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

• ClinicalTrials.gov Identifier: NCT01107418
• Recruitment Status: Completed
• First Posted: April 21, 2010
• Results First Posted: August 26, 2015
• Last Update Posted: August 26, 2015
• Sponsor: Hoffmann-La Roche
• Information provided by (Responsible Party): Hoffmann-La Roche

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Malignant Melanoma	Drug: RO5185426	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 52 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: May 2010
• Actual Primary Completion Date: February 2013
• Actual Study Completion Date: February 2013

Arms and Interventions

Arm	Intervention/treatment
Experimental: 1	Drug: RO5185426; 960 mg orally twice daily, from day 22 onward; Drug: RO5185426; dosage a) orally twice daily, days 1-15 (morning dose)
Experimental: 2	Drug: RO5185426; dosage b) orally twice daily, days 1-15 (morning dose); Drug: RO5185426; 960 mg orally twice daily, from day 22 onward
Experimental: 3	Drug: RO5185426; dosage c) orally twice daily, days 1-15 (morning dose); Drug: RO5185426; 960 mg orally twice daily, from day 22 onward
Experimental: 4	Drug: RO5185426; dosage d) orally twice daily, days 1-15 (morning dose); Drug: RO5185426; 960 mg orally twice daily, from day 22 onward

Outcome Measures

Primary Outcome Measures :

1. Area Under the Plasma Concentration-Time Curve From Time Zero to 8 Hours (AUC[0-8h]) of Vemurafenib on Day 1 [ Time Frame: Pre-dose, 1, 2, 4, 5, 8 hours post-dose on Day 1 ]
2. Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC[0-24h]) of Vemurafenib on Day 1 [ Time Frame: Pre-dose, 1, 2, 4, 5, 8, 24 hours post-dose on Day 1 ]
3. Maximum Plasma Concentration (Cmax) of Vemurafenib on Day 1 [ Time Frame: Pre-dose, 1, 2, 4, 5, 8 hours post-dose on Day 1 ]
4. Time to Reach Maximum Plasma Concentration (Tmax) of Vemurafenib on Day 1 [ Time Frame: Pre-dose, 1, 2, 4, 5, 8 hours post-dose on Day 1 ]
5. Area Under the Plasma Concentration-Time Curve From Time Zero to 8 Hours (AUC[0-8h]) of Vemurafenib on Day 9 [ Time Frame: Pre-dose, 1, 2, 4, 5, 8 hours post-dose on Day 9 ]
6. Maximum Plasma Concentration (Cmax) of Vemurafenib on Day 9 [ Time Frame: Pre-dose, 1, 2, 4, 5, 8 hours post-dose on Day 9 ]
7. Time to Reach Maximum Plasma Concentration (Tmax) of Vemurafenib on Day 9 [ Time Frame: Pre-dose, 1, 2, 4, 5, 8 hours post-dose on Day 9 ]
8. Area Under the Plasma Concentration-Time Curve From Time Zero to 8 Hours (AUC[0-8h]) of Vemurafenib on Day 15 [ Time Frame: Pre-dose, 1, 2, 4, 5, 8 hours post-dose on Day 15 ]
9. Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC[0-24h]) of Vemurafenib on Day 15 [ Time Frame: Pre-dose, 1, 2, 4, 5, 8, 24 hours post-dose on Day 15 ]
10. Area Under the Plasma Concentration-Time Curve From Time Zero to 168 Hours (AUC[0-168h]) of Vemurafenib on Day 15 [ Time Frame: Pre-dose, 1, 2, 4, 5, 8, 24, 28, 72, 76, 168 hours post-dose on Day 15 ]
11. Maximum Plasma Concentration (Cmax) of Vemurafenib on Day 15 [ Time Frame: Pre-dose, 1, 2, 4, 5, 8, 24, 28, 72, 76, 168 hours post-dose on Day 15 ]
12. Time to Reach Maximum Plasma Concentration (Tmax) of Vemurafenib on Day 15 [ Time Frame: Pre-dose, 1, 2, 4, 5, 8, 24, 28, 72, 76, 168 hours post-dose on Day 15 ]
13. Apparent Clearance (CL/F) of Vemurafenib on Day 15 [ Time Frame: Pre-dose, 1, 2, 4, 5, 8, 24, 28, 72, 76, 168 hours post-dose 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.
14. Terminal Elimination Half-Life (t1/2) of Vemurafenib on Day 15 [ Time Frame: Pre-dose, 1, 2, 4, 5, 8, 24, 28, 72, 76, 168 hours post-dose 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).
15. Accumulation Ratio of Vemurafenib on Day 15 [ Time Frame: Pre-dose, 1, 2, 4, 5, 8 hours post-dose on Day 1 and 15 ]
    Accumulation ratio was calculated as, AUC(0-8) on Day 15 divided by AUC(0-8) on Day 1.

Secondary Outcome Measures :

1. Percentage of Participants With a Confirmed Best Overall Response of Complete Response (CR) or Partial Response (PR) [ Time Frame: 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) ]
   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.
2. Overall Survival (OS) [ Time Frame: 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) ]
   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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

United States, California

La Jolla, California, United States, 92093

San Francisco, California, United States, 94115

Stanford, California, United States, 94305

United States, Connecticut

New Haven, Connecticut, United States, 06510-3289

United States, Illinois

Chicago, Illinois, United States, 60637

Park Ridge, Illinois, United States, 60068

United States, Iowa

Sioux City, Iowa, United States, 51101

United States, Nebraska

Omaha, Nebraska, United States, 68114

United States, Ohio

Columbus, Ohio, United States, 43219

United States, Rhode Island

East Providence, Rhode Island, United States, 02915

United States, Virginia

Charlottesville, Virginia, United States, 22908

Australia, South Australia

Adelaide, South Australia, Australia, 5000

Australia, Victoria

Melbourne, Victoria, Australia, 3181

Sponsors and Collaborators

Hoffmann-La Roche

Investigators

• Study Director: Clinical Trials; Hoffmann-La Roche

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Frederick DT, Salas Fragomeni RA, Schalck A, Ferreiro-Neira I, Hoff T, Cooper ZA, Haq R, Panka DJ, Kwong LN, Davies MA, Cusack JC, Flaherty KT, Fisher DE, Mier JW, Wargo JA, Sullivan RJ. Clinical profiling of BCL-2 family members in the setting of BRAF inhibition offers a rationale for targeting de novo resistance using BH3 mimetics. PLoS One. 2014 Jul 1;9(7):e101286. doi: 10.1371/journal.pone.0101286. eCollection 2014.

Lacouture ME, Duvic M, Hauschild A, Prieto VG, Robert C, Schadendorf D, Kim CC, McCormack CJ, Myskowski PL, Spleiss O, Trunzer K, Su F, Nelson B, Nolop KB, Grippo JF, Lee RJ, Klimek MJ, Troy JL, Joe AK. Analysis of dermatologic events in vemurafenib-treated patients with melanoma. Oncologist. 2013;18(3):314-22. doi: 10.1634/theoncologist.2012-0333. Epub 2013 Mar 1.

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT01107418
• Other Study ID Numbers: NP25163
• First Posted: April 21, 2010
• Results First Posted: August 26, 2015
• Last Update Posted: August 26, 2015
• Last Verified: July 2015

Additional relevant MeSH terms:

Melanoma; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas