| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| High-risk resected melanoma |
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| E.1.1.1 | Medical condition in easily understood language |
| High-risk resected melanoma |
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| 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 | 14.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10025651 |
| E.1.2 | Term | Malignant melanoma excision |
| E.1.2 | System Organ Class | 100000004865 |
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| 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 evaluate recurrence-free survival (RFS) between patients randomized to receive post-operative adjuvant ipilimumab given at either 10 mg/kg (high dose ipilimumab; HIP) or 3 mg/kg (low dose ipilimumab: LIP) versus those randomized to receive HDI utilizing a hierarchical design assessing HIP versus HDI first and LIP versus HDI second (if the first comparison is significant).
To evaluate overall survival (OS) between patients randomized to receive post-operative adjuvant ipilimumab given at either 10 mg/kg (HIP) or 3 mg/kg (LIP) versus those randomized to receive HDI utilizing a hierarchical design assessing HIP versus HDI first and LIP versus HDI second (if the first comparison is significant).
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| E.2.2 | Secondary objectives of the trial |
To evaluate safety and tolerability of post-operative adjuvant ipilimumab therapy given at either 10 mg/kg (HIP) or 3 mg/kg (LIP).
To compare the global QOL between the ipilimumab arms versus HDI using FACT-G form and to evaluate the effect of treatment-related side effects that may have an impact on the health-related domains of QOL using FACIT-D and FACT-BRM.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Age > 18 years.
2. All patients must have disease that is completely surgically resected in order to be eligible. Patients must have been surgically rendered free of disease with negative margins on resected specimen. Patients rendered free of disease by non-surgical means are not eligible. All patients must have disease-free status documented by a complete physical examination and imaging studies within 4 weeks prior to randomization. Imaging studies must include a total body PET-CT scan (with or without brain) and brain MRI or CT (if MRI is contraindicated). If PET-CT cannot be done, CT of neck, chest, abdomen, and pelvis should be done.
If for some reason a CT cannot be done, an MRI may be done instead. Any other imaging studies if performed (eg, bone scan) must show no evidence of disease.
3. Patients must have primary cutaneous melanoma that belong to one of the following AJCC stages: IIIB, IIIC, or IV (M1a or M1b). Patients with stage IV melanoma must have normal LDH and either distant skin, subcutaneous, lymph node or lung metastases, but no other visceral metastases in order to be eligible. For patients with resected stage IV melanoma, LDH within the institutional upper limit of normal (ULN) must be documented within 4 weeks prior to randomization.
4. Patients with disease recurrence after adequate surgical excision of the original primary cutaneous/unknown primary melanoma are allowed even if they don’t fit the strict staging criteria, but only as follows:
• Recurrence in a regional lymph node basin after a prior complete lymph node dissection. Relapsed disease must be completely surgically resected with free margins.
• Recurrence in the form of in-transit or satellite metastases or distant skin/subcutaneous, nodal or lung metastases that are completely surgically resected with free margins.
• Recurrence in a regional lymph node basin. Relapsed disease must be completely surgically resected with free margins.
Patients with unknown primary melanoma (Tx) who present with cutaneous, subcutaneous, nodal and/or lung metastases that are completely surgically resected with free margins are allowed. These patients are allowed even if they don’t fit the strict staging criteria. For stage IV patients LDH within the institutional ULN must be documented within 4 weeks prior to randomization (M1c is not eligible).
All subjects should be classified as IIIB, IIIC, M1a or M1b including subjects with disease recurrence after adequate surgical excision of the original primary melanoma. That is the treating team/physician investigator should review an overall TNM status (that includes primary tumor presentation and disease recurrence status) and provide a designation of IIIB, IIIC, M1a or M1b.
