| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
| Melanoma is a form of skin cancer that begins in the cells (melanocytes) that control the pigment in your skin |
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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 | 20.0 |
| E.1.2 | Level | HLT |
| E.1.2 | Classification code | 10027156 |
| E.1.2 | Term | Skin melanomas (excl ocular) |
| E.1.2 | System Organ Class | 100000004858 |
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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 |
- In Cohort 1 (resectable Stage III melanoma): To evaluate the efficacy of treatment on the basis of pathologic response rate (pRR) at time of surgery, as determined by independent pathologic review
- In Cohort 2 (Stage IV melanoma): To evaluate the efficacy of treatment on the basis of objective response rate (ORR)
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| E.2.2 | Secondary objectives of the trial |
- In Cohort 1: To evaluate the efficacy of treatment on the basis of pRR at time of surgery, as determined by local pathologic assessment, event-free survival (EFS), relapse-free survival (RFS), overall survival (OS), objective response rate (ORR)
- In Cohort 2: Progression-free survival (PFS), overall survival (OS), duration of response (DOR) and disease control
- Cohort 1 and 2: To evaluate the safety of treatment
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Age >=18 years
- ECOG performance status (PS) of 0 or 1
- Availability of a representative tumor specimen that is suitable for biomarker testing via central laboratory
- Adequate hematologic and end-organ function
- For patients receiving therapeutic anticoagulation: stable anticoagulant regimen
- Negative HIV test at screening, with the following exception: Patients with a positive HIV test at screening are eligible provided they are stable on anti-retroviral therapy, have a CD4 count >= 200/µL, and have an undetectable viral load
- Negative hepatitis B surface antibody (HBsAb), and negative total hepatitis B core antibody (HBcAb) test at screening. If a patient has a negative hepatitis B surface antigen (HBsAg) test and a positive total HBcAb test at screening, an hepatitis B virus (HBV) DNA test must also be performed to rule out active HBV.
- Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV antibody test followed by a negative HCV RNA test at screening
- For women of childbearing potential: agreement to remain abstinent or use contraceptive measures
- For men: agreement to remain abstinent or use contraceptive measures, and agreement to refrain from donating sperm
Inclusion Criteria for Cohort 1
- ECOG performance status (PS) of 0 or 1
- Histologically confirmed resectable Stage III melanoma and no history of in-transit metastases within the last 6 months
- Fit and planned for completion lymph node dissection (CLND)
- Measurable disease (at least one target lesion) according to RECIST v1.1
Inclusion Criteria for Cohort 2
- Patients must meet all of the following criteria to qualify for Cohort 2:
- ECOG PS of 0, 1, or 2
- Life expectancy >= 3 months, as determined by the investigator
- Histologically confirmed Stage IV (metastatic) cutaneous melanoma according to AJCC-8
- Disease progression during or following at least one but no more than two lines of treatment for metastatic disease
- Measurable disease (at least one target lesion) according to RECIST v1.1 |
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| E.4 | Principal exclusion criteria |
Exclusion Criteria for Cohort 1 and Cohort 2
- Mucosal and uveal melanoma. Acral lentiginous melanoma (excluded in Cohort 1)
- Treatment with investigational therapy within 28 days prior to initiation of study treatment
- Treatment with systemic immunostimulatory agents within 4 weeks or 5 drug-elimination half-lives (whichever is longer) prior to initiation of study treatment
- Prior allogeneic stem cell or solid organ transplantation
- Known immunodeficiency or conditions requiring treatment with systemic immunosuppressive medication
- Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during study treatment or within 5 months after the final dose of study treatment
- Active or history of autoimmune disease or immune deficiency
- History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan
- History of malignancy other than malignant melanoma within 2 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death
- Active tuberculosis (TB)
- Severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia, or any active infection that, in the opinion of the investigator, could impact patient safety
- Treatment with therapeutic or prophylactic oral or IV antibiotics within 2 weeks prior to initiation of study treatment
- Significant cardiovascular disease such as New York Heart Association cardiac disease (Class II or greater), myocardial infarction or cerebrovascular accident within 3 months prior to initiation of study treatment, unstable arrhythmia, or unstable angina
- Uncontrolled hypertension
- Major surgical procedure, other than for diagnosis, within 4 weeks prior to initiation of study treatment, or anticipation of need for a major surgical procedure other than CLND, during the study.
- Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, impair the ability of the patient to participate in the study, or may render the patient at high risk from treatment complications
- History of severe allergic reactions to chimeric or humanized antibodies or fusion proteins
- Known hypersensitivity to Chinese hamster ovary cell products or recombinant human antibodies
- Known allergy or hypersensitivity to any of the study drugs or their excipients
- Known intolerance to any of the drugs required for premedication
- Pregnancy or breastfeeding, or intention of becoming pregnant during the study. Women of childbearing potential must have a negative serum pregnancy test result within 14 days prior to initiation of study treatment.
- Eligible only for the control arm
Exclusion Criteria for Cohort 1
- Distantly metastasized melanoma
- History of in-transit metastases within the last 6 months
- Prior radiotherapy
- Prior immunotherapy, including anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies, and other systemic therapy for melanoma
Exclusion Criteria for Cohort 2
- Symptomatic, untreated, or progressing CNS metastases
- Active or history of carcinomatous meningitis/leptomeningeal disease
- Uncontrolled tumor-related pain
- Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures
- Uncontrolled or symptomatic hypercalcemia
- Any history of an immune-mediated Grade 4 adverse event attributed to prior CIT that resulted in permanent discontinuation of the prior immunotherapeutic agent
- All immune-mediated adverse events related to prior immunomodulatory therapy that have not resolved completely to baseline. Patients treated with corticosteroids for immune-mediated adverse events, except for corticosteroids replacement therapy for adrenal insufficiency, must not have related symptoms or signs for >= 4 weeks following discontinuation of corticosteroids
- Adverse events related to any prior radiotherapy, chemotherapy, targeted therapy, CPI therapy or surgical procedure must have resolved to Grade 1 or better, except alopecia (any grade), Grade 2 peripheral neuropathy, and hypothyroidism and/or hypopituitarism on a stable dosage of hormone replacement therapy
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| E.5 End points |
| E.5.1 | Primary end point(s) |
1. pRR (defined as the proportion of patients with pathologic complete response (pCR), pathologic near complete response (pnCR), and pathologic partial response (pPR) at time of surgery, as determined by independent pathologic review (Cohort 1)
2. ORR, defined as the proportion of patients with a complete response (CR) or partial response (PR) on two consecutive occasions >= 4 weeks apart, as determined by the investigator according to Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) (Cohort 2) |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Week 7 (time of surgery)
2. Up to 5 years |
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| E.5.2 | Secondary end point(s) |
1. pRR (defined as the proportion of patients with pCR, pnCR, and pPR) at time of surgery, as determined by local pathologic assessment (Cohort 1)
2. EFS, defined as the time from randomization to any of the following events (whichever occurs first): Disease progression that precludes surgery, as assessed by the investigator according to RECIST v1.1; local, regional or distant disease recurrence; or death from any cause (Cohort 1)
3. RFS, defined as the time from surgery to the first documented recurrence of disease or death from any cause (Cohort 1)
4. OS, defined as the time from randomization to death from any cause (Cohort 1 and 2)
5. ORR, defined as the proportion of patients with a CR or PR as determined by the investigator according to RECIST v1.1, prior to surgery (Cohort 1)
6. PFS after randomization/enrollment, defined as the time from randomization/enrollment to the first occurrence of disease progression or death from any cause (whichever occurs first), as determined by the investigator according to RECIST v1.1 (Cohort 2)
7. OS at specific timepoints (e.g., 6 months) (Cohort 2)
8. DOR, defined as the time from the first occurrence of a documented objective response to disease progression or death from any cause (whichever occurs first), as determined by the investigator according to RECIST v1.1 (Cohort 2)
9. Disease control, defined as stable disease for >= 12 weeks or a CR or PR, as determined by the investigator according to RECIST v1.1 (Cohort 2)
10. Incidence, nature, and severity of adverse events and laboratory abnormalities (Cohort 1 and 2)
11. Incidence and nature of immune-related adverse events Grade >= 3 during the first 12 weeks (Cohort 1)
12. Rate and duration of delayed surgery due to treatment-related adverse events (Cohort 1)
13. Surgical complication rates according to Clavien-Dindo surgical classification after CLND (Cohort 1) |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Week 7 (time of surgery)
2-6. Up to 5 years
7. Approximately every 6 months, up to 5 years
8. From the date of the first occurrence of a documented objective response to disease progression or death from any cause, whichever occurs first (up to 5 years)
9. From randomization until loss of clinical benefit (up to 5 years)
10-13. Up to 5 years |
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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 | 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) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| efficacy, safety, and pharmacokinetics of treatment combinations |
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| 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 6 |
| 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 | 12 |
| 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 |
| France |
| Italy |
| Netherlands |
| Spain |
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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 | 2 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
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