A Pharmacokinetic/Pharmacodynamic Study of RO5185426 in Previously Treated Patients With Metastatic Melanoma

Study Overview
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Brief Summary
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This open-label study will assess the pharmacokinetics, efficacy and safety of RO5185426 administered as 240mg tablets in previously treated patients with metastatic melanoma. Patients will be randomized to receive one of four dose-levels of RO5185426 [RG7204; PLEXXIKON; PLX4032] orally twice daily on days 1 to 15 (morning dose). Starting on day 22, treatment with RO5185426 may be resumed at a dose of 960 mg twice daily and continued until disease progression. Target sample size is <100 patients.

Official Title
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A Phase I, Randomized, Open-label, Multi-center, Multiple Dose Study to Investigate the Pharmacokinetics and Pharmacodynamics of RO5185426 Administered as 240 mg Tablets to Previously Treated BRAF V600E Positive Metastatic Melanoma Patients

Conditions
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Malignant Melanoma

Intervention / Treatment
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* Drug: RO5185426
* Drug: RO5185426
* Drug: RO5185426
* Drug: RO5185426
* Drug: RO5185426


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: adult patients, >/=18 years of age histologically confirmed metastatic melanoma, stage IIIc or IV (AJCC) failure of at least one prior standard of care regimen positive for BRAF V600E mutation (by Roche CoDx BRAF mutation assay) ECOG performance status 0 or 1 adequate hematologic, renal and liver function Exclusion Criteria: active CNS lesions on CT/MRI within 28 days prior to enrollment history of spinal cord compression o carcinomatous meningitis anticipated or ongoing anti-cancer therapies other than those administered in this study previous treatment with BRAF inhibitor (sorafenib allowed) or MEK inhibitor severe cardiovascular disease within 6 months prior to study previous malignancy within the past 5 years except for basal or squamous cell carcinoma of the skin, melanoma in-situ and carcinoma in-situ of the cervix

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br> | Drug: RO5185426<br>* 960 mg orally twice daily, from day 22 onward<br>Drug: RO5185426<br>* dosage a) orally twice daily, days 1-15 (morning dose)<br>|
| Experimental: 2<br> | Drug: RO5185426<br>* dosage b) orally twice daily, days 1-15 (morning dose)<br>Drug: RO5185426<br>* 960 mg orally twice daily, from day 22 onward<br>|
| Experimental: 3<br> | Drug: RO5185426<br>* dosage c) orally twice daily, days 1-15 (morning dose)<br>Drug: RO5185426<br>* 960 mg orally twice daily, from day 22 onward<br>|
| Experimental: 4<br> | Drug: RO5185426<br>* dosage d) orally twice daily, days 1-15 (morning dose)<br>Drug: RO5185426<br>* 960 mg orally twice daily, from day 22 onward<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Plasma Concentration-Time Curve From Time Zero to 8 Hours (AUC[0-8h]) of Vemurafenib on Day 1 |  | Pre-dose, 1, 2, 4, 5, 8 hours post-dose on Day 1 | 
| Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC[0-24h]) of Vemurafenib on Day 1 |  | Pre-dose, 1, 2, 4, 5, 8, 24 hours post-dose on Day 1 | 
| Maximum Plasma Concentration (Cmax) of Vemurafenib on Day 1 |  | Pre-dose, 1, 2, 4, 5, 8 hours post-dose on Day 1 | 
| Time to Reach Maximum Plasma Concentration (Tmax) of Vemurafenib on Day 1 |  | Pre-dose, 1, 2, 4, 5, 8 hours post-dose on Day 1 | 
| Area Under the Plasma Concentration-Time Curve From Time Zero to 8 Hours (AUC[0-8h]) of Vemurafenib on Day 9 |  | Pre-dose, 1, 2, 4, 5, 8 hours post-dose on Day 9 | 
| Maximum Plasma Concentration (Cmax) of Vemurafenib on Day 9 |  | Pre-dose, 1, 2, 4, 5, 8 hours post-dose on Day 9 | 
| Time to Reach Maximum Plasma Concentration (Tmax) of Vemurafenib on Day 9 |  | Pre-dose, 1, 2, 4, 5, 8 hours post-dose on Day 9 | 
| Area Under the Plasma Concentration-Time Curve From Time Zero to 8 Hours (AUC[0-8h]) of Vemurafenib on Day 15 |  | Pre-dose, 1, 2, 4, 5, 8 hours post-dose on Day 15 | 
| Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC[0-24h]) of Vemurafenib on Day 15 |  | Pre-dose, 1, 2, 4, 5, 8, 24 hours post-dose on Day 15 | 
| Area Under the Plasma Concentration-Time Curve From Time Zero to 168 Hours (AUC[0-168h]) of Vemurafenib on Day 15 |  | Pre-dose, 1, 2, 4, 5, 8, 24, 28, 72, 76, 168 hours post-dose on Day 15 | 
| Maximum Plasma Concentration (Cmax) of Vemurafenib on Day 15 |  | Pre-dose, 1, 2, 4, 5, 8, 24, 28, 72, 76, 168 hours post-dose on Day 15 | 
| Time to Reach Maximum Plasma Concentration (Tmax) of Vemurafenib on Day 15 |  | Pre-dose, 1, 2, 4, 5, 8, 24, 28, 72, 76, 168 hours post-dose on Day 15 | 
| Apparent Clearance (CL/F) of Vemurafenib on Day 15 | Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. | Pre-dose, 1, 2, 4, 5, 8, 24, 28, 72, 76, 168 hours post-dose on Day 15 | 
| Terminal Elimination Half-Life (t1/2) of Vemurafenib on Day 15 | Time measured for vemurafenib plasma concentrations to decrease by one-half (t1/2) was calculated as 0.693 divided by apparent first-order terminal elimination rate constant (0.693/kel). | Pre-dose, 1, 2, 4, 5, 8, 24, 28, 72, 76, 168 hours post-dose on Day 15 | 
| Accumulation Ratio of Vemurafenib on Day 15 | Accumulation ratio was calculated as, AUC(0-8) on Day 15 divided by AUC(0-8) on Day 1. | Pre-dose, 1, 2, 4, 5, 8 hours post-dose on Day 1 and 15 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With a Confirmed Best Overall Response of Complete Response (CR) or Partial Response (PR) | Confirmed best overall response was defined as having best objective response as CR or PR, as assessed by investigator and confirmed at least 28 days after initial response. Tumor response was assessed according to the Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST 1.1). CR was defined as the disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) were required to demonstrate a reduction to normal (short axis less than [<] 10 millimeters [mm]). PR was defined as a 30 percent (%) decrease in the sum of the diameters of the target lesions taking as a reference the baseline sum diameter. Percentage of participants with best overall response of confirmed CR or PR are reported. | Up to approximately 3 years (assessed at Cycle 1 Day 1, Cycle 3 Day 1, Cycle 5 Day 1, thereafter every 2 cycles and then every 4 cycles after Cycle 13) | 
| Overall Survival (OS) | OS was defined as the time, in months, from the date of the first study drug administration to the date of death, regardless of the cause of death. | Up to approximately 3 years (assessed at Cycle 1 Day 1, Cycle 3 Day 1, Cycle 5 Day 1, thereafter every 2 cycles and then every 4 cycles after Cycle 13) |