5. Patients must be randomized within 84 days (12 weeks) of surgical resection. If more than one surgical procedure is required to render the patient disease-free, the patient must be randomized within 12 weeks of the last surgery. Patients with clinically positive lymph nodes for melanoma involvement or those with positive lymph nodes identified through lymphoscintigraphic and/or dye lymphographic techniques in the groin, axilla, or neck should have additional lymphadenectomy in those sites. See Section 5.1 and Appendix VII for suggested guidelines on surgical management. The complete lymph node dissection procedure would be considered as the last surgery in counting the 84 days unless a subsequent surgical procedure(s) was clinically required to ensure the disease free status.
6. Patients must have ECOG performance status of 0-1.
7. Patients must have the following required values for initial laboratory tests obtained within 4 weeks prior to randomization (ULN: institutional upper limit of normal):
• WBC ≥ 3000/uL
• ANC ≥ 1500/uL
• Platelets ≥ 100 x 103/uL
• Hemoglobin ≥ 10 g/dL
• Serum creatinine ≤ 1.8 mg/dl
• AST/ALT ≤ 2.5 x ULN
• Serum bilirubin < 2 ULN, (except patients with Gilbert’s Syndrome, who must have a total bilirubin less than 3.0 mg/dL)
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| E.4 | Principal exclusion criteria |
1. Patients must not have received any adjuvant treatment (chemotherapy, biotherapy, or limb perfusion) after the resection(s) that make(s) them eligible for this trial. Previous radiation therapy, including after the surgical resection, is allowed as long as 21 days have elapsed between the radiation and initiation of this adjuvant systemic therapy.
2. Prior treatment with anti-CTLA4 monoclonal antibodies or prior CTLA-4 inhibitor or agonist or prior CD137 agonist or prior interferon-α is not allowed. Other forms of prior treatment for melanoma (e.g., IL-2, anti-tumor vaccine, chemotherapy) are allowed if given before the resection(s) that make(s) the patient eligible for this trial, but these must have been completed at least 4 weeks prior to randomization.
3. Patients must not have an active infection requiring current treatment with parenteral antibiotics.
4. Patients must not have other significant medical, surgical, or psychiatric conditions or require any medication or treatment that in the opinion of the investigator may interfere with compliance, make the administration of Ipilimumab or HDI hazardous or obscure the interpretation of AEs, such as a condition associated with frequent diarrhea.
5. Patients should be carefully screened for depression at baseline and if there are indications or a history of depression it is strongly recommended that these patients be closely followed together with behavioral health or psychiatric medical support. Patients with an established diagnosis of depression that, in the assessment of the investigator may make the administration of IFNα or ipilimumab hazardous, should not be enrolled on this protocol. The risks and benefits of being treated with standard adjuvant IFNα should be weighed very carefully in consultation with behavioral health or psychiatry.
6. Patients must not have a documented history of inflammatory bowel disease (including ulcerative colitis and Crohn’s disease) or diverticulitis (history of diverticulosis is allowed).
7. Patients must not have autoimmune disorders or conditions of immunosuppression that require current ongoing treatment with systemic corticosteroids (or other systemic immunosuppressants), including oral steroids (i.e., prednisone, dexamethasone) or continuous use of topical steroid creams or ointments or ophthalmologic steroids. A history of occasional (but not continuous) use of steroid inhalers is allowed. Replacement doses of steroids for patients with adrenal insufficiency are allowed. Patients who discontinue use of these classes of medication for at least 2 weeks prior to randomization are eligible if, in the judgment of the treating physician investigator, the patient is not likely to require resumption of treatment with these classes of drugs during the study.
Exclusion from this study also includes patients with a history of symptomatic autoimmune disease (e.g., rheumatoid arthritis, systemic progressive sclerosis [scleroderma], systemic lupus erythematosus, Sjögren's syndrome, autoimmune vasculitis [e.g., Wegener’s Granulomatosis]); motor neuropathy considered of autoimmune origin (e.g., Guillain-Barre Syndrome and Myasthenia Gravis); other CNS autoimmune disease (e.g., poliomyelitis, Multiple sclerosis). Patients with autoimmune hypothyroid disease or type I diabetes on replacement treatment are eligible.
