Safety Study of PLX4032 in Patients With Solid Tumors

A Study to Assess Safety, Pharmacokinetics, and Pharmacodynamics of PLX4032 in Patients With Solid Tumors

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.

Study Overview

• Status: Completed
• Conditions: Colorectal Carcinoma; Malignant Melanoma
• Intervention / Treatment: Drug: PLX4032

Detailed Description

Activating mutations of the BRAF gene have been observed in a variety of cancers, including 55-68% of malignant melanomas. In general, oncogenic mutations of BRAF correlate with a poor outcome. PLX4032 is a compound that selectively inhibits oncogenic B-Raf kinase.

Two extension cohorts of patients with confirmed V600E mutations will be recruited, consisting of advanced melanoma and metastatic colorectal carcinoma.

• Study Type: Interventional
• Enrollment (Actual): 109
• Phase: Phase 1

Contacts and Locations

Study Locations

• Australia
  • Victoria
    • East Melbourne, Victoria, Australia, 3002
      • Peter MacCallum Cancer Centre
    • Parkville, Victoria, Australia
      • Royal Melbourne Hospital
• United States
  • California
    • Los Angeles, California, United States, 90095
      • University of California Los Angeles
  • New York
    • New York, New York, United States, 10021
      • Memorial Sloan-Kettering Cancer Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt Ingram Cancer Center
  • Texas
    • Houston, Texas, United States, 77030
      • MD Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: PLX4032; Open-label, sequential dose escalation	Drug: PLX4032; Oral capsules administered BID

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area Under the Plasma Concentration-Time Curve (AUC) of RO5185426 on Day 1 - Dose Escalation: Original Formulation	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.	Pre-morning dose and at 0.5, 1, 2, 4, and 8, and 24 hours post-morning dose
Area Under the Plasma Concentration-Time Curve (AUC) of RO5185426 on Day 15 - Dose Escalation: Original Formulation	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.	Pre-morning dose and at 0.5, 1, 2, 4, and 8, and 24 hours post-morning dose
Peak Concentration (Cmax) of RO5185426 on Day 1 - Dose Escalation: Original Formulation		Pre-morning dose and at 0.5, 1, 2, 4, and 8 hours post-morning dose on Day 1, pre-morning dose on Day 2 and Day 8
Peak Concentration (Cmax) of RO5185426 on Day 15 - Dose Escalation: Original Formulation		Pre-morning dose and at 0.5, 1, 2, 4, and 8 hours post-morning dose on Day 15, pre-morning dose on Day 16
Time to Peak Concentration (Tmax) of RO5185426 on Day 1 - Dose Escalation: Original Formulation		Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 1, pre-morning dose on Day 2 and Day 8
Time to Peak Concentration (Tmax) of RO5185426 on Day 15 - Dose Escalation: Original Formulation		Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 15, pre-morning dose on Day 16
AUC of RO5185426 on Day 1 - Dose Escalation: MBP Formulation	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.	Pre-morning dose and at 0.5, 1, 2, 4, and 8, and 24 hours post-morning dose
AUC of RO5185426 on Day 15 - Dose Escalation: MBP Formulation	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.	Pre-morning dose and at 0.5, 1, 2, 4, and 8, and 24 hours post-morning dose
Mean RO5185426 Accumulation Ratios - Dose Escalation: MBP Formulation	Accumulation ratio is the ratio of AUC (0-8 hour) on Day 15 / AUC (0-8 hour) on Day 1.	Day 1 and Day 15: pre-morning dose and at 0.5, 1, 2, 4, and 8 hours post-morning dose
Mean RO5185426 Accumulation Ratios - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- Positive CRC	Accumulation ratio is the ratio of AUC (0-8 hour) on Day 15 / AUC (0-8 hour) on Day 1.	Day 1 and Day 15: pre-morning dose and at 0.5, 1, 2, 4, and 8 hours post-morning dose
Cmax of RO5185426 on Day 1 - Dose Escalation: MBP Formulation		Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 1, pre-morning dose on Day 2 and Day 8
Cmax of RO5185426 on Day 15 - Dose Escalation: MBP Formulation		Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 15, and pre-morning dose on Day 16
Tmax of RO5185426 on Day 1 - Dose Escalation: MBP Formulation		Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 1, pre-morning dose on Day 2 and Day 8
Tmax of RO5185426 on Day 15 - Dose Escalation: MBP Formulation		Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 15, and pre-morning dose on Day 16
AUC of RO5185426 on Day 1 - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- Positive CRC	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.	Pre-morning dose and at 0.5, 1, 2, 4, and 8, and 24 hours post-morning dose
AUC of RO5185426 on Day 15 - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- Positive CRC	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.	Pre-morning dose and at 0.5, 1, 2, 4, and 8, and 24 hours post-morning dose
Cmax of RO5185426 on Day 1 - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- Positive CRC		Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 1, pre-morning dose on Day 2 and Day 8
Cmax of RO5185426 on Day 15 - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- Positive CRC		Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 15 and pre-morning dose on Day 16
Tmax of RO5185426 on Day 1 - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- CRC		Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 1, pre-morning dose on Day 2 and Day 8
Tmax of RO5185426 on Day 15 - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- CRC		Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 15, and pre-morning dose on Day 16
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	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.	Screening, BL, until PD, or end of efficacy follow-up, up to data cutoff (up to 337 days)
Percentage of Participants With BOR of CR or PR According to RECIST v1.0 - Extension: BRAFV600E- Positive CRC	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.	Screening, BL, until PD, or end of efficacy follow-up, up to data cutoff (up to 337 days)
Percentage of Participants With BOR of CR or PR According to RECIST v1.0 - Dose Escalation: Original Formulation	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.	Screening, BL, until PD, or end of efficacy follow-up, up to data cutoff (up to 337 days)
Percentage of Participants With BOR of CR or PR According to RECIST v1.0 - Dose Escalation: MBP Formulation	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.	Screening, BL, until PD, or end of efficacy follow-up, up to data cutoff (up to 337 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of CR or PR Using RECIST v 1.0 - Extension BRAFV600E- Positive Melanoma	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.	Screening, BL, until PD, or end of efficacy follow-up, up to data cutoff (up to 337 days)
Percentage of Participants With Progression-Free Survival (PFS) Using RECIST v 1.0 - Melanoma Extension Cohort	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.	Month 1, 3, 4, 6, 9, and Last event (350) days
PFS Using RECIST v1.0 - Extension BRAFV600E Positive Melanoma	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.	Screening, BL, until PD, or end of efficacy follow-up, up to data cutoff (up to 421 days)
Percentage of Participants Who Died - Extension: BRAFV600E- Positive Melanoma		Screening, BL, until PD, or end of efficacy follow-up, up to 444 days
Overall Survival (OS) - Extension: BRAFV600E- Positive Melanoma	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.	Screening, BL, until PD, or end of efficacy follow-up, up to 444 days
Time to CR or PR Using RECIST v1.0 - Extension: BRAFV600E- Positive Melanoma	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.	Screening, BL, and up to 168 days
Mean Dose-Normalized Steady-State AUC of RO5185426 80 mg and 120 mg Capsules - Dose Escalation: MBP Formulation and Extension: BRAFV600E- Positive Melanoma	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.	Pre-morning dose and at 0.5, 1, 2, 4, and 8, and 24 hours post-morning dose
Mean Dose-Normalized Steady-State Cmax of RO5185426 80 mg and 120 mg Capsules - Dose Escalation: MBP Formulation and Extension: BRAFV600E- Positive Melanoma		Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 1 and 15, pre-morning dose on Day 2 and Day 8, and Day 16
Decrease in Tumor Uptake of 18F-fluorodeoxyglucose (FDG)	Tumor uptake of FDG was assessed by means of positron-emission tomography (PET)	BL and Day 15
Cmax of RO5185426 - Food Effect		Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 1 and 15, pre-morning dose on Day 2, Day 8, and Day 16
Tumor Levels of Phosphorylated Extracellular Signal-Regulated Kinapse (ERK), Cyclin D1, and Ki-67	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.	BL and Day 15

