Malignant Melanoma
Conditions
Brief summary
This open-label, multicenter. single arm Phase I dose-escalation study with efficacy tail extension will evaluate the maximum tolerated dose/recommended dose, the safety and efficacy of vemurafenib (RO5185426) in pediatric participants (aged 12 through 17) with newly diagnosed or recurrent surgically incurable and unresectable Stage IIIC or Stage IV melanoma harboring BRAFV600 mutations. Participants will receive vemurafenib orally twice daily until disease progression or unacceptable toxicity occurs.
Interventions
DRUGvemurafenib
Cohort 1 (participants \>=45 kg): starting dose level 720mg; next dose level 960 mg Cohort 2 (participants \<45 kg): starting dose 480 mg
Sponsors
Hoffmann-La Roche
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
* Pediatric participants, 12 to 17 years of age inclusive * Histologically confirmed surgically incurable and unresectable Stage IIIC or Stage IV (AJCC) melanoma * Positive proto-oncogene B-Raf (BRAF) mutation result (Cobas 4800 BRAF V600 Mutation Test) * Measurable disease according to Response Evaluation Criteria In Solid Tumors (RECIST) criteria * Performance status: Karnofsky (for participants \>/= 16 years of age) or Lansky (for participants \< 16 years of age) score of \>/= 60 * Adequate bone marrow, liver and renal function * Participants must have fully recovered from the acute toxic effects of all prior therapy prior to first administration of study drug
Exclusion criteria
* Active or untreated central nervous system (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 selective/specific BRAF or Methyl Ethyl Ketone (MEK) inhibitor (previous treatment with sorafenib is allowed) * Any previous treatment with study drug (RO5185426) or participation in a clinical trial that includes RO5185426 * Pregnant or lactating females * Known human immunodeficiency virus (HIV) positivity or acquired immune deficiency syndrome (AIDS)-related illness, active hepatitis B virus, or active hepatitis C virus
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose (MTD)/Recommended Dose | Up to 28 days of treatment | The MTD was defined as the dose level at which six evaluable participants had been treated and at most one participant experienced a dose limiting toxicity (DLT) and the next highest dose level was too toxic. Dose escalation occurred if 0 out of 3 or at most 1 out of 6 participant experienced DLT while being treated at a dose level; otherwise the dose was declared unsafe and thus above the MTD. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With an Adverse Event (AE) | Up to approximately 2 years 11 months | An AE was defined as any untoward medical occurrence in a patient administered a pharmaceutical product and which did not necessarily have to have a causal relationship with study treatment. |
| Best Overall Response Rate (BORR) | Up to 2 years | BORR was assessed by the investigators according to the Response Evaluation Criteria In Solid Tumors (RECIST) v1.1. BORR was defined as the number of participants who achieved a complete response (CR) or partial response (PR). CR was defined as complete disappearance of all target lesions and non-target disease. PR was defined as a \>=30% decrease under baseline of the sum of diameters of all target lesions. BORR was summarized along with the associated exact 95% confidence interval (CI) using the method of Clopper-Pearson. |
| Area Under the Concentration-Time Curve for Vemurafenib | Pre-dose, 2, 4, 8, 12 hours post dose on Cycle 1 Day 1 and Cycle 1 Day 22 (each cycle is of 28 days) | — |
| Progression-free Survival (PFS) | Randomization date of first subject until disease progression or death or which ever occur first (2 years) | PFS was defined as the time between the day of first treatment and the first documentation of progressive disease or death. Progression was defined as a 20% increase in the sum of the longest diameter of target lesions, the appearance of new lesions and increase of at least 5 mm in the sum of diameters of target lesions. Participants who were withdrawn from the study without documented progression were to be censored at the date of the last known tumor assessment when the participant was known to be progression free. Median PFS was estimated using Kaplan-Meier method and 95% CI for median was computed using the Brookmeyer and Crowley method. |
| Overall Survival (OS) | Randomization date of first subject until death (2 years) | Overall survival was defined as the time between the date of first treatment to the date of death, regardless of the cause of death. Participants who were alive at the time of the analysis were censored at the date of their last being known alive. Median overall survival was estimated using Kaplan-Meier method and 95% CI for median was computed using the Brookmeyer and Crowley method. |
| Clinical Benefit Rate (CBR) | Up to 2 years | CBR was defined as the number of participants that achieved a CR, PR or stable disease (SD) (SD for at least 6 weeks) as assessed by investigators according to the RECIST v1.1. CR was defined as complete disappearance of all target lesions and non-target disease. PR was defined as at \>=30% decrease under baseline of the sum of diameters of all target lesions. SD was defined as steady state of disease with neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD). |
Countries
Australia, France, Germany, Israel, Italy, Poland, Slovakia, Spain, United Kingdom, United States
Participant flow
Recruitment details
First investigational site was activated on 22 December 2011.
Pre-assignment details
Participants were enrolled in two separate cohorts with different starting doses based on greater than or equal to (\>=)45 kilogram (kg) and other weighing less than (\<)45 kg. Participants \>=45 kg were then enrolled in a dose escalation period. No participants were enrolled in the \<45 kg cohort.
