The primary objective of this FIH study is to assess the safety and pharmacokinetics of PLX4032 in patients with solid tumors. The secondary objective is to assess the pharmacodynamic activity in paired biopsy specimens obtained from patients with malignant melanoma who have the V600E BRAF oncogenic mutation.
Name: PLX4032
Description: Oral capsules administered BIDType: DrugPLX4032
Description: 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.
Measure: Area Under the Plasma Concentration-Time Curve (AUC) of RO5185426 on Day 1 - Dose Escalation: Original Formulation Time: Pre-morning dose and at 0.5, 1, 2, 4, and 8, and 24 hours post-morning doseDescription: 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.
Measure: Area Under the Plasma Concentration-Time Curve (AUC) of RO5185426 on Day 15 - Dose Escalation: Original Formulation Time: Pre-morning dose and at 0.5, 1, 2, 4, and 8, and 24 hours post-morning doseDescription: 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.
Measure: AUC of RO5185426 on Day 1 - Dose Escalation: MBP Formulation Time: Pre-morning dose and at 0.5, 1, 2, 4, and 8, and 24 hours post-morning doseDescription: 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.
Measure: AUC of RO5185426 on Day 15 - Dose Escalation: MBP Formulation Time: Pre-morning dose and at 0.5, 1, 2, 4, and 8, and 24 hours post-morning doseDescription: Accumulation ratio is the ratio of AUC (0-8 hour) on Day 15 / AUC (0-8 hour) on Day 1.
Measure: Mean RO5185426 Accumulation Ratios - Dose Escalation: MBP Formulation Time: Day 1 and Day 15: pre-morning dose and at 0.5, 1, 2, 4, and 8 hours post-morning doseDescription: Accumulation ratio is the ratio of AUC (0-8 hour) on Day 15 / AUC (0-8 hour) on Day 1.
Measure: Mean RO5185426 Accumulation Ratios - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- Positive CRC Time: Day 1 and Day 15: pre-morning dose and at 0.5, 1, 2, 4, and 8 hours post-morning doseDescription: 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.
Measure: AUC of RO5185426 on Day 1 - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- Positive CRC Time: Pre-morning dose and at 0.5, 1, 2, 4, and 8, and 24 hours post-morning doseDescription: 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.
Measure: AUC of RO5185426 on Day 15 - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- Positive CRC Time: Pre-morning dose and at 0.5, 1, 2, 4, and 8, and 24 hours post-morning doseDescription: 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.
Measure: Percentage of Participants With a Confirmed and an Unconfirmed Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR) According to RECIST Version (v) 1.0 - Extension: BRAFV600E- Positive Melanoma Time: Screening, BL, until PD, or end of efficacy follow-up, up to data cutoff (up to 337 days)Description: 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.
Measure: Percentage of Participants With BOR of CR or PR According to RECIST v1.0 - Extension: BRAFV600E- Positive CRC Time: Screening, BL, until PD, or end of efficacy follow-up, up to data cutoff (up to 337 days)Description: 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.
Measure: Percentage of Participants With BOR of CR or PR According to RECIST v1.0 - Dose Escalation: Original Formulation Time: Screening, BL, until PD, or end of efficacy follow-up, up to data cutoff (up to 337 days)Description: 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.
Measure: Percentage of Participants With BOR of CR or PR According to RECIST v1.0 - Dose Escalation: MBP Formulation Time: Screening, BL, until PD, or end of efficacy follow-up, up to data cutoff (up to 337 days)Description: Duration of response for participants with confirmed CR or PR was the period of time measured between the date that the criteria for objective CR or PR (whichever status was recorded first) was met, and the first date that recurrent or PD was objectively documented (or death if before progression). PD was at least a 20% increase in the sum of longest diameters of TLs taking as reference the smallest sum of longest diameters recorded since the baseline measurements, or the appearance of one or more new lesion(s). In the event of no disease progression or documented death prior to study termination, analysis cutoff, or initiation of confounding anticancer therapy, duration of response was censored at the date of the last evaluable tumor assessment.
