E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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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 the rate of Grade 2+ diarrhea in patients treated with intravenous ipilimumab when given with either prophylactic oral budesonide (Entocort EC) or placebo. |
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E.2.2 | Secondary objectives of the trial |
1)Evaluate BORR in this pt population receiving ipilimumab 10mg/kg +prophylactic oral budesonide or placebo 2)Estimate in this population receiving ipilimumab 10mg/kg: -Disease control rate -Progression free survival rate at Week12 -PFS -Overall survival -Survival rate at 1 year -Duration of response +proportion of pts whose duration of resp is ≥24 wks -Time to Response 3)Safety of ipilimumab 10mg/kg +prophylactic oral budesonide or placebo 4)Identify potential predictors of response by analyzing mRNA, protein & microscopic profiles in pre-treatment (optional) tumor biopsies 5)Compare pre- & post-treatment mRNA, protein & microscopic profiles in tumor specimens (optional) & PBMCs functional attributes 6)Evaluate incidence of grade 2+ diarrhea, & grade 2+ clinical colitis 7)Explore incidence of histologic colitis & association between histologic colitis pattern, grade 2+ diarrhea & grade 2+ clinical colitis 8)identify predictors of grade 2+ diarrhea 9)PK blood samples |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1) Signed Informed Consent Form
2)Target population a) Able to comply with visits/procedures required by the protocol. b) Life expectancy of at least 4 months. c) ECOG performance status score 0-1 (see Protocol Appendix 1). d) Histologic or cytologic diagnosis of unresectable Stage III or IV malignant melanoma (excluding ocular melanoma). e) Measurable disease as defined in Protocol Section 3.3.3.2. f) At least 4 Weeks must have elapsed since the last chemotherapy, immunotherapy, hormonal therapy, radiotherapy or major surgery and the beginning of protocol therapy. At least 6 Weeks for nitrosoureas, mitomycin C and liposomal doxorubicin. g) Toxicity related to prior therapy must either have returned to ≤ grade 1, baseline, or been deemed irreversible.
3) Age and Sex
a) Men and women, ages 18 and above. − Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study in such a manner that the risk of pregnancy is minimized. Suggested precautions should be used to minimize the risk or pregnancy for at least 1 month before dosing, and while women are on study and for up to 3 months after last dose of study drug. − WOCBP must have a negative pregnancy test within 72 hours prior to the start of study medication. − Men must be willing and able to use an acceptable method of birth control, for at least 3 months after completion of the study, if their sexual partners are WOCBP.
4) Required values for initial laboratory tests: • WBC ≥ 3000 x 1 000/mL • ANC ≥ 1500 x 1 000/mL • Platelets ≥ 100 x 1 000 000/mL • Hemoglobin ≥ 10 g/dL • AST ≤ 2.5 x ULN for patients without liver metastasis; ≤ 5 x ULN for patients with liver metastasis • Bilirubin ≤ 1.5 x ULN, (except patients with Gilbert’s Syndrome, who must have a total bilirubin less than 3.0 mg/mL); • Creatinine ≤ 1.5 x ULN. |
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E.4 | Principal exclusion criteria |
1) Sex and Reproductive Status a) WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for up to 12 weeks after the study. b) WOCBP using a prohibited contraceptive method. c) Women who are pregnant or breastfeeding. d) Women with a positive pregnancy test on enrollment or prior to study drug administration. e) Sexually active fertile men who are unwilling or unable to use a barrier contraceptive (eg, condom) or whose partners are WOCBP not using a method of birth control from the time of enrollment and for 12 Weeks after participation in the study. 2) Target Disease Exclusion a) 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, carcinoma in situ of the cervix. b) Ocular melanoma. 3) Medical History and Concurrent Diseases a) Active, untreated central nervous system (CNS) metastasis (including metastasis identified during screening MRI or contrast CT). b) Autoimmune disease: Patients with a history of Inflammatory Bowel Disease are excluded from this study as are patients with a history of autoimmune disease (e.g. Systemic Lupus Erythematosus, vasculitis, infiltrating lung disease) whose possible progression during treatment would be considered by the Investigator to be unacceptable. Patients with a history of well-controlled and/or clinically manageable autoimmune disease (e.g. vitiligo, well-controlled thyroid disease, mild psoriasis) may be considered for inclusion in consultation with the BMS Medical Monitor. c) Any underlying medical condition, which in the opinion of the Investigator, will make the administration of study drug hazardous or obscure the interpretation of adverse events, such as a condition associated with frequent diarrhea; d) Positive screening tests for HIV, HepB, and HepC. If positive results are not indicative of true active or chronic infection, the patient can be admitted after discussion with and agreement by the BMS Medical Monitor. 