Metastatic, Uveal Melanoma
Conditions
Keywords
uveal melanoma
Brief summary
Selumetinib therapy in patients with metastatic uveal melanoma.
Detailed description
A randomised double-blind study to assess the efficacy of selumetinib (AZD6244, Hyd-Sulfate) in combination with Dacarbazine compared with placebo in combination with Dacarbazine as first systemic therapy in patients with metastatic uveal melanoma (SUMIT)
Interventions
DRUG75mg selumetinib
selumetinib tablets p.o. twice daily taken in combination with dacarbazine 1000mg/m2 iv on day 1 of every 21-day cycle.
DRUGplacebo
placebo tablets p.o. twice daily taken in combination with dacarbazine 1000mg/m2 iv on day 1 of every 21-day cycle.
DRUGDacarbazine
dacarbazine 1000mg/m2 iv on day 1 of every 21-day cycle taken in combination with either selumetinib or placebo tablets p.o. twice daily.
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
Clinical diagnosis of metastatic uveal melanoma; Written consent from female or male patients aged 18 years and over. Histological or cytological confirmation of melanoma who are suitable for treatment with dacarbazine chemotherapy. * At least one lesion that can be accurately measured at baseline as\>/=10mm in the longest diameter. (except lymph nodes which must have short axis ≥15 mm) with CT or MRI and which is suitable for accurate repeated measurements * ECOG performance status 0-1 * life expectancy \>12 weeks * Normal organ and marrow function * Evidence of post-menopausal status, or negative urinary or serum pregnancy test for female pre-menopausal patients * Patients should be able to swallow selumetinib/placebo capsules
Exclusion criteria
-Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site) * Previous randomisation in the present study * Patients cannot have previously been treated with a systemic anti-cancer therapy. Patients can have prior intra-hepatic or non-systemic therapy. -Having received any of the following within the specified timeframe: Any prior systemic anti-cancer therapy for the treatment of this current diagnosis, An investigational drug within 30 days of starting treatment or within five half-lives of the compound (whichever is the most appropriate is at the discretion of the Investigator), or have not recovered from side effects of an investigational drug Any non-systemic anti-cancer therapy which has not been cleared from the body by the time of starting study treatment Radiation therapy within 4 weeks prior to starting study treatment, or limited field of radiation for palliation within 7 days of the first dose of study treatment Major surgery within 4 weeks prior to entry into the study (excluding the placement of vascular access) which would prevent administration of study treatment, Any prior investigational therapy comprising inhibitors of RAS, RAF or MEK at any time, Previous treatment with dacarbazine. Any unresolved toxicity \>CTCAE grade 2 from previous anti-cancer therapy, excluding alopecia -History of allergic reactions attributed to compounds of similar chemical or biologic composition to selumetinib or dacarbazine --Symptomatic brain metastases or spinal cord compression (patients must be treated and stable off steroids and anti-convulsants for at least 1 month prior to entry into the study) Cardiac conditions as follows: * Uncontrolled hypertension (BP ≥150/95 mmHg despite medical therapy) * Acute coronary syndrome within 6 months prior to starting treatment * Uncontrolled Angina - Canadian Cardiovascular Society grade II-IV despite medical therapy - Symptomatic heart failure (New York Heart Association \[NYHA\] Class II-IV,- Prior or current cardiomyopathy * Baseline LVEF \<55% measured by echocardiography or MUGA. Appropriate correction to be used if a MUGA is performed * Severe valvular heart disease * Atrial fibrillation with a ventricular rate \>100 bpm on ECG at rest * QTcF \>450 ms or other factors that increase the risk of QTc prolongation * Any evidence of severe or uncontrolled systemic disease, active infection, active bleeding diatheses or renal transplant, including any patient known to have hepatitis B, hepatitis C or human immunodeficiency virus (HIV) * Refractory nausea and vomiting, chronic gastrointestinal diseases (eg inflammatory bowel disease), or significant bowel resection that would preclude adequate absorption * History of another primary malignancy within 5 years prior to starting study treatment, except for adequately treated basal or squamous cell carcinoma of the skin or cancer of the cervix in situ and the disease under study * Ophthalmologic conditions: * Current or past history of central serous retinopathy * Current or past history of retinal vein occlusion * IOP \>21 mmHg or uncontrolled glaucoma (irrespective of IOP) * Female patients who are breast-feeding a child and male or female patients of reproductive potential who are not employing an effective method of birth control * Clinical judgement by the Investigator that the patient should not participate in the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Assessment of the Efficacy of Selumetinib in Combination With Dacarbazine Compared With Placebo in Combination With Dacarbazine Measured as Progression Free Survival (PFS) Using BICR According to RECIST 1.1. | From Randomization, then every 6 weeks up until progression or death (whichever is sooner) assessed up to 15th May 2015 | Progression free survival (PFS) using blinded independent central review (BICR) according to the Response Evaluation Criteria in Solid Tumours version 1.1 (RECIST 1.1). Progression is defined as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Assessment of the Efficacy of Selumetinib in Combination With Dacarbazine Compared With Placebo in Combination With Dacarbazine in Terms of Objective Response Rate (ORR) by BICR | From Randomization, then every 6 weeks up until progression or death (whichever is sooner) assessed up to 15th May 2015 | ORR at Week 6 using BICR according to RECIST 1.1 |
| Assessment of the Efficacy of Selumetinib in Combination With Dacarbazine Compared With Placebo in Combination With Dacarbazine in Terms of Change in Tumour Size at Week 6 by BICR | From Randomization, then every 6 weeks up until progression or death (whichever is sooner) assessed up to 15th May 2015 | Percent change in tumour size at Week 6 using BICR according to RECIST 1.1 |
| Assessment of the Overall Survival (OS) in Patients Taking Selumetinib in Combination With Dacarbazine Compared With Those Taking Placebo in Combination With Dacarbazine | From Randomization, up until death assessed up to 15th May 2015 | Overall Survival |
Countries
Belgium, Canada, Czechia, Finland, France, Germany, Israel, Netherlands, Spain, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Selumetinib 75 mg BD + Dacarbazine 1000 mg/m2 Selumetinib 75 mg BD + Dacarbazine 1000 mg/m2 | 97 |
| Placebo + Dacarbazine 1000 mg/m2 Placebo + Dacarbazine 1000 mg/m2 | 32 |
| Total | 129 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 33 | 11 |
| Overall Study | Lost to Follow-up | 2 | 0 |
| Overall Study | Other Eligibility Criteria | 0 | 1 |
| Overall Study | Withdrawal by Subject | 2 | 3 |
Baseline characteristics
| Characteristic | Selumetinib 75 mg BD + Dacarbazine 1000 mg/m2 | Placebo + Dacarbazine 1000 mg/m2 | Total |
|---|---|---|---|
| Age, Continuous | 61.0 Years STANDARD_DEVIATION 12.28 | 59.6 Years STANDARD_DEVIATION 11.28 | 60.6 Years STANDARD_DEVIATION 12.01 |
| Age, Customized <55 years | 26 Participants | 11 Participants | 37 Participants |
| Age, Customized >=55 years To <65 years | 25 Participants | 9 Participants | 34 Participants |
| Age, Customized >=65 years | 46 Participants | 12 Participants | 58 Participants |
| Gender Female | 42 Participants | 19 Participants | 61 Participants |
| Gender Male | 55 Participants | 13 Participants | 68 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized White | 96 Participants | 31 Participants | 127 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 32 / 32 | 97 / 97 |
| serious Total, serious adverse events | 2 / 32 | 20 / 97 |
Outcome results
Primary
Assessment of the Efficacy of Selumetinib in Combination With Dacarbazine Compared With Placebo in Combination With Dacarbazine Measured as Progression Free Survival (PFS) Using BICR According to RECIST 1.1.