8. Due to the possible effect of treatment with ipilimumab on the immunologic response to infectious disease vaccines, patients must not have had any infectious disease vaccination (e.g., standard influenza, H1N1 influenza, pneumococcal, meningococcal, tetanus toxoid) within 4 weeks prior to randomization.
9. Patients must not be prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (e.g., infectious) illness. This is due to concerns about subject safety and compliance with study procedures.
10. Patients who have other current malignancies are not eligible. Patients with other malignancies are eligible if they have been continuously disease free for > 5 years prior to the time of randomization. Patients with prior history at any time of any in situ cancer, lobular carcinoma of the breast in situ, cervical cancer in situ, atypical melanocytic hyperplasia or melanoma in situ are eligible. Patients with prior history of basal or squamous skin cancer are eligible. Patients who have had multiple primary melanomas are eligible.
11. Women must not be pregnant or breast-feeding due to the unknown effects of ipilimumab and HDI on conception and the fetus. All females of childbearing potential must have a blood test or urine study during screening to rule out pregnancy.
12. No active or chronic infection with HIV, Hepatitis B, or Hepatitis C due to the unknown effects of ipilimumab. Patients must have negative testing for HIV, HBV, HCV within 4 weeks prior to randomization.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
To evaluate recurrence-free survival (RFS) between patients randomized to receive post-operative adjuvant ipilimumab given at either 10 mg/kg (high dose ipilimumab; HIP) or 3 mg/kg (low dose ipilimumab: LIP) versus those randomized to receive HDI utilizing a hierarchical design assessing HIP versus HDI first and LIP versus HDI second (if the first comparison is significant).
To evaluate overall survival (OS) between patients randomized to receive post-operative adjuvant ipilimumab given at either 10 mg/kg (HIP) or 3 mg/kg (LIP) versus those randomized to receive HDI utilizing a hierarchical design assessing HIP versus HDI first and LIP versus HDI second (if the first comparison is significant).
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The recurrence-free survival (RFS) is defined from the time from randomization to the time of disease recurrence or death from any cause. For the RFS endpoint, the main analysis will take place when the full information (655 events in High-dose ipilimumab and HDI groups) is reached. With additional follow up time, a total duration of study is expected to be less than 6 years.
The main analysis of Overall Survival (OS) will take place when the full information (after 416 deaths in High-dose Ipilimumab and HDI groups) is reached. With additional follow up time, a total duration of study is expected to be less than 6 years.
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| E.5.2 | Secondary end point(s) |
To evaluate safety and tolerability of post-operative adjuvant ipilimumab therapy given at either 10 mg/kg (HIP) or 3 mg/kg (LIP).
To compare the global QOL between the ipilimumab arms versus HDI using FACT-G form and to evaluate the effect of treatment-related side effects that may have an impact on the health-related domains of QOL using FACIT-D and FACT-BRM.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
To evaluate safety and tolerability of post-operative adjuvant ipilimumab therapy given at either 10 mg/kg (HIP) or 3 mg/kg (LIP).
To compare the global QOL between the ipilimumab arms versus HDI using FACT-G form and to evaluate the effect of treatment-related side effects that may have an impact on the health-related domains of QOL using FACIT-D and FACT-BRM.
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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 | Yes |
| 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 | Yes |
| 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 |
Quality of Life
Pharmacogenetic/Pharmacogenomic:
Pathology samples must be submitted for review and classification (baseline only). The residuals and/or derivatives of the blocks/slides submitted will be retained at the ECOG Central Repository for possible use in future ECOG approved studies. Blood samples are being collected for future use in laboratory corollary studies, including the performance of novel biomarker evaluations that are of prognostic and therapeutic predictive value. |
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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) | 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 7 |
| E.8.5 | The trial involves multiple Member States | No |
| 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 |
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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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| Overall survival of patients is a primary endpoint. Patients will be followed up until death. |
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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 | 6 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
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