E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Previously treated unresectable Stage III 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 estimate best overall response rate (BORR) (as per modified WHO criteria) in patients with previously treated, therapy-refractory or -intolerant, Stage III (unresectable) or Stage IV melanoma receiving ipilimumab doses of 0.3, 3, and 10 mg/kg. |
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E.2.2 | Secondary objectives of the trial |
1) To evaluate the dose-response relationship based on BORR; 2) To estimate the difference in BORR in patients receiving 3 vs. 0.3 mg/kg, 10 vs. 0.3 mg/kg and 10 vs. 3 mg/kg; 3) To estimate progression free survival (PFS) rate at the Week 12 assessment; 4) To estimate disease control rate (proportion with best response of CR + PR + SD); 5) To estimate PFS; 6) To estimate overall survival (OS); 7) To estimate survival rate at one year; 8) To estimate duration of BOR and define the proportion of patients with duration of response lasting ≥ 24 weeks; 9) To estimate time to BOR; 10) To evaluate the safety profile of ipilimumab during the Induction and Maintenance Phase at each dosage level of ipilimumab; 11) To evaluate HRQoL; 12) To obtain PK samples for population PK analysis; |
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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) Histologically confirmed malignant melanoma; 3) Measurable melanoma, as per modified WHO criteria; 4) Stage III (unresectable) or Stage IV melanoma; 5) Patient must have demonstrated one of the following in response to treatment with at least one prior regimen (non-experimental or experimental) with the exception of a CD137 agonist or CTLA-4 inhibitor or agonist: 1) relapse following an objective response of PR or CR; or 2) failed to demonstrate an objective response of PR or CR based on an assessment period of at least 12 weeks from prior regimen start; or 3) inability to tolerate treatment due to toxicity; 6) Have a complete set of baseline (i.e., Screening) digital images of lesions and radiographic images, including, but not limited to: brain, bone, chest, abdomen and pelvis. All images must be of adequate quality as detailed in Section 3.3 of the protocol; 7) Required values for initial laboratory tests: • WBC ≥ 2500/uL • ANC ≥ 1000/uL • Platelets ≥ 75 x 103/uL • Hemoglobin ≥ 9 g/dL • Creatinine ≤ 2.5 x ULN • AST ≤ 3 x ULN for patients without liver metastasis ≤ 5 x ULN for patients with liver metastasis • Bilirubin ≤ 3 x ULN, (except patients with Gilbert’s Syndrome, who must have a total bilirubin less than 3 mg/mL); 8) ECOG performance status of 0 or 1; 9) Life expectancy of ≥ 16 weeks; 10) Accessible for treatment and follow-up; 11) 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 Medical Monitor; 12) Male and female patients ≥ 16 years of age (or minimum age of consent required per given regulatory authority);
Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and for up to 8 weeks after the study in such a manner that the risk of pregnancy is minimized. |
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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 documented history of symptomatic autoimmune 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 medication hazardous to the patient, obscure the interpretation of adverse events (such as a condition associated with frequent diarrhea) or may render the patient incapable of complying with the requirements of the study; 10) Concomitant therapy with any anti-cancer agent; immunosuppressive agents; any non-oncology vaccine therapy used for prevention of infectious diseases (for up to one month prior to or after any dose of study drug); surgery or radiotherapy (except as described in Sections 6.2.8.3 and 6.2.8.4); other investigational anti-cancer therapies; or chronic use of systemic corticosteroids (used in the management of cancer or non-cancer-related illnesses); 11) Previous treatment with other investigational products, including cancer immunotherapy, within 30 days; 12) Previous treatment in another ipilimumab clinical trial or prior treatment with a CD137 agonist, CTLA-4 inhibitor or agonist; 13) Inability to provide adequate informed consent; 14) Prisoners or subjects who are compulsorily detained. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Efficacy Analyses The efficacy analyses will be performed when the last randomized patient has been followed to Week 24. Efficacy analyses in all randomized patients will be performed as randomized. The BORR will be estimated in each randomized arm, and the corresponding exact two-sided 95% confidence interval will be computed using the method of Clopper and Pearson. Two sided 95% confidence intervals for all pairwise differences in BORR (3 vs. 0.3 mg/kg, 10 vs. 0.3 mg/kg, and 10 vs. 3 mg/kg) will be computed using the method of DerSimonian and Laird. A one-sided exact Cochran-Armitage trend test with a 0.05 significance level will be used to evaluate whether a positive dose-response relationship based on the BORRs in the randomized arms.
