Optimal Neo-adjuvant Combination Scheme of Ipilimumab and Nivolumab

NCT ID: NCT02977052

Last Updated: 2023-11-15

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 186 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-11-24
• Study Completion Date: 2025-06-30

Brief Summary

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.

Conditions

Malignant Melanoma Stage III

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

Ipilimumab

Intervention Type: DRUG

Nivolumab

Intervention Type: DRUG

Surgery

Intervention Type: PROCEDURE

Surgery will be done at 6 weeks

Blood for PBMCs

Intervention Type: PROCEDURE

Blood will be taken for translational research on PBMCs

Biopsies

Intervention Type: PROCEDURE

Biopsies will be taken during screening and at relapse.

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.

Group Type: EXPERIMENTAL

Ipilimumab

Intervention Type: DRUG

Nivolumab

Intervention Type: DRUG

Surgery

Intervention Type: PROCEDURE

Surgery will be done at 6 weeks

Blood for PBMCs

Intervention Type: PROCEDURE

Blood will be taken for translational research on PBMCs

Biopsies

Intervention Type: PROCEDURE

Biopsies will be taken during screening and at relapse.

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.

Group Type: EXPERIMENTAL

Ipilimumab

Intervention Type: DRUG

Nivolumab

Intervention Type: DRUG

Surgery

Intervention Type: PROCEDURE

Surgery will be done at 6 weeks

Blood for PBMCs

Intervention Type: PROCEDURE

Blood will be taken for translational research on PBMCs

Biopsies

Intervention Type: PROCEDURE

Biopsies will be taken during screening and at relapse.

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

Group Type: EXPERIMENTAL

Ipilimumab

Intervention Type: DRUG

Nivolumab

Intervention Type: DRUG

Surgery

Intervention Type: PROCEDURE

Surgery will be done at 6 weeks

Blood for PBMCs

Intervention Type: PROCEDURE

Blood will be taken for translational research on PBMCs

Biopsies

Intervention Type: PROCEDURE

Biopsies will be taken during screening and at relapse.

Interventions

Ipilimumab

Intervention Type: DRUG

Nivolumab

Intervention Type: DRUG

Surgery

Surgery will be done at 6 weeks

Intervention Type: PROCEDURE

Blood for PBMCs

Blood will be taken for translational research on PBMCs

Intervention Type: PROCEDURE

Biopsies

Biopsies will be taken during screening and at relapse.

Intervention Type: PROCEDURE

Eligibility Criteria

Inclusion Criteria

• Adults at least 18 years of age
• World Health Organization (WHO) Performance Status 0 or 1
• Cytologically or histologically confirmed resectable stage III melanoma with one or more macroscopic lymph node metastases (measurable according to RECIST 1.1), that can be biopsied, and no history of in-transit metastases within the last 6 months
• No other malignancies, except adequately treated and a cancer-related life-expectancy of more than 5 years
• Patient willing to undergo triple tumor biopsies and extra blood withdrawal during screening and in case of relapse
• No prior immunotherapy targeting CTLA-4, PD-1 or PD-L1
• No immunosuppressive medications within 6 months prior study inclusion
• Screening laboratory values must meet the following criteria: WBC ≥ 2.0x109/L, Neutrophils ≥1.5x109/L, Platelets ≥100 x109/L, Hemoglobin ≥5.5 mmol/L, Creatinine ≤1.5x ULN, AST ≤ 1.5 x ULN, ALT ≤ 1.5 x ULN, Bilirubin ≤1.5 X ULN
• Normal LDH
• Women of childbearing potential (WOCBP) must use appropriate method(s) of contra-ception. WOCBP should use an adequate method to avoid pregnancy for 23 weeks (30 days plus the time required for nivolumab to undergo five half-lives) after the last dose of investigational drug
• Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of ipilimumab + nivolumab
• Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year. Men receiving nivolumab and who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 31 weeks after the last dose of investigational product
• Women who are not of childbearing potential (i.e., who are postmenopausal), or surgically sterile as well as azoospermic men do not require contraception
• Patient is capable of understanding and complying with the protocol requirements and has signed the Informed Consent document.

Exclusion Criteria

• Distantly metastasized melanoma
• History of in-transit metastases within the last 6 months
• No measurable lesion according to RECIST 1.1
• Subjects with any active autoimmune disease or a documented history of autoimmune disease, or history of syndrome that required systemic steroids or immunosuppressive medications, except for subjects with vitiligo or resolved childhood asthma/atopy
• Prior CTLA-4 or PD-1/PD-L1 targeting immunotherapy
• Radiotherapy prior or post-surgery
• Patients will be excluded if they test positive for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody), indicating acute or chronic infection
• Patients will be excluded if they have known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
• Allergies and Adverse Drug Reaction

• History of allergy to study drug components
• History of severe hypersensitivity reaction to any monoclonal antibody
• Underlying medical conditions that, in the Investigator's opinion, will make the administration of study drug hazardous or obscure the interpretation of toxicity determination or adverse events;
• Concurrent medical condition requiring the use of immunosuppressive medications, or immunosuppressive doses of systemic or absorbable topical corticosteroids;
• Use of other investigational drugs before study drug administration 30 days and 5 half-times before study inclusion
• Pregnant or nursing

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Bristol-Myers Squibb

INDUSTRY

Sponsor Role: collaborator

The Netherlands Cancer Institute

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Christian Blank, Prof.

Role: STUDY_CHAIR

Medical oncologist/researcher

Locations

Melanoma Institute Australia

Sydney, New South Wales, Australia

Medical University of Vienna

Vienna, , Austria

Netherlands Cancer Institute

Amsterdam, North Holland, Netherlands

Karolinska Institutet

Stockholm, , Sweden

Countries

Australia; Austria; Netherlands; Sweden

References

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Reference Type: DERIVED

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Other Identifiers

2016-001984-35

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

CA209-701

Identifier Type: OTHER

Identifier Source: secondary_id

M16OPN

Identifier Type: -

Identifier Source: org_study_id