Progression free survival (PFS) using blinded independent central review (BICR) according to the Response Evaluation Criteria in Solid Tumours version 1.1 (RECIST 1.1). Progression is defined as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time frame: From Randomization, then every 6 weeks up until progression or death (whichever is sooner) assessed up to 15th May 2015
Population: All randomised patients and will compare the treatment groups on the basis of randomised treatment, regardless of the treatment actually received. Note, this is also known as the Full Analysis set (FAS).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Selumetinib 75 mg BD + Dacarbazine 1000 mg/m2 | Assessment of the Efficacy of Selumetinib in Combination With Dacarbazine Compared With Placebo in Combination With Dacarbazine Measured as Progression Free Survival (PFS) Using BICR According to RECIST 1.1. | 82 number of progression events |
| Placebo + Dacarbazine 1000 mg/m2 | Assessment of the Efficacy of Selumetinib in Combination With Dacarbazine Compared With Placebo in Combination With Dacarbazine Measured as Progression Free Survival (PFS) Using BICR According to RECIST 1.1. | 24 number of progression events |
p-value: 0.319595% CI: [0.48, 1.27]Log Rank
Secondary
Assessment of the Efficacy of Selumetinib in Combination With Dacarbazine Compared With Placebo in Combination With Dacarbazine in Terms of Change in Tumour Size at Week 6 by BICR
Percent change in tumour size at Week 6 using BICR according to RECIST 1.1
Time frame: From Randomization, then every 6 weeks up until progression or death (whichever is sooner) assessed up to 15th May 2015
Population: All randomised patients and will compare the treatment groups on the basis of randomised treatment, regardless of the treatment actually received. Note, this is also known as the Full Analysis set (FAS).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Selumetinib 75 mg BD + Dacarbazine 1000 mg/m2 | Assessment of the Efficacy of Selumetinib in Combination With Dacarbazine Compared With Placebo in Combination With Dacarbazine in Terms of Change in Tumour Size at Week 6 by BICR | 6.94 percent change | Standard Deviation 18.001 |
| Placebo + Dacarbazine 1000 mg/m2 | Assessment of the Efficacy of Selumetinib in Combination With Dacarbazine Compared With Placebo in Combination With Dacarbazine in Terms of Change in Tumour Size at Week 6 by BICR | 19.76 percent change | Standard Deviation 38.264 |
p-value: 0.128495% CI: [0.88, 1.02]ANCOVA
Secondary
Assessment of the Efficacy of Selumetinib in Combination With Dacarbazine Compared With Placebo in Combination With Dacarbazine in Terms of Objective Response Rate (ORR) by BICR
ORR at Week 6 using BICR according to RECIST 1.1
Time frame: From Randomization, then every 6 weeks up until progression or death (whichever is sooner) assessed up to 15th May 2015
Population: Full Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Selumetinib 75 mg BD + Dacarbazine 1000 mg/m2 | Assessment of the Efficacy of Selumetinib in Combination With Dacarbazine Compared With Placebo in Combination With Dacarbazine in Terms of Objective Response Rate (ORR) by BICR | 3 number of responders |
| Placebo + Dacarbazine 1000 mg/m2 | Assessment of the Efficacy of Selumetinib in Combination With Dacarbazine Compared With Placebo in Combination With Dacarbazine in Terms of Objective Response Rate (ORR) by BICR | 0 number of responders |
Secondary
Assessment of the Overall Survival (OS) in Patients Taking Selumetinib in Combination With Dacarbazine Compared With Those Taking Placebo in Combination With Dacarbazine
Overall Survival
Time frame: From Randomization, up until death assessed up to 15th May 2015
Population: All randomised patients and will compare the treatment groups on the basis of randomised treatment, regardless of the treatment actually received. Note, this is also known as the Full Analysis set (FAS).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Selumetinib 75 mg BD + Dacarbazine 1000 mg/m2 | Assessment of the Overall Survival (OS) in Patients Taking Selumetinib in Combination With Dacarbazine Compared With Those Taking Placebo in Combination With Dacarbazine | 34 Number of Overall Survival Events |
| Placebo + Dacarbazine 1000 mg/m2 | Assessment of the Overall Survival (OS) in Patients Taking Selumetinib in Combination With Dacarbazine Compared With Those Taking Placebo in Combination With Dacarbazine | 14 Number of Overall Survival Events |
p-value: 0.401195% CI: [0.39, 1.46]Log Rank