Back to resultsA 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
Primary Purpose
Malignant Melanoma
Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
RO5185426
RO5185426
RO5185426
Sponsored by
About this trial
This is an interventional treatment trial for Malignant Melanoma
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
Sites / Locations
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm Type
Experimental
Experimental
Experimental
Arm Label
1
2
C
Arm Description
Outcomes
Primary Outcome Measures
Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC [0-inf]) in the Fasted and Fed States
Pharmacokinetic (PK) analyses was performed after the completion of Period A and Period B of this study for all participants.
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
PK analyses was performed after the completion of Period A and Period B of this study for all participants.
Maximal Observed Plasma Concentration (Cmax) in the Fasted and Fed States
PK analyses was performed after the completion of Period A and Period B of this study for all participants.
Minimum Observed (Trough) Plasma Concentration (Cmin) in the Fasted and Fed States
Single dose Pre-dose concentration is referred as Cmin here. PK analyses was performed after the completion of Period A and Period B of this study for all participants.
Time to Reach Maximal Plasma Concentration (Tmax) in the Fasted and Fed States
PK analyses was performed after the completion of Period A and Period B of this study for all participants.
Terminal Elimination Half-Life (t1/2) in the Fasted and Fed States
T1/2 is the time required for the concentration of the drug to reach half of its original value. PK analyses was performed after the completion of Period A and Period B of this study for all participants.
Apparent First-order Terminal Elimination Rate Constant (Kel) in the Fasted and Fed States
Apparent first-order terminal elimination rate constant (kel), was calculated as the negative slope of the linear regression of the terminal phase in plasma vemurafenib concentration-time profile using specific appropriate time points. PK analyses was performed after the completion of Period A and Period B of this study for all participants.
Secondary Outcome Measures
Percentage of Participants With Best Objective Response (BOR) as Complete Response (CR) or Partial Response (PR)
BOR was defined as the best objective response assessed by investigator during the treatment period according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. BOR was the best response recorded from the start of the study treatment until the end of treatment taking into account any requirement for confirmation. It is defined as the number of participants whose best objective response was complete response (CR) or partial response (PR) divided by the total number of efficacy evaluable participants. CR: disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes (whether target or non-target) were non-pathological in size (less than [<] 10 millimeter [mm] short axis). PR: at least a 30 percent (%) decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Overall Survival (OS)
OS was defined as the time, in months, from the date of the first study drug to the date of death, regardless of the cause of death.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT01264380
Brief Title
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
2. Study Status
Record Verification Date
November 2016
Overall Recruitment Status
Completed
Study Start Date
January 2011 (undefined)
Primary Completion Date
May 2013 (Actual)
Study Completion Date
May 2013 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Hoffmann-La Roche
4. Oversight
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Malignant Melanoma
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Crossover Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
16 (Actual)
8. Arms, Groups, and Interventions
Arm Title
1
Arm Type
Experimental
Arm Title
2
Arm Type
Experimental
Arm Title
C
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
RO5185426
Intervention Description
Single oral dose, fasted
Intervention Type
Drug
Intervention Name(s)
RO5185426
Intervention Description
Single oral dose, with high fat meal
Intervention Type
Drug
Intervention Name(s)
RO5185426
Intervention Description
Continuous administration, orally twice daily
Primary Outcome Measure Information:
Title
Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC [0-inf]) in the Fasted and Fed States
Description
Pharmacokinetic (PK) analyses was performed after the completion of Period A and Period B of this study for all participants.
Time Frame
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
Title
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
Description
PK analyses was performed after the completion of Period A and Period B of this study for all participants.
Time Frame
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
Title
Maximal Observed Plasma Concentration (Cmax) in the Fasted and Fed States
Description
PK analyses was performed after the completion of Period A and Period B of this study for all participants.
Time Frame
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
Title
Minimum Observed (Trough) Plasma Concentration (Cmin) in the Fasted and Fed States
Description
Single dose Pre-dose concentration is referred as Cmin here. PK analyses was performed after the completion of Period A and Period B of this study for all participants.
Time Frame
Pre-dose on Periods A and B
Title
Time to Reach Maximal Plasma Concentration (Tmax) in the Fasted and Fed States
Description
PK analyses was performed after the completion of Period A and Period B of this study for all participants.
Time Frame
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
Title
Terminal Elimination Half-Life (t1/2) in the Fasted and Fed States
Description
T1/2 is the time required for the concentration of the drug to reach half of its original value. PK analyses was performed after the completion of Period A and Period B of this study for all participants.
Time Frame
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
Title
Apparent First-order Terminal Elimination Rate Constant (Kel) in the Fasted and Fed States
Description
Apparent first-order terminal elimination rate constant (kel), was calculated as the negative slope of the linear regression of the terminal phase in plasma vemurafenib concentration-time profile using specific appropriate time points. PK analyses was performed after the completion of Period A and Period B of this study for all participants.
Time Frame
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 Outcome Measure Information:
Title
Percentage of Participants With Best Objective Response (BOR) as Complete Response (CR) or Partial Response (PR)
Description
BOR was defined as the best objective response assessed by investigator during the treatment period according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. BOR was the best response recorded from the start of the study treatment until the end of treatment taking into account any requirement for confirmation. It is defined as the number of participants whose best objective response was complete response (CR) or partial response (PR) divided by the total number of efficacy evaluable participants. CR: disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes (whether target or non-target) were non-pathological in size (less than [<] 10 millimeter [mm] short axis). PR: at least a 30 percent (%) decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Time Frame
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)
Title
Overall Survival (OS)
Description
OS was defined as the time, in months, from the date of the first study drug to the date of death, regardless of the cause of death.
Time Frame
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)
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Clinical Trials
Organizational Affiliation
Hoffmann-La Roche
Official's Role
Study Director
Facility Information:
City
La Jolla
State/Province
California
ZIP/Postal Code
92037
Country
United States
City
Los Angeles
State/Province
California
ZIP/Postal Code
90095-1752
Country
United States
City
San Francisco
State/Province
California
ZIP/Postal Code
94115-1705
Country
United States
City
Aurora
State/Province
Colorado
ZIP/Postal Code
80045
Country
United States
City
Indianapolis
State/Province
Indiana
ZIP/Postal Code
46202
Country
United States
City
Iowa City
State/Province
Iowa
ZIP/Postal Code
52242
Country
United States
City
Lebanon
State/Province
New Hampshire
ZIP/Postal Code
03756
Country
United States
City
Charleston
State/Province
South Carolina
ZIP/Postal Code
29425
Country
United States
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37232
Country
United States
City
Dallas
State/Province
Texas
ZIP/Postal Code
75246
Country
United States
12. IPD Sharing Statement
Citations:
PubMed Identifier
24983357
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.
Results Reference
derived
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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
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