BORR subgroup analyses will be performed by the following baseline variables: age (<65, >65), race (White, Black, Asian, Other), gender (male, female), M stage (M0, M1a, M1b, M1c), ECOG performance status (0, 1), prior treatment with IL-2, fotemustine, dacarbazine or temozolamide (yes, no), prior therapy with cancer vaccines (yes, no), response to prior therapy (yes, no), and emergence of immune breakthrough events (yes, no).
Disease control rate, major durable response rate, and PFS rate at Week 12 will be calculated in each randomized arm along with corresponding two-sided exact 95% confidence intervals.
Survival rate at one year will be calculated in each randomized arm using the Kaplan-Meier method along with a corresponding two-sided 95% confidence interval.
PFS, OS, time to BOR, and duration of BOR will be calculated in each randomized arm using Kaplan-Meier estimates, and medians with corresponding two-sided 95% confidence intervals will be reported. Time to BOR will also be summarized for patients with BOR of CR or PR using descriptive statistics.
OR and date of OR at each time point will be determined by the Investigator and by the IRC. BOR, the date of BOR, date of first overall response, date of last tumor assessment, and date of progression will be programmatically derived for both Investigator and IRC assessments.
Safety Analyses The analysis of safety, reported for each treatment arm as treated, will be based on the frequency of adverse events and their severity for all treated patients. Worst toxicity grades per patient will be tabulated for adverse events and laboratory measurements using the NCI CTCAE v3. The reporting period for safety data will be from the date of the first dose of study medication to 70 days (5 half-lives) after the last dose is received.
Pharmacokinetic Analyses Ipilimumab serum concentration versus time data from this study will be used in conjunction with samples from other ipilimumab studies as part of a population PK evaluation. A separate PK evaluation of serum ipilimumab concentration is not planned for this study. Serum HAHA will also be evaluated.
Health-related Quality of Life Analyses Health-related quality of life (HRQoL) will be assessed both for all randomized patients as-randomized and for all treated patients as-treated using the EORTC QLQ-C30.29 The EORTC QLQ-C30 will be scored according to the manual provided separately by the Sponsor. Changes from baseline will be summarized on each subscale score for each randomized or treatment arm, respectively, using descriptive statistics. The primary comparison of the EORTC HRQoL between treatment arms will be a Wei-Lachin test on differences from baseline. Separate two-sided Wei-Lachin tests30 will be conducted for each scale, separately far as-randomized and as-treated analyses, comparing the 3 vs 0.3 mg/kg, 10 vs. 0.3 mg/kg and 10 vs. 3 mg/kg other studies as part of the population PK assessment. |
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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 | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
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 Analyses; Immunogenicity testing |
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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 | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | Information not present in EudraCT |
E.8.1.2 | Open | Information not present in EudraCT |
E.8.1.3 | Single blind | Information not present in EudraCT |
E.8.1.4 | Double blind | Information not present in EudraCT |
E.8.1.5 | Parallel group | Information not present in EudraCT |
E.8.1.6 | Cross over | Information not present in EudraCT |
E.8.1.7 | Other | Information not present in EudraCT |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 36 |
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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The end of the study will occur at the same time as the primary analysis performed when the last randomized patient has been followed to the tumor re-staging assessment at Week 24. |
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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 | 1 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |