Clinical trial NCT00405587: Safety Study of PLX4032 in Patients With Solid Tumors
Official title: A Study to Assess Safety, Pharmacokinetics, and Pharmacodynamics of PLX4032 in Patients With Solid Tumors
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Malignant Melanoma
Colorectal Carcinoma
Lead sponsor: Plexxikon
Sponsor class: INDUSTRY
Collaborators: name: Roche Pharma AG
First posted: 2006-11-30
Enrollment: 109
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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.

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.

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

Primary outcomes:
measure: Area Under the Plasma Concentration-Time Curve (AUC) of RO5185426 on Day 1 - Dose Escalation: Original Formulation
timeFrame: Pre-morning dose and at 0.5, 1, 2, 4, and 8, and 24 hours post-morning dose
measure: Area Under the Plasma Concentration-Time Curve (AUC) of RO5185426 on Day 15 - Dose Escalation: Original Formulation
timeFrame: Pre-morning dose and at 0.5, 1, 2, 4, and 8, and 24 hours post-morning dose
measure: Peak Concentration (Cmax) of RO5185426 on Day 1 - Dose Escalation: Original Formulation
timeFrame: 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
measure: Peak Concentration (Cmax) of RO5185426 on Day 15 - Dose Escalation: Original Formulation
timeFrame: 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
measure: Time to Peak Concentration (Tmax) of RO5185426 on Day 1 - Dose Escalation: Original Formulation
timeFrame: 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
measure: Time to Peak Concentration (Tmax) of RO5185426 on Day 15 - Dose Escalation: Original Formulation
timeFrame: Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 15, pre-morning dose on Day 16
measure: AUC of RO5185426 on Day 1 - Dose Escalation: MBP Formulation
timeFrame: Pre-morning dose and at 0.5, 1, 2, 4, and 8, and 24 hours post-morning dose
measure: AUC of RO5185426 on Day 15 - Dose Escalation: MBP Formulation
timeFrame: Pre-morning dose and at 0.5, 1, 2, 4, and 8, and 24 hours post-morning dose
measure: Mean RO5185426 Accumulation Ratios - Dose Escalation: MBP Formulation
timeFrame: Day 1 and Day 15: pre-morning dose and at 0.5, 1, 2, 4, and 8 hours post-morning dose
measure: Mean RO5185426 Accumulation Ratios - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- Positive CRC
timeFrame: Day 1 and Day 15: pre-morning dose and at 0.5, 1, 2, 4, and 8 hours post-morning dose
measure: Cmax of RO5185426 on Day 1 - Dose Escalation: MBP Formulation
timeFrame: 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
measure: Cmax of RO5185426 on Day 15 - Dose Escalation: MBP Formulation
timeFrame: Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 15, and pre-morning dose on Day 16
measure: Tmax of RO5185426 on Day 1 - Dose Escalation: MBP Formulation
timeFrame: 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
measure: Tmax of RO5185426 on Day 15 - Dose Escalation: MBP Formulation
timeFrame: Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 15, and pre-morning dose on Day 16
measure: AUC of RO5185426 on Day 1 - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- Positive CRC
timeFrame: Pre-morning dose and at 0.5, 1, 2, 4, and 8, and 24 hours post-morning dose
measure: AUC of RO5185426 on Day 15 - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- Positive CRC
timeFrame: Pre-morning dose and at 0.5, 1, 2, 4, and 8, and 24 hours post-morning dose
measure: Cmax of RO5185426 on Day 1 - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- Positive CRC
timeFrame: 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
measure: Cmax of RO5185426 on Day 15 - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- Positive CRC
timeFrame: Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 15 and pre-morning dose on Day 16
measure: Tmax of RO5185426 on Day 1 - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- CRC
timeFrame: 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
measure: Tmax of RO5185426 on Day 15 - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- CRC
timeFrame: Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 15, and pre-morning dose on Day 16
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
timeFrame: Screening, BL, until PD, or end of efficacy follow-up, up to data cutoff (up to 337 days)
measure: Percentage of Participants With BOR of CR or PR According to RECIST v1.0 - Extension: BRAFV600E- Positive CRC
timeFrame: Screening, BL, until PD, or end of efficacy follow-up, up to data cutoff (up to 337 days)
measure: Percentage of Participants With BOR of CR or PR According to RECIST v1.0 - Dose Escalation: Original Formulation
timeFrame: Screening, BL, until PD, or end of efficacy follow-up, up to data cutoff (up to 337 days)
measure: Percentage of Participants With BOR of CR or PR According to RECIST v1.0 - Dose Escalation: MBP Formulation
timeFrame: Screening, BL, until PD, or end of efficacy follow-up, up to data cutoff (up to 337 days)
Secondary outcomes:
measure: Duration of CR or PR Using RECIST v 1.0 - Extension BRAFV600E- Positive Melanoma
timeFrame: Screening, BL, until PD, or end of efficacy follow-up, up to data cutoff (up to 337 days)
measure: Percentage of Participants With Progression-Free Survival (PFS) Using RECIST v 1.0 - Melanoma Extension Cohort
timeFrame: Month 1, 3, 4, 6, 9, and Last event (350) days
measure: PFS Using RECIST v1.0 - Extension BRAFV600E Positive Melanoma
timeFrame: Screening, BL, until PD, or end of efficacy follow-up, up to data cutoff (up to 421 days)
measure: Percentage of Participants Who Died - Extension: BRAFV600E- Positive Melanoma
timeFrame: Screening, BL, until PD, or end of efficacy follow-up, up to 444 days
measure: Overall Survival (OS) - Extension: BRAFV600E- Positive Melanoma
timeFrame: Screening, BL, until PD, or end of efficacy follow-up, up to 444 days
measure: Time to CR or PR Using RECIST v1.0 - Extension: BRAFV600E- Positive Melanoma
timeFrame: Screening, BL, and up to 168 days
measure: Mean Dose-Normalized Steady-State AUC of RO5185426 80 mg and 120 mg Capsules - Dose Escalation: MBP Formulation and Extension: BRAFV600E- Positive Melanoma
timeFrame: Pre-morning dose and at 0.5, 1, 2, 4, and 8, and 24 hours post-morning dose
measure: Mean Dose-Normalized Steady-State Cmax of RO5185426 80 mg and 120 mg Capsules - Dose Escalation: MBP Formulation and Extension: BRAFV600E- Positive Melanoma
timeFrame: 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
measure: Decrease in Tumor Uptake of 18F-fluorodeoxyglucose (FDG)
timeFrame: BL and Day 15
measure: Cmax of RO5185426 - Food Effect
timeFrame: 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
measure: Tumor Levels of Phosphorylated Extracellular Signal-Regulated Kinapse (ERK), Cyclin D1, and Ki-67
timeFrame: BL and Day 15
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: University of California Los Angeles
state: California
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center
state: New York
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt Ingram Cancer Center
state: Tennessee
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: East Melbourne
country: Australia
facility: Peter MacCallum Cancer Centre
state: Victoria
city: Parkville
country: Australia
facility: Royal Melbourne Hospital
state: Victoria
Study officials:
affiliation: Plexxikon
name: Henry Hsu, MD
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.