| 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 |
| Melanoma, which, although it has been successfully treated with surgery, has a high probability of coming back. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| 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 |
a. To compare overall survival (OS) of patients with resected Stage III and IV
melanoma treated with physician/patient choice of either high dose interferon alfa-2b or ipilimumab versus MK-3475 (pembrolizumab)
b. Among patients who are PD-L1 positive, to compare OS of patients with resected Stage III and IV melanoma treated with physician/patient choice of either high dose interferon alfa-2b or ipilimumab versus MK-3475 (pembrolizumab).
c. To compare relapse-free survival (RFS) of patients with resected Stage III and IV
melanoma treated with physician/patient choice of either high dose interferon alfa-2b or ipilimumab to MK-3475 (pembrolizumab).
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| E.2.2 | Secondary objectives of the trial |
Secondary Objectives:
a. Estimate OS & RFS for PD-L1 negative or PD-L1 indeterminate patients.
b. Compare OS & RFS of patients between the two arms within PD-L1 positive
& negative subgroups & interaction between PD-L1 (positive
versus negative) & treatment arm.
c. Assess safety & tolerability of the regimens.
Additional Objectives:
a. Bank tissue & whole blood in anticipation of future correlative studies.
b. Evaluate PD-L1 expression through IHC assay.
c. Evaluate effect of treatment-related side effects that may have an impact on the health-related domains of quality of life.
d. Pharmacokinetic and anti-drug antibody (ADA) testing will be performed on all patients receiving MK-3475.
Translational Objectives:
a. Evaluate the association between TCRβ variable gene (TRBV) haplotype & Grade 3-4 immune-related adverse events among Stage III melanoma patients treated w/adjuvant Ipilimumab or Pembrolizumab.
b. Describe TRBV haplotype distribution.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Principal inclusion criteria are listed below. Please refer to the study protocol for full criteria.
STEP 1 REGISTRATION
Disease Related Criteria
• Patients must have completely resected melanoma of cutaneous origin or of unknown primary. Patients must be classified as Stage IIIA (N2a), IIIB, IIIC, or Stage IV melanoma. Patients with non-ulcerated T1b N1a disease are not eligible. Patients with melanoma of mucosal or other non-cutaneous origin are eligible. Patients with melanoma of ocular origin are not eligible. Patients with a history of brain metastases are ineligible.
• Patients are eligible for this trial either at initial presentation of their melanoma or at the time of the first detected nodal, satellite/in-transit, distant metastases, or recurrent disease in prior lymphadenectomy basin or distant site. Nodal, satellite/in-transit metastasis, distant metastases or disease in a prior complete lymphadenectomy basin must have been confirmed histologically by H & E stained slides.
• Patients with multiple regional nodal basin involvement are eligible. Gross or microscopic extracapsular nodal extension is permitted.
• Patients at initial presentation of melanoma must undergo an adequate wide excision of the primary lesion, if present. Patients with previously diagnosed melanoma must have had all current disease resected with pathologically negative margins & must have no evidence of disease at the primary site or must undergo re-resection of the primary site. A full lymphadenectomy is required for all node-positive patients including those with positive sentinel nodes. Patients with recurrent disease who have had a prior complete lymphadenectomy fulfill this requirement as long as all recurrent disease has been resected. For all patients, all disease must have been resected with negative pathological margins & no clinical, radiologic, or pathological evidence of any incompletely resected melanoma. Patients must be registered within 98 days of the last surgery performed to render the patient free of disease.
Specimen Submission Criteria
• Patients must have available&be willing to submit a minimum of 5 unstained slides from primary, lymph node, or metastatic site to determine PD-L1 expression.
• Patients must be offered the opportunity to participate in specimen banking.
• Patients must be willing to have blood draws for PK/ADA analysis (MK-3475 arm).
Prior/Concurrent Therapy Criteria
• Patients may have received prior radiation therapy, including after the surgical resection. All AEs associated with prior surgery & radiation therapy must have resolved to ≤ Grade 1 prior to registration.
Clinical/Laboratory Criteria
• Patients must be ≥ 18 years of age.
• All patients must have disease-free status documented by a complete physical exam & imaging studies within 42 days prior to registration. Refer to protocol for imaging requirements.
