanoma, including studies conducted in the United States and Switzerland.
RO5185426 is in Phase 2 clinical development. It has not been approved by the FDA and remains investigational. Five trials have been completed, including Phase 1 pharmacokinetic studies and Phase 2 studies in metastatic melanoma, with no active trials currently listed.
Completed trials of RO5185426 include NCT01248936, a Phase 2 study in 374 patients with metastatic melanoma, and NCT01253564, a Phase 2 study in 24 previously treated melanoma patients with brain metastases. Phase 1 studies NCT01264380 and NCT01164891 evaluated food effects, pharmacokinetics, and metabolism.
Across the completed clinical program, 473 patients have been enrolled in trials of RO5185426. The largest study, NCT01248936, enrolled 374 patients with metastatic melanoma, while the remaining trials ranged from 7 to 24 participants and focused on pharmacokinetics, metabolism, and brain metastases.