Collaborators and Investigators

• Sponsor: Plexxikon
• Collaborators: Roche Pharma AG
• Investigators: Study Director: Henry Hsu, MD, Plexxikon

Publications and helpful links

General Publications

• Flaherty KT, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA, O'Dwyer PJ, Lee RJ, Grippo JF, Nolop K, Chapman PB. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med. 2010 Aug 26;363(9):809-19. doi: 10.1056/NEJMoa1002011.
• Kopetz S, Desai J, Chan E, Hecht JR, O'Dwyer PJ, Maru D, Morris V, Janku F, Dasari A, Chung W, Issa JP, Gibbs P, James B, Powis G, Nolop KB, Bhattacharya S, Saltz L. Phase II Pilot Study of Vemurafenib in Patients With Metastatic BRAF-Mutated Colorectal Cancer. J Clin Oncol. 2015 Dec 1;33(34):4032-8. doi: 10.1200/JCO.2015.63.2497. Epub 2015 Oct 12.
• Puzanov I, Amaravadi RK, McArthur GA, Flaherty KT, Chapman PB, Sosman JA, Ribas A, Shackleton M, Hwu P, Chmielowski B, Nolop KB, Lin PS, Kim KB. Long-term outcome in BRAF(V600E) melanoma patients treated with vemurafenib: Patterns of disease progression and clinical management of limited progression. Eur J Cancer. 2015 Jul;51(11):1435-43. doi: 10.1016/j.ejca.2015.04.010. Epub 2015 May 13.
• Su F, Viros A, Milagre C, Trunzer K, Bollag G, Spleiss O, Reis-Filho JS, Kong X, Koya RC, Flaherty KT, Chapman PB, Kim MJ, Hayward R, Martin M, Yang H, Wang Q, Hilton H, Hang JS, Noe J, Lambros M, Geyer F, Dhomen N, Niculescu-Duvaz I, Zambon A, Niculescu-Duvaz D, Preece N, Robert L, Otte NJ, Mok S, Kee D, Ma Y, Zhang C, Habets G, Burton EA, Wong B, Nguyen H, Kockx M, Andries L, Lestini B, Nolop KB, Lee RJ, Joe AK, Troy JL, Gonzalez R, Hutson TE, Puzanov I, Chmielowski B, Springer CJ, McArthur GA, Sosman JA, Lo RS, Ribas A, Marais R. RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N Engl J Med. 2012 Jan 19;366(3):207-15. doi: 10.1056/NEJMoa1105358.

Study record dates

Study Major Dates

• Study Start: November 1, 2006
• Primary Completion (Actual): July 1, 2015
• Study Completion (Actual): February 1, 2016

Study Registration Dates

• First Submitted: November 28, 2006
• First Submitted That Met QC Criteria: November 28, 2006
• First Posted (Estimate): November 30, 2006

Study Record Updates

• Last Update Posted (Actual): August 22, 2017
• Last Update Submitted That Met QC Criteria: August 18, 2017
• Last Verified: October 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Neuroendocrine Tumors; Nevi and Melanomas; Colorectal Neoplasms; Melanoma; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Vemurafenib
• Other Study ID Numbers: PLX06-02