Safe Stop Ipilimumab-nivolumab (IPI-NIVO) Trial

Study Overview
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Brief Summary
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Safe Stop IPI-NIVO Trial: Early discontinuation of nivolumab upon achieving a (confirmed) complete or partial response in patients with irresectable stage III or metastatic melanoma treated with first-line ipilimumab-nivolumab

Official Title
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Safe Stop IPI-NIVO Trial: Early Discontinuation of Nivolumab Upon Achieving a (Confirmed) Complete or Partial Response in Patients With Irresectable Stage III or Metastatic Melanoma Treated With First-line Ipilimumab-nivolumab

Conditions
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Melanoma Stage IV, Melanoma Stage III, Immunotherapy, Toxicity, Drug

Intervention / Treatment
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* Drug: nivolumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18 years of age or older Irresectable stage III or metastatic melanoma Treated with at least one dose of first-line ipilimumab-nivolumab and considered to be a candidate for maintenance treatment with nivolumab: previous systemic treatment, including immune-checkpoint inhibitors, in (neo)adjuvant setting for resectable melanoma is allowed in this protocol, nivolumab maintenance is interchangeable with pembrolizumab maintenance therapy. Response evaluation according to RECIST v1.1 30 using a diagnostic CT documenting target lesions every 12 (-2/+6) weeks from the start of ipilimumab-nivolumab: for patients with CR on a diagnostic CT at response evaluation, a low-dose CT (which is usually part of 18FDG-PET/CT) is allowed at baseline for patients with PR on a diagnostic CT at response evaluation, a low-dose CT (which is usually part of 18FDG-PET/CT) is allowed if sufficient target lesions are measurable for response evaluation according to RECIST v1.1 criteria 30 in case of asymptomatic brain metastases prior to start of first-line ipilimumab-nivolumab, intracerebral tumor response should be confirmed using an MRI for response evaluation prior to inclusion in this study. Patients should be included after first CR/PR or first confirmed CR/PR according to RECIST v1.1 30: inclusion should take place no later than 5 weeks after first confirmed CR/PR in case of SD at first response evaluation, confirmed CR/PR is required for inclusion planned and willing to discontinue nivolumab within 4(+1) weeks after inclusion, i.e. first CR/PR or first confirmed CR/PR no later than 9 months after start of treatment with ipilimumab-nivolumab Presence of MRI brain for the screening of brain metastases (prior to discontinuation of ipilimumab-nivolumab) Participants with previously locally treated brain metastases may participate in case they meet the following criteria: completely asymptomatic brain metastases at inclusion MRI of brain at baseline and for response evaluation during treatment Signed and dated informed consent form Exclusion Criteria: Patients with SD/PD according to RECIST v1.1 Malignant disease other than being treated in this study. Exceptions to this exclusion include the following: malignancies that were treated curatively and have not recurred within 2 years prior to start of study treatment; completely resected basal cell and squamous cell skin cancers and any completely resected carcinoma in situ. Presence of symptomatic brain metastases: prior to first-line treatment with ipilimumab-nivolumab, or; when defined as new or progressive brain metastases at the time of study entry; brain metastases with need for steroid treatment in the last 8 weeks prior to study entry Note: An incidental epileptic seizure caused by a brain lesion is not considered an exclusion criterion. (provided that the other in- and exclusion criteria are met); Presence of leptomeningeal metastases; Systemic chronic steroid therapy (>10mg/day prednisone or equivalent) at inclusion or patients who need or needed any other second-line immunosuppressive therapy (e.g. infliximab, mycophenolate mofetil) for the treatment of immune related adverse events (irAEs). Note: local steroids such as topical, inhaled, nasal and ophthalmic steroids are allowed. Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial

Ages Eligible for Study
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Minimum Age: 18 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Early discontinuation of nivolumab<br> | Drug: nivolumab<br>* Early discontinuation of nivolumab maintenance therapy in patients with irresectable stage III or metastatic melanoma<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ongoing response | The rate of ongoing response at 12 months in patients with irresectable stage III or metastatic melanoma who are treated with first-line ipilimumab-nivolumab and who early discontinue nivolumab upon achieving a CR or PR according to RECIST v1.1 | 12 months after start of ipilimumab-nivolumab combination therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ongoing response | Ongoing response at 24 months after start of first-line treatment with ipilimumab-nivolumab | 24 months after start of treatment | 
| Disease control | Disease control (CR/PR) at different time points | 5 years after inclusion | 
| duration of response | Duration of response (CR/PR) measured until progressive/recurrent disease | 5 years after inclusion | 
| Melanoma Specific Survival rate | Melanoma specific survival measured from start of first-line treatment with ipilimumab-nivolumab until melanoma related death | 5 years after inclusion | 
| Overall Survival | Overall survival (OS) measured from start of first-line treatment with ipilimumab-nivolumab until death by any cause | 5 years after inclusion | 
| (serious) adverse events | Impact of discontinuation treatment on (S)AEs | 5 years after inclusion | 
| ORR | Overall Response Rate (ORR) per RECIST v1.1 in retreated patients | 5 years after inclusion | 
| Re-treatment | Rate of re-treatment for melanoma | 5 years after inclusion | 
| Disease control (CR/PR/SD [stable disease]/not PD [progressive disease]) after restarting (systemic) treatment for melanoma | Disease control (CR/PR/SD [stable disease]/not PD [progressive disease]) after restarting (systemic) treatment for melanoma | 5 years after inclusion | 
| Quality of life questionnaires EuroQoL EQ-5D-5 | Quality of life is measured using questionnaires: EuroQoL EQ-5D-5 | 5 years after inclusion |