E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Stage III (Unresectable) or IV Melanoma |
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MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To compare PFS in patients with previously untreated Stage IIIc, N3 (unresectable) or Stage IV melanoma receiving dacarbazine plus 10mg/kg ipilimumab (MDX-010) vs. dacarbazine with placebo. |
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E.2.2 | Secondary objectives of the trial |
1) To compare overall survival (OS) between two arms; 2) To estimate survival rate at 1 year for each treatment arm; 3) To compare PFS rate at Week 12 between two arms; 4) To compare best overall response rate (BORR) between two arms; 5) To estimate duration of best overall response (BOR) and the proportion of patients with duration of response lasting ≥ 24 weeks for each treatment arm; 6) To compare disease control rate (proportion with best response of complete response [CR] + partial response [PR] + stable disease [SD]) between two arms; 7) To estimate time to BOR for each treatment arm; 8) To evaluate the safety profile for each treatment arm; 9) To evaluate Health Related Quality of Life (HRQoL) for each treatment arm; 10) To obtain serum samples for population pharmacokinetics |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1) Willing and able to give written informed consent; 2) Histologic diagnosis of malignant melanoma; 3) Untreated unresectable Stage III melanoma with N3 macroscopic lymph nodes or in-transit/satellite metastases or Stage IV melanoma (AJCC 2001) (note that prior adjuvant melanoma therapy is permitted [e.g., IFN therapy]); 4) Measurable/evaluable disease (as per modified WHO criteria), within 28 days of first dose of study drug; 5) Life expectancy of ≥ 16 weeks; 6) ECOG performance status of 0 or 1 (see Protocol Appendix 3); 7) Have the complete set of baseline (i.e., Screening) digital images of lesions and radiographic images, including, but not limited to: brain, chest, abdomen pelvis and bone scans. All images must be of adequate quality; 8) Required values for initial laboratory tests: • WBC ≥ 2500/uL • ANC ≥ 1000/uL • Platelets ≥ 75 x 103/uL • Hemoglobin ≥ 9 g/dL • Creatinine ≤ 2.5x ULN • AST ≤ 3 x ULN for patients without liver metastasis ≤ 5 x ULN for patients with liver metastasis • Bilirubin ≤ 3x ULN, (except patients with Gilbert’s Syndrome, who must have a total bilirubin less than 3.0 mg/dL; 9) Negative Screening tests for HIV, HepB, and HepC. If positive results are not indicative of true active or chronic infection, the patient can enter the study after discussion and agreement between the Investigator and the CRO Medical Monitor; 10) Accessible for treatment and Follow-Up; 11) Men and women > 18 years of age (or, ≥ 16, if allowable per local regulatory authority). WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to the start of study medication. |
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E.4 | Principal exclusion criteria |
1) WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for up to 8 weeks after the study. 2) Women who are pregnant or breastfeeding 3) Women with a positive pregnancy test on enrollment or prior to study drug administration. 4) Sexually active fertile men whose partners are WOCBP, unless using an adequate method of birth control 5) Evidence of brain metastases on brain imaging (i.e., MRI or contrast CT); 6) Any other malignancy from which the patient has been disease-free for less than 5 years, with the exception of adequately treated and cured basal or squamous cell skin cancer, superficial bladder cancer or carcinoma in situ of the cervix; 7) Primary ocular or mucosal melanoma; 8) Autoimmune disease: Patients with a documented history of inflammatory bowel disease, including ulcerative colitis and Crohn’s disease are excluded from this study as are patients with a history of symptomatic disease (e.g., rheumatoid arthritis, systemic progressive sclerosis [scleroderma], Systemic Lupus Erythematosus, autoimmune vasculitis [e.g., Wegener’s Granulomatosis]); 9) Any underlying medical or psychiatric condition, which in the opinion of the Investigator, will make the administration of study drug hazardous or obscure the interpretation of AEs, such as a condition associated with frequent diarrhea; 10) Prior or concomitant therapy with any anti-cancer agent, immunosuppressive agents, surgery or radiotherapy (except as defined in Sections 6.2.8.3 and 6.2.8.4 of the protocol); other investigational anti-cancer therapies, or chronic use of systemic corticosteroids (used in the management of cancer or non-cancer-related illnesses). Prior adjuvant therapy is not exclusionary; 11) Any non-oncology vaccine therapy used for prevention of infectious diseases (for up to 4 weeks prior to or after any dose of ipilimumab or dacarbazine); 12) Prior treatment with a CD137 agonist or CTLA-4 inhibitor or agonist; 13) Previous participation in another ipilimumab (MDX-010) clinical trial; 14) Treatment with other investigational products within the last 4 weeks prior to randomization into this study; 15) Prisoners or patients who are compulsorily detained |
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E.5 End points |
E.5.1 | Primary end point(s) |
Efficacy Measures: Investigator and Independent Review Committee (IRC) tumor evaluations will be based on modified WHO criteria. Throughout the study each respective Investigator will determine disease status of patients at the defined time points and as clinically indicated. For the purpose of final analysis of study results, an IRC will review all images from all time points for all patients and assess response parameters as specified.
Pharmacokinetics: Blood draws to assess the serum PK of ipilimumab will be drawn at the time points listed in section 7.3.5.1. of the protocol. Serum concentration data will be used in conjunction with samples from other studies as part of the population PK assessment. Serum Human Anti-Human Antibodies (HAHA) will be collected as per Table 7.3.5.1. of the protocol.
Safety Measures: Safety will be evaluated for all treated patients using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events v3.0 (CTCAE). Safety assessments will be based on medical review of AE reports and the results of vital sign measurements, physical examinations and clinical laboratory tests. The incidence of AEs will be tabulated and reviewed for potential significance and clinical importance. The reporting period for safety data will be from the date of first on-study dose to 70 days (5 half-lives) after the last dose is received.
Health-related quality of life (HRQoL): will be assessed as measured by the European Organization for Research and Treatment of Cancer Quality of Life questionnaire (EORTC) and will be administered at multiple time-points throughout the study. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Health-related quality of life (HRQoL) |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | Information not present in EudraCT |
E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
E.7.1.3 | Other | Information not present in EudraCT |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 64 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 10 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 10 |
E.8.9.2 | In all countries concerned by the trial days | 0 |