| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| High Risk Stage III melanoma |
|
| E.1.1.1 | Medical condition in easily understood language |
| High Risk Stage III Melanoma |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10025670 |
| E.1.2 | Term | Malignant melanoma stage III |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 determine whether post-operative adjuvant therapy with ipilimumab improves recurrence-free survival (RFS) as compared to placebo. |
|
| E.2.2 | Secondary objectives of the trial |
- To determine whether post-operative adjuvant therapy with ipilimumab improves overall survival (OS) as compared to placebo.
- To determine whether post-operative adjuvant therapy with ipilimumab improves distant metastases-free survival (DMFS) as compared to placebo.
- To compare adverse event profiles between patients receiving ipilimumab versus patients receiving placebo.
- To compare quality of life and quality-of-life-adjusted-survival between the two treatment groups (ipilimumab versus placebo). |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Protocol Amendment 05: Biomarker substudy (dated 02-Oct-2009), amended on 21-Sep-2011 (Protocol Amendment 07): Biobanking and Translational Research Study related to EORTC protocol 18081/CA184-029.
The objectives of the biomarker study are to:
- Allow the collection and storage of whole blood, serum/plasma and melanoma tumor tissue samples from patients enrolled in the EORTC 18071/ CA 184-029 for use in future biomarker research studies.
- Analyze the association of biomarkers present in the subject’s blood, serum/plasma and/or tumor tissue with clinical benefit post-treatment in the form of Recurrence Free Survival, Distant-Metastasis Free Survival and Overall Survival in order to identify candidate markers predictive of response to ipilimumab.
- Describe the ALC analyses which will be performed for all patients using data from the hematology panel collected in the main protocol. No additional samples or separate informed consent will be obtained to perform these analyses.
Biomarkers to be tested may include but are not restricted to: ALC, NY-ESO-1 antigen specific antibody titers, and tumor tissue markers such as FOXP3 and IDO.
BMS and EORTC will use data collected from the main clinical trial EORTC18071 / CA184029 case report forms, to study the association between biomarkers and cancer recurrence, distant metastases and survival. Samples from this and other clinical studies may also be used in conjunction to accomplish this objective. |
|
| E.3 | Principal inclusion criteria |
1) Signed Written Informed Consent
- Written informed consent required prior to clinical trial participation, including informed consent for any screening procedures conducted to establish subject eligibility for the trial registration, according to ICH/EU GCP, and national/local regulations
2) Target Population
- No mucosal or ocular melanoma, or melanoma with unknown origin of the primary
- Complete resection of Stage III melanoma (AJCC R0) with histologically confirmed cutaneous melanoma metastatic to lymph node, classified as (AJCC, 2002): Stage IIIA with metastasis > 1mm; any Stage IIIB or IIIC (no in-transit metastases)
- Adequate resection of Stage III lymph nodes per Criteria for adequate surgical procedures for complete lymph node dissection (CLND) as documented on the operating report and pathology report. An adequate resection of Stage III lymph nodes is defined as a surgical and pathological procedure performed in full compliance with the "Surgical and pathological considerations for melanoma " that are described in Appendix J. Patients without documentation of adequate resection are not eligible.
- Only patients who were treated with adequate surgical and pathological procedures that were documented are eligible for the study.
To be considered as adequate, the surgical and pathological procedures should have included at least the following:
a) Head and Neck
- Minimum of 15 pathologically investigated nodes
- Face, ear, and anterior scalp: parotidectomy plus modified radical neck dissection
- Posterior scalp: modified radical neck dissection plus suboccipital nodes. For this specific localization, a CLND will be considered as adequate if at least 5 LN have been investigated
b) Upper Extremity
- Minimum of 10 pathologically investigated nodes
- Axillary node dissection included at least 10 nodes taken from Levels I and II
- Level III nodes dissected if they were clinically involved
- Pectoralis minor muscle was divided or sacrificed
c) Lower Extremity
- Minimum of 5 pathologically investigated nodes
- Superficial inguinal node dissection was performed for non-palpable nodal involvement
- If Cloquet’s node was positive, a deep inguinal node dissection was performed
d) Lymph Node Dissection for Nodal Recurrence
- Regional node recurrence was treated using the appropriate lymphadenectomy as above
- Diagnosis of regional node recurrence was made by fine needle aspiration technique to avoid contaminating the region with tumor, followed by CLND as above
- Full lymphadenectomy must be performed within 12 weeks (84 days) prior to randomization
- Disease status for the post-surgery baseline assessment must be documented by full Chest/Abdomen/Pelvis CT and/or MRI with Neck CT and/or MRI (for Head and Neck primaries) and complete clinical examination after the informed consent and prior to randomization
- The complete set of baseline radiographic images must be available before randomization and all images must be of adequate quality
3) Physical and Laboratory Test Findings
- Disease-free (no loco-regional relapse or distant metastasis); no clinical evidence for brain metastases
- ECOG performance status of 0 or 1 (see Appendix B)
- Adequate cardiac function (less or equal to NYHA II, see Appendix C)
- Adequate hematologic, renal and liver function as defined by laboratory values performed within 4-6 weeks from enrollment
- White blood count (WBC) greater than or equal to 2.5x10 (9)/L
- Absolute neutrophil count (ANC) greater than or equal to 1x10 (9)/L
- Platelet count greater than or equal to 75x10 (9)/L
- Hemoglobin greater than or equal to 9 g/dL (5.6 mmol/L)
- Serum creatinine less or equal to 2.5 times upper limit of laboratory normal range (ULN)
- Total serum bilirubin, AST, ALT, alkaline phosphatase and LDH less or equal to 2 times ULN
4) Age and Sex
- At least 18 years of age
- WOCBP (including women who are using oral implanted or injectable contraceptive hormones or mechanical products such as an intrauterine device or barrier methods to prevent pregnancy or practicing abstinence or where partner is sterile) must have a negative pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) before randomization and within 72 hours prior to the start of study medication. It is the investigators responsibility to repeat the pregnancy test should start of treatment be delayed.