Participants by arm
| Arm | Count |
|---|---|
| Vemurafenib Participants received vemurafenib into two separate cohorts with different starting doses based on greater than or equal to (\>=)45 kilogram (kg) and other weighing less than (\<)45 kg. The starting dose for participants (\>=45 kg) was 720 milligram (mg) of vemurafenib by mouth twice daily (BID) and the next dose level for participants in this cohort was 960 mg by mouth BID. The starting dose level for participants weighing \<45 kg was to be 480 mg of vemurafenib by mouth BID, but no participants were enrolled into this cohort. | 6 |
| Total | 6 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 3 | 2 |
| Overall Study | Study terminated by sponsor | 0 | 1 |
Baseline characteristics
| Characteristic | Vemurafenib |
|---|---|
| Age, Continuous | 15.8 years STANDARD_DEVIATION 0.8 |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 6 / 6 |
| serious Total, serious adverse events | 3 / 6 |
Outcome results
Primary
Maximum Tolerated Dose (MTD)/Recommended Dose
The MTD was defined as the dose level at which six evaluable participants had been treated and at most one participant experienced a dose limiting toxicity (DLT) and the next highest dose level was too toxic. Dose escalation occurred if 0 out of 3 or at most 1 out of 6 participant experienced DLT while being treated at a dose level; otherwise the dose was declared unsafe and thus above the MTD.
Time frame: Up to 28 days of treatment
Population: A MTD could not be determined in this study because of the low number of participants enrolled.
Secondary
Area Under the Concentration-Time Curve for Vemurafenib
Time frame: Pre-dose, 2, 4, 8, 12 hours post dose on Cycle 1 Day 1 and Cycle 1 Day 22 (each cycle is of 28 days)
Population: Pharmacokinetic (PK) population included all enrolled participants who received at least one dose or a partial dose of study treatment and provided at least one post-dose blood sample for PK analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Vemurafenib | Area Under the Concentration-Time Curve for Vemurafenib | Cycle 1 Day 1 | 16300 hour*nanogram per millitre (h*ng/mL) | Geometric Coefficient of Variation 80.5 |
| Vemurafenib | Area Under the Concentration-Time Curve for Vemurafenib | Cycle 1 Day 22 | 486000 hour*nanogram per millitre (h*ng/mL) | Geometric Coefficient of Variation 26.7 |
| Vemurafenib 960 mg | Area Under the Concentration-Time Curve for Vemurafenib | Cycle 1 Day 1 | 57000 hour*nanogram per millitre (h*ng/mL) | Geometric Coefficient of Variation 95.5 |
| Vemurafenib 960 mg | Area Under the Concentration-Time Curve for Vemurafenib | Cycle 1 Day 22 | 963000 hour*nanogram per millitre (h*ng/mL) | Geometric Coefficient of Variation 23.4 |
Secondary
Best Overall Response Rate (BORR)
BORR was assessed by the investigators according to the Response Evaluation Criteria In Solid Tumors (RECIST) v1.1. BORR was defined as the number of participants who achieved a complete response (CR) or partial response (PR). CR was defined as complete disappearance of all target lesions and non-target disease. PR was defined as a \>=30% decrease under baseline of the sum of diameters of all target lesions. BORR was summarized along with the associated exact 95% confidence interval (CI) using the method of Clopper-Pearson.
Time frame: Up to 2 years
Population: Intent to treat population included all participants enrolled.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vemurafenib | Best Overall Response Rate (BORR) | 0 percentage of participants |
Secondary
Clinical Benefit Rate (CBR)
CBR was defined as the number of participants that achieved a CR, PR or stable disease (SD) (SD for at least 6 weeks) as assessed by investigators according to the RECIST v1.1. CR was defined as complete disappearance of all target lesions and non-target disease. PR was defined as at \>=30% decrease under baseline of the sum of diameters of all target lesions. SD was defined as steady state of disease with neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD).
Time frame: Up to 2 years
Population: Intent to treat population included all participants enrolled.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vemurafenib | Clinical Benefit Rate (CBR) | 66.7 percentage of participants |
Secondary
Number of Participants With an Adverse Event (AE)
An AE was defined as any untoward medical occurrence in a patient administered a pharmaceutical product and which did not necessarily have to have a causal relationship with study treatment.
Time frame: Up to approximately 2 years 11 months
Population: Safety population included all participants who received at least one dose or a partial dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vemurafenib | Number of Participants With an Adverse Event (AE) | 6 participants |
Secondary
Overall Survival (OS)
Overall survival was defined as the time between the date of first treatment to the date of death, regardless of the cause of death. Participants who were alive at the time of the analysis were censored at the date of their last being known alive. Median overall survival was estimated using Kaplan-Meier method and 95% CI for median was computed using the Brookmeyer and Crowley method.
Time frame: Randomization date of first subject until death (2 years)
Population: Intent to treat population included all participants enrolled.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vemurafenib | Overall Survival (OS) | 246.5 days |
Secondary
Progression-free Survival (PFS)
PFS was defined as the time between the day of first treatment and the first documentation of progressive disease or death. Progression was defined as a 20% increase in the sum of the longest diameter of target lesions, the appearance of new lesions and increase of at least 5 mm in the sum of diameters of target lesions. Participants who were withdrawn from the study without documented progression were to be censored at the date of the last known tumor assessment when the participant was known to be progression free. Median PFS was estimated using Kaplan-Meier method and 95% CI for median was computed using the Brookmeyer and Crowley method.
Time frame: Randomization date of first subject until disease progression or death or which ever occur first (2 years)
Population: Intent to treat population included all participants enrolled.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vemurafenib | Progression-free Survival (PFS) | 134.5 days |