Melanoma
Conditions
Keywords
BRAF mutation positive, advanced melanoma, Advanced cutaneous melanoma, Unknown primary melanoma
Brief summary
To assess the efficacy in terms of overall survival of AZD6244 in combination with dacarbazine, compared with dacarbazine alone, in first line patients with BRAF mutation positive advanced cutaneous or unknown primary melanoma
Interventions
DRUGAZD6244
oral capsules, 75mg twice daily
DRUGDacarbazine
1000 mg/m2 iv infusion over at least 60 min. on day 1 of each 21 cycle
DRUGPlacebo
Placebo
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 130 Years
Healthy volunteers
No
Inclusion criteria
* Histological or cytological confirmation of advanced (inoperable stage III and stage IV) cutaneous or unknown primary melanoma * Tumor sample confirmed as BRAF mutation positive
Exclusion criteria
* Diagnosis of uveal or mucosal melanoma * Any prior Investigational therapy comprising inhibitors of Ras, Raf or MEK * Having received an investigational drug within 30 days of starting treatment, or have not recovered from side effects of an investigational drug
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | From date of randomization until death, withdrawal of consent or the end of the study. The end of the study was defined as the date all AZD6244 patients had been followed for a minimum of 12 months, or the date of final analysis, whichever was later | Following progression survival data was collected until documentation of death, withdrawal of consent, loss to follow-up or the final data cut-off, whichever occurred first. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival | From randomization until evidence of RECIST-defined objective disease progression or data cut off, for a minimum of 12 months since start of treatment | PFS is the time from randomisation until the date of objective disease progression as defined by Response Evaluation Criteria In Solid Tumours (RECIST version 1.1) or death (by any cause in the absence of progression). Progression is defined using RECIST (v1.1), as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm. |
| Objective Response Rate | From randomization until evidence of RECIST-defined objective disease progression or data cut off, for a minimum of 12 months since start of treatment | ORR rate is defined as the number (%) of subjects with at least one visit response of Complete Response (CR) or Partial Response (PR) , as defined by Response Evaluation Criteria in Solid Tumours (RECIST v1.1) for target lesions and assessed by CT or MRI. CR, Disappearance of all target lesions; PR, ≥30% decrease in the sum of the longest diameter of target lesions. Data obtained up until progression, or last evaluable assessment in the absence of progression, was included in the assessment of ORR |
| Change in Target Lesion Tumour Size at Week 12 | randomization to week 12 | — |
Countries
Brazil, Czechia, France, Germany, Hungary, Netherlands, Norway, Spain, Sweden, Switzerland, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Selumetinib 75mg BD +Dacarbazine selumetinib 75mg twice daily + Dacarbazine | 45 |
| Placebo BD + Dacarbazine Placebo twice daily + Dacarbazine | 46 |
| Total | 91 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Selumetinib 75mg BD +Dacarbazine | Placebo BD + Dacarbazine | Total |
|---|---|---|---|
| Age, Continuous | 55.7 Years STANDARD_DEVIATION 14.89 | 51.6 Years STANDARD_DEVIATION 16.21 | 53.6 Years STANDARD_DEVIATION 15.62 |
| Sex: Female, Male Female | 23 Participants | 18 Participants | 41 Participants |
| Sex: Female, Male Male | 22 Participants | 28 Participants | 50 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 44 / 44 | 44 / 45 |
| serious Total, serious adverse events | 22 / 44 | 8 / 45 |
Outcome results
Primary
Overall Survival
Following progression survival data was collected until documentation of death, withdrawal of consent, loss to follow-up or the final data cut-off, whichever occurred first.
Time frame: From date of randomization until death, withdrawal of consent or the end of the study. The end of the study was defined as the date all AZD6244 patients had been followed for a minimum of 12 months, or the date of final analysis, whichever was later
Population: Intention to Treat (ITT)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Selumetinib 75mg BD + Dacarbazine | Overall Survival | 424 Days |
| Placebo + Dacarbazine | Overall Survival | 321 Days |
Comparison: If the true hazard ratio (HR) is 0.57, 58 deaths provides at least 80% power to demonstrate a statistically significant difference for OS, assuming a 1-sided 10% significance level.p-value: 0.387380% CI: [0.67, 1.28]Regression, Cox
Secondary
Change in Target Lesion Tumour Size at Week 12
Time frame: randomization to week 12
Population: Intention to Treat (ITT)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Selumetinib 75mg BD + Dacarbazine | Change in Target Lesion Tumour Size at Week 12 | -8.85 % change |
| Placebo + Dacarbazine | Change in Target Lesion Tumour Size at Week 12 | 0.22 % change |
Secondary
Objective Response Rate
ORR rate is defined as the number (%) of subjects with at least one visit response of Complete Response (CR) or Partial Response (PR) , as defined by Response Evaluation Criteria in Solid Tumours (RECIST v1.1) for target lesions and assessed by CT or MRI. CR, Disappearance of all target lesions; PR, ≥30% decrease in the sum of the longest diameter of target lesions. Data obtained up until progression, or last evaluable assessment in the absence of progression, was included in the assessment of ORR
Time frame: From randomization until evidence of RECIST-defined objective disease progression or data cut off, for a minimum of 12 months since start of treatment
Population: Intention to Treat (ITT)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Selumetinib 75mg BD + Dacarbazine | Objective Response Rate | Response | 18 Participants |
| Selumetinib 75mg BD + Dacarbazine | Objective Response Rate | Complete Response | 1 Participants |
| Selumetinib 75mg BD + Dacarbazine | Objective Response Rate | Partial Response | 17 Participants |
| Selumetinib 75mg BD + Dacarbazine | Objective Response Rate | Non-response | 27 Participants |
| Selumetinib 75mg BD + Dacarbazine | Objective Response Rate | Stable Disease >=6 weeks | 13 Participants |
| Selumetinib 75mg BD + Dacarbazine | Objective Response Rate | Progression | 14 Participants |
| Placebo + Dacarbazine | Objective Response Rate | Stable Disease >=6 weeks | 10 Participants |
| Placebo + Dacarbazine | Objective Response Rate | Response | 12 Participants |
| Placebo + Dacarbazine | Objective Response Rate | Non-response | 34 Participants |
| Placebo + Dacarbazine | Objective Response Rate | Complete Response | 1 Participants |
| Placebo + Dacarbazine | Objective Response Rate | Progression | 24 Participants |
| Placebo + Dacarbazine | Objective Response Rate | Partial Response | 11 Participants |
Secondary
Progression Free Survival
PFS is the time from randomisation until the date of objective disease progression as defined by Response Evaluation Criteria In Solid Tumours (RECIST version 1.1) or death (by any cause in the absence of progression). Progression is defined using RECIST (v1.1), as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm.
Time frame: From randomization until evidence of RECIST-defined objective disease progression or data cut off, for a minimum of 12 months since start of treatment
Population: Intention to Treat (ITT)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Selumetinib 75mg BD + Dacarbazine | Progression Free Survival | 169 Days |
| Placebo + Dacarbazine | Progression Free Survival | 92 Days |