Malignant Melanoma
Conditions
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.
Interventions
DRUGRO5185426
Single oral dose, fasted
Sponsors
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Apparent First-order Terminal Elimination Rate Constant (Kel) in the Fasted and Fed States | 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 | 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 to Reach Maximal Plasma Concentration (Tmax) in the Fasted and Fed States | 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 | 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 | 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 | 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. |
| Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC [0-inf]) in the Fasted and Fed States | 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 | 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 | 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 | 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 | 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 | 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 | Pre-dose on Periods A and B | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | 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) | 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. |
| Percentage of Participants With Best Objective Response (BOR) as Complete Response (CR) or Partial Response (PR) | 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) | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| All Participants Included all participants who received single oral dose of vemurafenib tablet at 960 mg in fasted condition first and fed condition first in Period A and Period B and twice daily dose of vemurafenib tablet at 960 mg in Period C. | 16 |
| Total | 16 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Period C | Adverse Event | 0 | 0 | 1 |
| Period C | Death | 0 | 0 | 2 |
| Period C | Disease Progression | 0 | 0 | 4 |
| Period C | Follow-up for survival status | 0 | 0 | 6 |
| Period C | Withdrawal by Subject | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Continuous | 60.6 years STANDARD_DEVIATION 10.31 |
| Gender Female | 6 Participants |
| Gender Male | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 16 | 5 / 16 | 16 / 16 |
| serious Total, serious adverse events | 0 / 16 | 0 / 16 | 9 / 16 |
Outcome results
Primary
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.
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
Population: PK analysis population. Here number of participants analyzed=participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vemurafenib (RO5185426): Fasted | Apparent First-order Terminal Elimination Rate Constant (Kel) in the Fasted and Fed States | 0.04 1/h | Standard Deviation 0.03 |
| Vemurafenib (RO5185426): Fed | Apparent First-order Terminal Elimination Rate Constant (Kel) in the Fasted and Fed States | 0.04 1/h | Standard Deviation 0.02 |
Primary
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.
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
Population: PK analysis population included participants who received both single doses of vemurafenib in Periods A and B without protocol violation and provided adequate PK assessments to calculate important PK parameters. Here number of participants analyzed=participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vemurafenib (RO5185426): Fasted | Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC [0-inf]) in the Fasted and Fed States | 115 micrograms*hour per milliliter (µg*h/mL) | Standard Deviation 110 |
| Vemurafenib (RO5185426): Fed | Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC [0-inf]) in the Fasted and Fed States | 351 micrograms*hour per milliliter (µg*h/mL) | Standard Deviation 189 |
Comparison: The point estimate and 90 percent (%) confidence interval (CI) of vemurafenib plasma AUC geometric means ratios of the Fed to Fasted conditions following an oral administration of a single dose of 960 mg vemurafenib were analyzed.90% CI: [2.83, 7.6]
Primary
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.
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
Population: PK analysis population. Here number of participants analyzed=participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vemurafenib (RO5185426): Fasted | 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 | 94.3 µg*h/mL | Standard Deviation 81.8 |
| Vemurafenib (RO5185426): Fed | 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 | 320 µg*h/mL | Standard Deviation 158 |
Comparison: The point estimate and 90% CI of vemurafenib plasma AUC geometric means ratios of the Fed to Fasted conditions following an oral administration of a single dose of 960 mg vemurafenib were analyzed.90% CI: [2.99, 8.55]
Primary
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.
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
Population: PK analysis population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vemurafenib (RO5185426): Fasted | Maximal Observed Plasma Concentration (Cmax) in the Fasted and Fed States | 3.48 µg/mL | Standard Deviation 2.02 |
| Vemurafenib (RO5185426): Fed | Maximal Observed Plasma Concentration (Cmax) in the Fasted and Fed States | 7.38 µg/mL | Standard Deviation 1.98 |
Comparison: The point estimate and 90% CI of vemurafenib plasma Cmax geometric means ratios of the Fed to Fasted conditions following an oral administration of a single dose of 960 mg vemurafenib were analyzed.90% CI: [1.81, 3.32]
Primary
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 frame: Pre-dose on Periods A and B
Population: PK analysis population.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Vemurafenib (RO5185426): Fasted | Minimum Observed (Trough) Plasma Concentration (Cmin) in the Fasted and Fed States | NA µg/mL |
| Vemurafenib (RO5185426): Fed | Minimum Observed (Trough) Plasma Concentration (Cmin) in the Fasted and Fed States | NA µg/mL |
Primary
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.
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
Population: PK analysis population. Here number of participants analyzed=participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vemurafenib (RO5185426): Fasted | Terminal Elimination Half-Life (t1/2) in the Fasted and Fed States | 24.6 hour | Standard Deviation 17.2 |
| Vemurafenib (RO5185426): Fed | Terminal Elimination Half-Life (t1/2) in the Fasted and Fed States | 26.0 hour | Standard Deviation 17.1 |
Primary
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.
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
Population: PK analysis population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vemurafenib (RO5185426): Fasted | Time to Reach Maximal Plasma Concentration (Tmax) in the Fasted and Fed States | 4 hour |
| Vemurafenib (RO5185426): Fed | Time to Reach Maximal Plasma Concentration (Tmax) in the Fasted and Fed States | 7.51 hour |
Secondary
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.
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)
Population: Data for OS was not collected as there was a change in planned analysis, not to collect the data.
Secondary
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.
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)
Population: Intent-to-treat (ITT) population included participants with measurable disease who received at least 1 dose of vemurafenib. Here number of participants analyzed=participants who were evaluable for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vemurafenib (RO5185426): Fasted | Percentage of Participants With Best Objective Response (BOR) as Complete Response (CR) or Partial Response (PR) | 64.3 percentage of participants |