E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Stage III melanoma (AJCC R0) with histologically confirmed cutaneous melanoma metastatic to lymph node, classified as (AJCC, 2010): Stage IIIA with metastasis > 1 mm; any Stage IIIB or IIIC (no in-transit metastases) |
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E.1.1.1 | Medical condition in easily understood language |
Clinical and histologic stage III melanoma with a high risk of recurrence |
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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 | 18.0 |
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) |
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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 prospectively assess whether post-operative adjuvant therapy with pembrolizumab improves recurrence-free survival, as compared to placebo in high-risk patients with complete resection of Stage IIIA (>1 mm metastasis), IIIB and IIIC melanoma.
- To prospectively assess whether in the subgroup of patients with PD-L1-positive tumor expression, pembrolizumab improves recurrence-free survival as compared to placebo.
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E.2.2 | Secondary objectives of the trial |
- To prospectively assess whether post-operative adjuvant therapy with pembrolizumab improves distant metastasis free survival as compared to placebo.
- To prospectively assess whether in the subgroup of patients with PD-L1-positive tumor expression pembrolizumab improves distant metastasis free survival as compared to placebo.
- To prospectively assess whether post-operative adjuvant therapy with pembrolizumab improves overall survival, as compared to placebo.
- To prospectively assess whether in the subgroup of patients with PD-L1-positive tumor expression pembrolizumab improves overall survival as compared to placebo.
- To compare adverse event profiles (AE and Serious Adverse Event (SAE)) between patients receiving pembrolizumab versus patients in the placebo arm.
- To evaluate the pharmacokinetics (PK) of pembrolizumab when pembrolizumab is administered at 200 mg every three weeks.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- At least 18 years of age.
- Complete resection of Stage III melanoma (AJCC R0) with histologically confirmed cutaneous melanoma metastatic to lymph node, classified as (AJCC, 2010): Stage IIIA with metastasis > 1 mm; any Stage IIIB or IIIC (no in-transit metastases).
- Melanoma with unknown origin of the primary is eligible
- Mandatory to ship tumor sample for evaluation of PD-L1 expression.
- The treatment should start no later than 13 weeks after surgery and only after complete wound healing from the surgery.
- 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 enrollment.
- Disease-free (no loco-regional relapse or distant metastasis); no clinical evidence for brain metastases.
- BRAF mutation status
- ECOG performance status of 0 or 1.
- Patient demonstrates adequate organ function as defined in the protocol
- Women of child bearing potential (WOCBP) must have a negative serum (or urine) pregnancy test within 72 hours prior to the first dose of study treatment.
- Patients of childbearing / reproductive potential should use adequate birth control methods.
- Female patients who are breast feeding should discontinue nursing prior to the first dose of study treatment and until 120 days after the last dose of study drug .
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E.4 | Principal exclusion criteria |
- Mucosal or ocular melanoma.
- Prior therapy for melanoma except surgery for primary melanoma lesions.
- history of pneumonitis requiring treatment with steroids, no history of interstitial lung disease.
- history of a hematologic or primary solid tumor malignancy, unless no evidence of that disease for 5 years.
- 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 (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
- active infection requiring therapy.
- diagnosis of immunodeficiency, no systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment
- known history of human immunodeficiency virus (HIV), active Hepatitis B or Hepatitis C.
- treatment with live vaccines within 30 days prior to the first dose of study medication are not eligible.
- prior treatment with any anti-CTLA4 monoclonal antibody or anti-PD-1, or PD-L1 or PD-L2 agent.
- Patient is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigation device within 4 weeks prior to the first dose of treatment
- patient is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or child) who is investigational site or Sponsor staff directly involved with this trial, unless prospective IRB approval (by chair or designee) is given allowing exception to this criterion for a specific subject.
- female patients who are Breast feeding |
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E.5 End points |
E.5.1 | Primary end point(s) |
1. Recurrence free survival (RFS)
2. RFS in subgroup of patients with PD-L1-positive tumor expression receiving either pembrolizumab or placebo
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Every 12 weeks during treatment and for the first two years. From year 3 to 5, every 6 months and yearly thereafter.
2. Every 12 weeks during treatment and for the first two years. From year 3 to 5, every 6 months and yearly thereafter |
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E.5.2 | Secondary end point(s) |
1. Distant metastases-free survival (DMFS)
2. DMFS in subgroup of patients with PD-L1-positive tumor expression receiving either pembrolizumab or placebo
3. Overall survival (OS)
4. OS in subgroup of patients with PD-L1-positive tumor expression receiving either pembrolizumab or placebo
5. Toxicity profile according to Common Terminology Criteria for Adverse Events (CTCAE) v. 4.0
6. To evaluate the PK of pembrolizumab when pembrolizumab is administered 200 mg every 3 weeks
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Every 12 weeks during treatment and for the first two years. From year 3 to 5, every 6 months and yearly thereafter.
2. Every 12 weeks during treatment and for the first two years. From year 3 to 5, every 6 months and yearly thereafter.
3. OS will be measured from the date of randomization until the date of
death.
4. OS will be measured from the date of randomization until the date of
death.
5. Every 6 weeks during treatment and at 12 weeks after the last treatment
6. prior to traetment start (before injection 1), week 4 (before injection N°2), week 10 (before injection N°4 ), week 22 (before injection N°8 ) and at 12 months (before injection 16). At 30 days and 3 months after the last treatment |
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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 | No |
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 | 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 | 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 | Yes |
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 | 21 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 89 |
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 |
Israel |
Italy |
Japan |
Korea, Republic of |
Netherlands |
New Zealand |
Norway |
Poland |
Portugal |
Russian Federation |
Serbia |
Singapore |
Slovenia |
Spain |
Sweden |
Switzerland |
United Kingdom |
United States |
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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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When all criteria have been satisfied:
1. 30 days after all patients have stopped protocol treatment
2. The trial is mature for the 3 final analyses of the efficacy endpoints: one for RFS (overall, and in PD-L1-positive), one for DMFS (overall, and in PD-L1-positive) and one for OS (overall, and in PD-L1-positive)
3. The database has been fully cleaned and frozen
4. As in other EORTC melanoma adjuvant trials, a very long term follow-up, when all patients have a 10-year follow-up is foreseen |
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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 | 8 |
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 | 8 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |