Phase 1
N=109
Safety Study of PLX4032 in Patients With Solid Tumors
Malignant Melanoma · Colorectal Carcinoma
Bottom Line
View on ClinicalTrials.gov: NCT00405587 ↗Enrolled (actual)
109
Serious AEs
34.3%
Results posted
Aug 2017
Primary outcome: Primary: Area Under the Plasma Concentration-Time Curve (AUC) of RO5185426 on Day 1 - Dose Escalation: Original Formulation — 2.02; 3.28; 4.47; 4.23 ug*hr/mL
Study Design & Population
- Study type
- Interventional
- Phase
- Phase 1
- Interventions
- PLX4032 (Drug)
- Age
- Adult, Older Adult · 18+ yrs
- Sex
- All
- Sponsor
- Plexxikon
- Primary completion
- Jul 2015
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Area Under the Plasma Concentration-Time Curve (AUC) of RO5185426 on Day 1 - Dose Escalation: Original Formulation |
2.02; 3.28; 4.47; 4.23; 8.43; 14.86 | — |
| PRIMARY Area Under the Plasma Concentration-Time Curve (AUC) of RO5185426 on Day 15 - Dose Escalation: Original Formulation |
9.37; 30.90; 30.58; 33.89; 46.28; 105.10 | — |
| PRIMARY Peak Concentration (Cmax) of RO5185426 on Day 1 - Dose Escalation: Original Formulation |
0.37; 0.58; 0.85; 0.73 | — |
| PRIMARY Peak Concentration (Cmax) of RO5185426 on Day 15 - Dose Escalation: Original Formulation |
1.34; 4.57; 5.41; 5.34 | — |
| PRIMARY Time to Peak Concentration (Tmax) of RO5185426 on Day 1 - Dose Escalation: Original Formulation |
9.98; 4; 3.01; 4 | — |
| PRIMARY Time to Peak Concentration (Tmax) of RO5185426 on Day 15 - Dose Escalation: Original Formulation |
0.02; 0.5; 0; 3 | — |
| PRIMARY AUC of RO5185426 on Day 1 - Dose Escalation: MBP Formulation |
5.98; 15.85; 14.95; 39.09; 39.48; 44.94 | — |
| PRIMARY AUC of RO5185426 on Day 15 - Dose Escalation: MBP Formulation |
33.91; 71.64; 114.50; 212.28; 229.96; 536.47 | — |
| PRIMARY Mean RO5185426 Accumulation Ratios - Dose Escalation: MBP Formulation |
4.75; 4.47; 8.66; 8.89; 10.11; 13.86 | — |
| PRIMARY Mean RO5185426 Accumulation Ratios - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- Positive CRC |
11.61; 9.31 | — |
| PRIMARY Cmax of RO5185426 on Day 1 - Dose Escalation: MBP Formulation |
1.14; 2.93; 2.72; 7.2; 7.12; 7.73 | — |
| PRIMARY Cmax of RO5185426 on Day 15 - Dose Escalation: MBP Formulation |
5.16; 11.64; 17.90; 31.15; 34.10; 84.30 | — |
| PRIMARY Tmax of RO5185426 on Day 1 - Dose Escalation: MBP Formulation |
2; 3; 3.21; 6.29; 3.29; 4.33 | — |
| PRIMARY Tmax of RO5185426 on Day 15 - Dose Escalation: MBP Formulation |
1.5; 2.0; 4.10; 4.07; 4.33; 0.41 | — |
| PRIMARY AUC of RO5185426 on Day 1 - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- Positive CRC |
31.35; 31.53; 108.52; NA | — |
| PRIMARY AUC of RO5185426 on Day 15 - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- Positive CRC |
289.26; 262.42; 924.65; 752.64 | — |
| PRIMARY Cmax of RO5185426 on Day 1 - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- Positive CRC |
5.84; 5.53 | — |
| PRIMARY Cmax of RO5185426 on Day 15 - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- Positive CRC |
44.31; 38.55 | — |
| PRIMARY Tmax of RO5185426 on Day 1 - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- CRC |
4; 4 | — |
| PRIMARY Tmax of RO5185426 on Day 15 - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- CRC |
1.01; 2.0 | — |
| PRIMARY 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 |
56.3; 81.3 | — |
