Safety Study of PLX4032 in Patients With Solid Tumors

Malignant Melanoma Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00405587
• Other study ID #: PLX06-02
• Status: Completed
• Phase: Phase 1
• First received: November 28, 2006
• Last updated: August 18, 2017
• Start date: November 2006
• Est. completion date: February 2016

Study information

• Verified date: October 2016
• Source: Plexxikon
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 109
• Est. completion date: February 2016
• Est. primary completion date: July 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Colorectal Carcinoma
• Colorectal Neoplasms
• Malignant Melanoma
• Melanoma

Intervention

Drug:
• PLX4032
Oral capsules administered BID

Locations

Country	Name	City	State
Australia	Peter MacCallum Cancer Centre	East Melbourne	Victoria
Australia	Royal Melbourne Hospital	Parkville	Victoria
United States	MD Anderson Cancer Center	Houston	Texas
United States	University of California Los Angeles	Los Angeles	California
United States	Vanderbilt Ingram Cancer Center	Nashville	Tennessee
United States	Memorial Sloan-Kettering Cancer Center	New York	New York
United States	University of Pennsylvania	Philadelphia	Pennsylvania

Sponsors (2)

Lead Sponsor	Collaborator
Plexxikon	Roche Pharma AG

Countries where clinical trial is conducted

United States,  Australia, 

References & Publications (1)

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
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	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)
Primary	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)
Primary	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)
Primary	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	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)
Secondary	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
Secondary	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)
Secondary	Percentage of Participants Who Died - Extension: BRAFV600E- Positive Melanoma		Screening, BL, until PD, or end of efficacy follow-up, up to 444 days
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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