Study to Compare Adjuvant Immunotherapy of Bempegaldesleukin Combined With Nivolumab Versus Nivolumab After Complete Resection of Melanoma in Patients at High Risk for Recurrence

Study Overview
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Brief Summary
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The main purpose of this study is to compare the efficacy of bempegaldesleukin plus nivolumab versus nivolumab in patients with completely resected Stage IIIA/B/C/D, or Stage IV cutaneous melanoma who are at high risk for recurrence.

Detailed Description
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The main purpose of this study is to compare the efficacy, as measured by recurrence-free survival (RFS) by blinded independent central review (BICR), of bempegaldesleukin plus nivolumab versus nivolumab in patients with completely resected Stage IIIA (lymph node [LN] metastasis > 1 mm), Stage IIIB/C/D, or Stage IV (American Joint Committee on Cancer [AJCC] 8th edition) cutaneous melanoma with no evidence of disease (NED) who are at high risk for recurrence.

Official Title
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A Phase 3, Randomized, Open-label Study to Compare Adjuvant Immunotherapy of Bempegaldesleukin Combined With Nivolumab Versus Nivolumab After Complete Resection of Melanoma in Patients at High Risk for Recurrence (PIVOT-12)

Conditions
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Melanoma, Melanoma Stage III, Melanoma Stage IV, Melanoma (Skin)

Intervention / Treatment
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* Biological: Bempegaldesleukin
* Biological: Nivolumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patients, age 12 years or older at the time of signing the informed consent form (age 18 years or older where local regulations, countries, and/or institutional policies do not allow for patients < 18 years of age (adolescents) to participate). In regions where adolescents are not allowed to participate in the study due to age restrictions, enrolled patients must be ≥ 18 years of age. Histologically confirmed Stage IIIA (LN metastasis > 1 mm), IIIB/C/D, or IV (M1a/b/c/d) cutaneous melanoma by AJCC (8th edition) at study entry that has been completely surgically resected within 12 weeks prior to randomization. Tumor tissue available from biopsy or resected disease must be provided to central laboratory for PD-L1 status analysis. Must have PD-L1 expression classification for stratification purposes. Disease-free status documented by a complete physical examination and imaging studies within 28 days prior to randomization. Exclusion Criteria: History of ocular/uveal melanoma or mucosal melanoma. Active, known or suspected autoimmune disease. Patients with Type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll. Conditions requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of randomization. Inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease. Prior therapy for melanoma except surgery for the melanoma lesion(s) and/or adjuvant radiation therapy for central nervous system lesions. Prior therapy with interferon, talimogene laherparepvec (Imylgic®), interleukin-2 (IL-2) directed therapy, anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-cytotoxic T lymphocyte-associated protein 4 antibody (including ipilimumab or any other antibody or drug specifically targeting T cell co-stimulation or checkpoint pathways). Prior malignancy active within the previous 3 years except for locally potentially curable cancers that have been apparently cured.

Ages Eligible for Study
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Minimum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Patients will be randomized in a 1:1 ratio to one of two treatment arms
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Combination of bempegaldesleukin (NKTR-214) + nivolumab<br>Arm A: Participants will receive bempegaldesleukin (NKTR-214) IV in combination with nivolumab every 3 weeks. | Biological: Bempegaldesleukin<br>* Specified dose on specified days<br>* Other names: BMS-986321;Biological: Nivolumab<br>* Specified dose on specified days<br>* Other names: BMS-936558;|
| Active Comparator: Nivolumab<br>Arm B: Participants will receive nivolumab IV alone every 4 weeks. | Biological: Nivolumab<br>* Specified dose on specified days<br>* Other names: BMS-936558;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recurrence-free Survival (RFS) by Blinded Independent Central Review (BICR) of Bempegaldesleukin Plus Nivolumab Versus Nivolumab Alone. | Recurrence-free Survival (RFS) of bempegaldesleukin plus nivolumab versus nivolumab alone is determined based on the disease recurrence date provided by Blinded Independent Central Review (BICR) and is defined as the time between date of randomization and date of first recurrence (local, regional, or distant metastasis by BICR), new primary melanoma (by BICR), or all-cause death, whichever occurs first. | Up to 21 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) of Bempegaldesleukin Plus Nivolumab Versus Nivolumab Alone | Overall Survival (OS) is defined as the time between the date of randomization and the date of death due to any cause. Patients who do not have a date of death will be censored on the last date for which a patient was known to be alive. | Up to 21 months | 
| Distant Metastasis-Free Survival (DMFS) by Investigator in Patients Who Are Stage III at Study Entry. | Distant metastasis-free survival (DMFS) by Investigator is defined as the time between the date of randomization and the date of first distant metastasis by Investigator or date of death due to any cause, in patients who have Stage III melanoma at study entry. | Up to 21 months | 
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | To evaluate safety and tolerability of (NKTR-214) 0.006 mg/kg in combination with nivolumab 360 mg IV infusion (or 4.5 mg/kg IV infusion q3w for patients <40 kg) and nivolumab 480 mg IV infusion (or 6.0 mg/kg IV infusion q4w for patients < 40 kg). Treatment-emergent adverse event (TEAE) is defined as an AE that was not present prior to treatment with study drug but appeared following treatment or was present at treatment start date but worsened during treatment-emergent period. The treatment-emergent period is defined as the period from the date of the first dose of study drug up to 30 days after the date of the last dose of study drug or the day prior to the initiation of subsequent anticancer treatment, whichever occurs first. | Approximately up to 21 months | 
| Changes at 6 Months of Treatment From Baseline in Scores for the Global Health/Quality of Life (GH/QoL) and Physical Functioning Subscales of the European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire | The EORTC QLQ-C30 comprises 30 items (i.e. single questions). 24 of which are aggregated into nine multi-item scales, that is, five functioning scales (physical, role, cognitive, emotional and social), three symptom scales (fatigue, pain and nausea/vomiting) and one global health status scale. Participants rate items and a score ranging from 0 to 100 is calculated. A higher score on the global health status/quality of life scale indicates a better level of functioning, and positive changes from baseline indicate improvement. A change of 5 - 10 points is considered a small change, and a change of 10 - 20 points is considered a moderate change. Due to the study termination, results for the mean change from baseline for GH/QoL and the physical functioning subscale were analyzed at approximately 6 months of treatment. | From baseline, up to approximately 6 months | 
| Programmed Death-Ligand 1 (PD-L1) Expression as a Predictive Biomarker for Recurrence-free Survival (RFS) | The predictive strength of Programmed Death-Ligand 1 (PD-L1) expression as a biomarker will be measured by the endpoint RFS by BICR based on PD-L1 expression level. | Up to 21 months | 
| Recurrence-free Survival (RFS) by Investigator of Bempegaldesleukin Plus Nivolumab Versus Nivolumab Alone. | Recurrence-free Survival by Investigator is defined as the time between the date of randomization and the date of first recurrence (local, regional, or distant metastasis by Investigator), new primary melanoma (by Investigator), or all-cause death, whichever occurs first. | Up to 21 months | 
| Time to Disease Progression After the Next Line of Treatment for Study Patients Following Discontinuation of Bempegaldesleukin Plus Nivolumab Versus Nivolumab | Time to disease progression after the next line of treatment is defined as time from randomization to progression per Investigator after the start of next line of therapy or death, whichever occurs first. Patients who were alive and without progression after the next line of therapy can be censored at last known alive date. | Up to 21 months | 
| Distant Metastasis-Free Survival (DMFS) by Blinded Independent Central Review (BICR) in Patients Who Are Stage III at Study Entry. | Distant Metastasis-Free Survival (DMFS) by Blinded Independent Central Review (BICR) is defined as the time between the date of randomization and the date of first distant metastasis by BICR or date of death due to any cause, whichever occurs first, in patients who have Stage III melanoma at study entry. | Up to 21 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CD122-Biased Agonist, CD122-Biased Cytokine, IL-2 Receptor Agonist, NKTR-214, Bempegaldesleukin, IL-2, Immunotherapy, BEMPEG, Nivolumab, Opdivo®, NIVO, Adjuvant, Skin Cancer, Resectable Melanoma, High Risk of Recurrence Melanoma, Post Resection, Checkpoint Inhibitor