| PRIMARY Percentage of Participants With BOR of CR or PR According to RECIST v1.0 - Extension: BRAFV600E- Positive CRC |
5.0 | — |
| PRIMARY Percentage of Participants With BOR of CR or PR According to RECIST v1.0 - Dose Escalation: Original Formulation |
0; 0; 10.0; 0 | — |
| PRIMARY Percentage of Participants With BOR of CR or PR According to RECIST v1.0 - Dose Escalation: MBP Formulation |
0; 25.0; 33.3; 40.0; 28.6; 50.0 | — |
| SECONDARY Duration of CR or PR Using RECIST v 1.0 - Extension BRAFV600E- Positive Melanoma |
227 | — |
| SECONDARY Percentage of Participants With Progression-Free Survival (PFS) Using RECIST v 1.0 - Melanoma Extension Cohort |
96.9; 87.5; 75.0; 59.4; 43.3; 16.9 | — |
| SECONDARY PFS Using RECIST v1.0 - Extension BRAFV600E Positive Melanoma |
233 | — |
| SECONDARY Percentage of Participants Who Died - Extension: BRAFV600E- Positive Melanoma |
0; 3.1; 6.2; 12.7; 29.4; 43.2 | — |
| SECONDARY Overall Survival (OS) - Extension: BRAFV600E- Positive Melanoma |
NA | — |
| SECONDARY Time to CR or PR Using RECIST v1.0 - Extension: BRAFV600E- Positive Melanoma |
56.5 | — |
| SECONDARY Mean Dose-Normalized Steady-State AUC of RO5185426 80 mg and 120 mg Capsules - Dose Escalation: MBP Formulation and Extension: BRAFV600E- Positive Melanoma |
0.179; 0.197; 0.524; 0.482 | — |
| SECONDARY Mean Dose-Normalized Steady-State Cmax of RO5185426 80 mg and 120 mg Capsules - Dose Escalation: MBP Formulation and Extension: BRAFV600E- Positive Melanoma |
0.028; 0.030 | — |
| SECONDARY Decrease in Tumor Uptake of 18F-fluorodeoxyglucose (FDG) |
— | — |
| SECONDARY Cmax of RO5185426 - Food Effect |
— | — |
| SECONDARY Tumor Levels of Phosphorylated Extracellular Signal-Regulated Kinapse (ERK), Cyclin D1, and Ki-67 |
— | — |
Summary
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.
Eligibility Criteria
Inclusion Criteria
- Solid tumors confirmed histologically whose tumors are refractory to standard therapy, or for whom standard or curative therapy does not exist
- Patients from whom paired melanoma biopsies are planned must have a V600E+ BRAF mutation confirmed prior to the administration of PLX4032
- Previous chemotherapy, immunotherapy, or radiation therapy must have been completed at least 2 weeks prior to starting PLX4032 therapy, and all associated toxicity must be resolved prior to administration of PLX4032
- Patients in the Extension cohorts (melanoma or adenocarcinoma of the colon or rectum) must have both a V600E+ BRAF mutation and measurable disease (by RECIST V 1.0 criteria) prior to the administration of PLX4032. All patients enrolled must provide archival or fresh melanoma tumor biopsy for confirmation of V600E+ BRAF mutation status by TaqMan assay
- ECOG performance status 0 or 1
- Life expectancy ≥ 3 months
- Adequate hematologic, hepatic, and renal function
Exclusion Criteria
- Brain metastases that are progressing or have been documented to be stable for less than 3 months, or for which systemic corticosteroids are required
- Investigational drug use within 28 days of the first dose of PLX4032
- Uncontrolled intercurrent illness
- Refractory nausea and vomiting, malabsorption, or significant bowel resection that would preclude adequate absorption
Data sourced from ClinicalTrials.gov (NCT00405587). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication.