Clinical trial NCT01264380: A Study of the Effect of Food on the Pharmacokinetics of Single Dose RO5185426 And the Safety And Efficacy of Continuous Administration in Patients With BRAF V600E Mutation-Positive Metastatic Melanoma
Official title: A Phase I, Randomized, Open-label, Multi-center, Two Period Crossover Study to Investigate the Effect of Food on the Pharmacokinetics of a Single Oral Dose of RO5185426, Followed by Administration of 960 mg RO5185426 Twice Daily to BRAF V600E Positive Metastatic Melanoma Patients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Malignant Melanoma
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2010-12-21
Enrollment: 16
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: This randomized, open-label, two period crossover study will evaluate the effect of food on the pharmacokinetics of a single dose of RO5185426 and the efficacy and safety of continuous administration in patients with BRAF V600E mutation-positive metastatic melanoma. Patients will be randomized to receive in a crossover design single oral doses of RO5185426 with or without food, with a 10-day washout period between doses. Following the crossover periods, patients will receive RO5185426 orally twice daily on a continuous basis until disease progression or unacceptable toxicity occurs.


Eligibility criteria: Inclusion Criteria:

* Adult patients, \>/= 18 years of age
* Histologically confirmed metastatic melanoma (Stage IV, American Joint Committee on Cancer)
* Positive BRAF V600E mutation result determined by Cobas 4800 BRAF V600 Mutation Test
* Previously treated patients must have failed at least one prior treatment regimen; if patients have received prior systemic treatments for metastatic melanoma, the time elapsed from previous therapy must be \>/= 28 days; patients must have recovered fully from toxicities of all prior therapy
* Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
* Evaluable disease (measurable for disease progression according to RECIST criteria)
* Adequate hematological, renal and liver function

Exclusion Criteria:

* Active CNS lesions
* History of or known spinal cord compression or carcinomatous meningitis
* Anticipated or ongoing administration of anti-cancer therapies other than those administered in this 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
* Previous treatment with BRAF inhibitor (sorafenib allowed) or MEK inhibitor
* Refractory nausea or vomiting, malabsorption, external biliary shunt, or history of any type of gastrointestinal surgery that would preclude adequate absorption of study drug

Primary outcomes:
measure: Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC [0-inf]) in the Fasted and Fed States
timeFrame: Period A: pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16 hours (h) post-dose (pd) on Day 1; 24, 36, 48, 72, 96, 144, 192, and 240 h pd and Period B: pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16 h pd on Day 11; 24, 36, 48, 72, 96, 144, 192, and 240 h pd
measure: Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Sample With Last Measurable Concentration (AUC[0-last]) in the Fasted and Fed States
timeFrame: Period A: pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16 h pd on Day 1; 24, 36, 48, 72, 96, 144, 192, and 240 h pd and Period B: pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16 h pd on Day 11; 24, 36, 48, 72, 96, 144, 192, and 240 h pd
measure: Maximal Observed Plasma Concentration (Cmax) in the Fasted and Fed States
timeFrame: Period A: pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16 h pd on Day 1; 24, 36, 48, 72, 96, 144, 192, and 240 h pd and Period B: pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16 h pd on Day 11; 24, 36, 48, 72, 96, 144, 192, and 240 h pd
measure: Minimum Observed (Trough) Plasma Concentration (Cmin) in the Fasted and Fed States
timeFrame: Pre-dose on Periods A and B
measure: Time to Reach Maximal Plasma Concentration (Tmax) in the Fasted and Fed States
timeFrame: Period A: pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16 h pd on Day 1; 24, 36, 48, 72, 96, 144, 192, and 240 h pd and Period B: pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16 h pd on Day 11; 24, 36, 48, 72, 96, 144, 192, and 240 h pd
measure: Terminal Elimination Half-Life (t1/2) in the Fasted and Fed States
timeFrame: Period A: pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16 h pd on Day 1; 24, 36, 48, 72, 96, 144, 192, and 240 h pd and Period B: pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16 h pd on Day 11; 24, 36, 48, 72, 96, 144, 192, and 240 h pd
measure: Apparent First-order Terminal Elimination Rate Constant (Kel) in the Fasted and Fed States
timeFrame: Period A: pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16 h pd on Day 1; 24, 36, 48, 72, 96, 144, 192, and 240 h pd and Period B: pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16 h pd on Day 11; 24, 36, 48, 72, 96, 144, 192, and 240 h pd
Secondary outcomes:
measure: Percentage of Participants With Best Objective Response (BOR) as Complete Response (CR) or Partial Response (PR)
timeFrame: From Baseline then Day 1 of Cycle 3 and 5 (21-day cycle) at Period C thereafter every 2 cycles until Cycle 12 followed by every 4 cycles from Cycle 13 until disease progression or death (Up to Week 124)
measure: Overall Survival (OS)
timeFrame: From Baseline then Day 1 of Cycle 3 and 5 (21-day cycle) at Period C thereafter every 2 cycles until Cycle 12 followed by every 4 cycles from Cycle 13 until death (Up to Week 124)
Other outcomes:
Locations:
city: La Jolla
country: United States
state: California
city: Los Angeles
country: United States
state: California
city: San Francisco
country: United States
state: California
city: Aurora
country: United States
state: Colorado
city: Indianapolis
country: United States
state: Indiana
city: Iowa City
country: United States
state: Iowa
city: Lebanon
country: United States
state: New Hampshire
city: Charleston
country: United States
state: South Carolina
city: Nashville
country: United States
state: Tennessee
city: Dallas
country: United States
state: Texas
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References:
citation: 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.