Optimal Neo-adjuvant Combination Scheme of Ipilimumab and Nivolumab

Conditions

• Malignant Melanoma Stage III

Eligibility Criteria

Sex

ALL

Age

18 Years - N/A

Healthy Volunteers

Not accepted

Interventions

• Ipilimumab — DRUG
• Nivolumab — DRUG
• Surgery — PROCEDURE
  Surgery will be done at 6 weeks
• Blood for PBMCs — PROCEDURE
  Blood will be taken for translational research on PBMCs
• Biopsies — PROCEDURE
  Biopsies will be taken during screening and at relapse.

Study Details

This is an open-label three-arm phase 2 trial (including a Simon stage 2 design) consisting of 90 stage III melanoma patients randomized 1:1:1 to receive either 2 courses 3 mg/kg ipilimumab + 1 mg/kg nivolumab every 3 weeks (Arm A), 2 courses 1 mg/kg ipilimumab + 3 mg/kg nivolumab every 3 weeks (Arm B), or 2 courses ipilimumab 3 mg/kg, directly followed by 2 courses nivolumab 3 mg/kg every 2 weeks (Arm C). All three treatment arms are applied prior to surgery at week 6, 30 patients per arm. Patients will be stratified according to treatment center. An interim analysis will be performed after 13 patients have been included in each arm, thus in total 39 patients have been included. PRADO extension cohort The trial will enroll in total about 100-110 melanoma patients with macroscopic stage III disease (RECIST measurable disease); inclusion will stop when 50 patients have achieved a pCR or pnCR. All patients will be treated (after marker placement into the largest lymph node metastasis) with the winner combination identified in the first part of the OpACIN-neo study which is 2 courses ipilimumab 1mg/kg + nivolumab 3mg/kg, q3wks. After 6 weeks of treatment, the patients will undergo only surgical resection of the marked index lymph node. Thereafter subsequent surgery and adjuvant therapy will be performed according to the achieved pathologic response.

Key Dates

Start date

Nov 24, 2016

Status verified

Nov 2023

Primary completion

Jan 3, 2020

Completion

Jun 30, 2025

Study Design

Enrollment

186 participants (actual)

Allocation

NON_RANDOMIZED

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Arms

• Experimental: Arm A: 2 courses ipi 3 + nivo 1
  Patients receive 2 courses standard combination of ipilimumab 3 mg/kg + nivolumab 1 mg/kg q3wk prior to surgery at week 6. Blood for PBMCs and biopsies will be taken for translation research.
• Experimental: Arm B: 2 courses ipi 1 + nivo 3
  Patients receive 2 courses ipilimumab 1 mg/kg + nivolumab 3 mg/kg q3wk prior to surgery at week 6. Blood for PBMCs and biopsies will be taken for translation research.
• Experimental: Arm C: 2 courses ipi 3 + 2 courses nivo 3
  Patients receive 2 courses of ipilimumab 3 mg/kg q3wks, directly followed (\> 2 hours and \< 24 hours) by 2 courses nivolumab 3 mg/kg every 2 weeks prior to surgery at week 6. Blood for PBMCs and biopsies will be taken for translation research.
• Experimental: PRADO extension cohort
  Patients will be treated with 2 courses ipilimumab and nivolumab at the dose level defined as the winner dosing scheme from OpACIN-neo, which is the dosing schedule of arm B. Surgery and adjuvant therapy * Patients achieving a pCR or pnCR will not undergo CLND and will not receive any adjuvant treatment. Structural follow-up will be perfomed every 12 weeks by CT, ultrasound of regional lymph nodes. * Patients achieving a pPR will undergo CLND and start structural follow-up (including CT and physical examination) every 12 weeks thereafter without any adjuvant treatment. * Patients achieving no response (pNR) will undergo CLND and start at week 12 with adjuvant nivolumab 480mg q4wks for 52 weeks + radiotherapy (according to patient's and physicians' decision). In patients that are BRAF V600E/K mutation positive, adjuvant BRAF+MEK

Primary Outcome Measure

Safety as measured by the frequency of grade 3/4 immune-related adverse events, using CTCAE 4.03 [ Time Frame: During the first 12 weeks. ]