• All patients must have a CT or MRI of the brain within 90 days prior to registration (with intravenous contrast (unless contraindicated)).
• Adequate bone marrow function as evidenced by all of the following: ANC ≥ 1,500 mcL; platelets ≥ 100,000/mcL; Hemoglobin ≥ 10 g/dL.
• Adequate hepatic function as evidenced by the following: total bilirubin ≤ 1.5 x institutional upper limit of normal (IULN) (except Gilbert’s Syndrome, who must have a total bilirubin < 3.0 mg/dL), and SGOT (AST) and SGPT (ALT) and alkaline phosphatase ≤ 2 x IULN.
• Adequate renal function as evidenced by ONE of the following: serum creatinine ≤ IULN OR measured or calculated creatinine clearance ≥ 60 mL/min.
• LDH performed within 42 days prior to registration.
• Zubrod Performance Status ≤ 1.
• A baseline ECG performed within 42 days of registration that is normal or considered not clinically significant.
• Patients known to be HIV positive are eligible if they meet the following criteria within 30 days prior to registration: stable and adequate CD4 counts (≥ 350 mm3), and serum HIV viral load of < 25,000 IU/ml. Patients may be on or off anti-viral therapy so long as they meet the CD4 count criteria.
• Women of childbearing potential must have a negative urine or serum pregnancy test within 28 days prior to registration. Women/men of reproductive potential must have agreed to use an effective contraceptive method for the course of the study through 120 days after the last dose of study medication.
• Patients who are able to complete questionnaires in English, Spanish or French
must participate in the quality of life assessments. (Those patients who cannot
complete the quality of life questionnaires can be registered to S1404).
STEP 2 REGISTRATION (Randomization)
• Women of childbearing potential must plan to have a urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication.
• Patients who are known to have a change in eligibility status after Step 1 registration are not eligible for Step 2 registration.
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| E.4 | Principal exclusion criteria |
Principal exclusion criteria are listed below. Please refer to the study protocol for full criteria.
STEP 1 REGISTRATION
Prior/Concurrent Therapy Criteria
• Patients must not have received neoadjuvant treatment for their melanoma.
Patients must not have had prior immunotherapy including, but not limited to ipilimumab, interferon alfa-2b, high dose IL-2, PEG-IFN, anti-PD-1, anti-PD-L1 intra-tumoral or vaccine therapies. Patients must not be planning to receive any of the prohibited therapies listed in protocol Section 7.2 during the screening or treatment phases of the study.
• Patients must not be planning to receive concomitant other biologic therapy, radiation therapy, hormonal therapy, other chemotherapy, surgery or other therapy after Step 2 registration.
Clinical/Laboratory Criteria
• Patients must not have a history of (non-infectious) pneumonitis that required steroids or current pneumonitis.
• Patients must not have an active infection requiring systemic therapy.
• Patients must not have active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
• Patients must not have received live vaccines within 42 days prior to registration. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken pox, shingles, yellow fever, rabies, BCG, and typhoid (oral) vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.
• Patients must not have known active Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV) infection prior to registration.
• Patients must not have a history or current evidence of any condition, therapy or laboratory abnormality that might confound the trial results, interfere with the patient's participation for the full duration of the trial, or indicate that participation in the trial is not in the patient's best interests, in the opinion of the treating investigator.
Clinical Laboratory
• No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, lobular carcinoma of the breast in situ, atypical melanocytic hyperplasia or melanoma in situ, adequately treated Stage I or II cancer (including multiple primary melanomas) from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for three years.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
- Progression/Relapse
- Relapse-Free Survival
- Overall Survival
- Performance Status |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
-Progression/Relapse: Appearance of any new lesion/site. Death due to disease without prior documentation of progression.
- Relapse-Free Survival: Measured from date of randomization to date of first documentation of relapse or death due to any cause. Patients last known to be alive and relapse-free are censored at date of last contact.
- Overall Survival: Measured from date of randomization to date of death due to any cause. Patients known to be alive are censored at date of last contact.
- Performance Status: Measured at regular intervals throughout treatment and follow-up phase. Patients will be graded according to the Zubrod Performance Status Scale. |
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| E.5.2 | Secondary end point(s) |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| 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 | No |
| 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 | 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 | 3 |
| 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 | No |
| 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 | 11 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 12 |
| 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 |
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