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|
| E.4 | Principal exclusion criteria |
1) Sex and Reproductive Status
- WOCBP unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for up to 12 weeks after the last administration of the perfusion, women who are pregnant or breastfeeding, women with a positive pregnancy test on enrollment or prior to study drug administration, and sexually active fertile men whose partners are WOCBP, unless using an adequate method of birth control
2) Medical History and Concurrent Diseases
- No radiation therapy to the lymph node dissection field after surgery
- No prior therapy for melanoma except surgery for primary melanoma lesions; patients who have previously received IFN are not eligible
- No prior or concomitant therapy with any anti-cancer agents, immunosuppressive agents; other investigational anti-cancer therapies, or chronic use of systemic corticosteroids (used in the management of cancer or non-cancer-related illnesses)
- No non-oncology vaccine therapy can be used for prevention of infectious diseases (up-to) 4 weeks prior and after any dose of ipilimumab or placebo
- No prior treatment with a CD137 agonist or CTLA-4 inhibitor or agonist
- No previous participation in another ipilimumab (MDX-010) clinical trial
- No treatment with other investigational products within the last 4 weeks prior to randomization into this study
- No uncontrolled infectious disease including negative testing for HIV, HBV, HCV
- No 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, autoimmune thyroiditis (e.g. Hashimoto’s disease), autoimmune hepatitis, systemic progressive sclerosis (scleroderma), Systemic Lupus Erythematosus, autoimmune vasculitis (e.g., Wegener’s Granulomatosis). Subjects with motor neuropathy considered of autoimmune origin (e.g., Guillain-Barré Syndrome) are excluded from this study. Patients with vitiligo are eligible to enter the study.
- Patients must not present immunodeficiency or previous splenectomy or radiation therapy to the spleen
- No second malignancies in the past 5 years with the exception of surgically cured carcinoma in-situ of the cervix and basal or squamous cell carcinoma of the skin
6) Other Exclusion Criteria
- Patients must have absence of 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 or efficacy, such as a condition associated with frequent diarrhea
- No prisoners or patients who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (e.g., infectious disease) illness must be randomized into this study
- Patients must have absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
To determine whether post-operative adjuvant therapy with ipilimumab
improves recurrence-free survival (RFS) as compared to placebo |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Time Frame: Upon occurrence |
|
| E.5.2 | Secondary end point(s) |
To determine whether post-operative adjuvant therapy with ipilimumab
improves overall survival (OS) as compared to placebo [ Time Frame:
Upon occurrence ]
To determine whether post-operative adjuvant therapy with ipilimumab improves distant metastases-free survival (DMFS) as compared to
placebo [ Time Frame: Upon occurrence ]
To compare adverse event profiles between patients receiving
ipilimumab versus patients receiving placebo [ Time Frame: Upon
occurrence ]
To compare quality of life and quality-of-life-adjusted survival between
the two treatment groups (ipilimumab versus placebo) [ Time Frame:
Upon occurrence ] |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | No |
| 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 | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Immunogenicity sample testing (HAHA); QoL assessment |
|
| 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) | 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 | Yes |
| 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.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 54 |
| 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 | No |
| 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 |
| Australia |
| Austria |
| Belgium |
| Canada |
| Czech Republic |
| Denmark |
| Finland |
| France |
| Germany |
| Italy |
| Netherlands |
| Norway |
| Poland |
| Portugal |
| Russian Federation |
| Spain |
| Sweden |
| Switzerland |
| United Kingdom |
| United States |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 9 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 7 |
| E.8.9.2 | In all countries concerned by the trial years | 10 |
| 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 | 7 |
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