Measure: Duration of CR or PR Using RECIST v 1.0 - Extension BRAFV600E- Positive Melanoma Time: Screening, BL, until PD, or end of efficacy follow-up, up to data cutoff (up to 337 days)Description: PFS was the period of time measured from the date of initiation of therapy to the date of the appearance of new metastatic lesions, objective tumor progression, or death if before progression. PD was defined according to the RECIST criteria (v 1.0) as increase by at least 20% in the sum of the longest diameters of each TL, taking as a reference the smallest sum of the longest diameters, reported since the start of treatment, or appearance of one or more new lesions. For Non-TLs, PD was defined as the appearance of one or more new lesions and/or unequivocal progression of existing non-TLs.
Measure: Percentage of Participants With Progression-Free Survival (PFS) Using RECIST v 1.0 - Melanoma Extension Cohort Time: Month 1, 3, 4, 6, 9, and Last event (350) daysDescription: PFS was the period of time measured from the date of initiation of therapy to the date of the appearance of new metastatic lesions, objective tumor progression, or death if before progression. PD was at least a 20% increase in the sum of longest diameters of TLs taking as reference the smallest sum of longest diameters recorded since the baseline measurements, or the appearance of one or more new lesion(s). For Non-TLs, disease progression was defined as the appearance of one or more new lesions and/or unequivocal progression of existing non-TLs. In the event of no disease progression or documented death prior to study termination, analysis cutoff, or start of confounding anticancer therapy, PFS was censored at the date of the last evaluable tumor assessment.
Measure: PFS Using RECIST v1.0 - Extension BRAFV600E Positive Melanoma Time: Screening, BL, until PD, or end of efficacy follow-up, up to data cutoff (up to 421 days)Description: OS was the period of time measured from the date of initiation of therapy to the date of the death. In the event of no death prior to study termination or analysis data cutoff, OS was censored at the last known date that the patient was alive as documented on the follow-up case report form. If this date was not available, then the last known alive date from the database was used.
Measure: Overall Survival (OS) - Extension: BRAFV600E- Positive Melanoma Time: Screening, BL, until PD, or end of efficacy follow-up, up to 444 daysDescription: Time to CR or PR was defined as the interval between the date of the first treatment to the date of the first documentation of confirmed CR or PR whichever occurred first, and not the date of confirmation at the subsequent tumor assessment. Time to response = Date of first response - initial dose date + 1.
Measure: Time to CR or PR Using RECIST v1.0 - Extension: BRAFV600E- Positive Melanoma Time: Screening, BL, and up to 168 daysDescription: 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.
Measure: Mean Dose-Normalized Steady-State AUC of RO5185426 80 mg and 120 mg Capsules - Dose Escalation: MBP Formulation and Extension: BRAFV600E- Positive Melanoma Time: Pre-morning dose and at 0.5, 1, 2, 4, and 8, and 24 hours post-morning doseDescription: Tumor uptake of FDG was assessed by means of positron-emission tomography (PET)
Measure: Decrease in Tumor Uptake of 18F-fluorodeoxyglucose (FDG) Time: BL and Day 15Description: The immunohisto-chemical analyses of the expression of phosphorylated ERK, cyclin D1, and Ki-67 in tumor-biopsy specimens was performed using hematoxylin and eosin staining.
Measure: Tumor Levels of Phosphorylated Extracellular Signal-Regulated Kinapse (ERK), Cyclin D1, and Ki-67 Time: BL and Day 15Single Group Assignment
There is one SNP
The secondary objective is to assess the pharmacodynamic activity in paired biopsy specimens obtained from patients with malignant melanoma who have the V600E BRAF oncogenic mutation. --- V600E ---
Two extension cohorts of patients with confirmed V600E mutations will be recruited, consisting of advanced melanoma and metastatic colorectal carcinoma. --- V600E ---