4) Prohibited Therapies and/or Medications a) Exposure to any investigational products within 4 Weeks prior to Day 1 of treatment. b) Prior treatment with an anti-CTLA-4 antibody. c) Use of any immunosuppressing treatments including corticosteroids (patients on stable doses of hormone replacement therapy are exempt), cyclosporine, mycophenolate mofetil (Cellcept) chemotherapy, radiation, etc, within 4 Weeks prior to Day 1 of treatment. d) Concomitant therapy with any of the following: IL-2, interferon or other nonstudy anti-melanoma immunotherapy regimens; cytotoxic chemotherapy; immunosuppressive agents; other investigational therapies; or chronic use of systemic corticosteroids (patients on stable doses of hormone replacement therapy are exempt). e) While there is no limit to prior chemotherapy, concomitant chemotherapy is prohibited. 5) Prisoners or patients who are compulsorily detained. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary Safety Outcome 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 adverse event reports and the results of vital sign measurements, sigmoidoscopy, physical examinations, and clinical laboratory tests. The incidence of adverse events will be tabulated and reviewed for potential significance and clinical importance.
Efficacy Measures:
Tumor evaluations by each investigator and an independent review committee (IRC) will be based on modified WHO criteria. Throughout the study, each respective Investigator will determine the disease status of patients at the defined time points and as clinically indicated. The primary efficacy analysis will be based on the investigator response assessments. The IRC will conduct a retrospective review of all radiologic images and the clinical data dossier (as specified in the IRC charter) for all patients to determine overall response at the assessment time point as well as global tumor assessments defined in Section 3.1.2 and the IRC charter.
Pharmacodynamic Measures:
Pre- and Post- treatment immune response will be assessed using: i) Flow cytometry to measure peripheral T-cell subsets, activation status and intracellular cytokines; ii) ELISPOT to measure cytokine production of antigen specific T-cells; iii) mRNA expression in peripheral blood and tumor biopsies (optional) to assess lymphocyte activation and markers of immune inhibition; iv) Immunohistochemistry (IHC) on tumor biopsies (optional) to assess infiltrating lymphocyte subsets, activation status, expression of tumor specific antigens, and tumor necrosis; v) Protein profiling of tumor biopsies (optional) to assess lymphocyte activation and markers of immune inhibition; vii) Antibody response to tumor specific antigen(s); viii) Stool samples for leukocyte markers; and ix) Serum samples for markers associated with inflammation and inflammatory bowel disease (IBD).
Pharmacokinetics:
MDX-010 (BMS-734016) serum concentration data will be used in conjunction with samples from 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 | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
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 |
Exploratory Pharmacodynamic and Immune Response Analysis |
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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 | 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
| 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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 5 |
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 primary analysis will be performed when the last randomized patient has been followed to the tumor re-staging assessment at Week 24. The end of the study will occur at the same time as the primary analysis. Any patients who remain on treatment with MDX-010 (BMS-734016) at the end of the trial will be switched to a follow-up protocol to enable the current study to be closed and reported. |
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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 | 7 |
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 | 7 |
E.8.9.2 | In all countries concerned by the trial days | 0 |