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

Study Description

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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

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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

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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

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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

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Ages Eligible for Study:	18 Years and older (Adult, Senior)
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

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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

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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 History of Changes
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