Optimal Neo-adjuvant Combination Scheme of Ipilimumab and Nivolumab

NCT02977052 | Unknown Phase 2 DMC

• 3 other identifiers: M16OPN2016-001984-35CA209-701
• Study Type: interventional
• Target: 186
• Locations: 3 countries
• Sites: 3

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

Keywords

Melanoma; Ipilimumab; Nivolumab; Neo-adjuvant

Outcome Measures

Primary Outcomes (6)

• Safety as measured by the frequency of grade 3/4 immune-related adverse events, using CTCAE 4.03

  During the first 12 weeks.

• Response rate according to RECIST 1.1

  At 6 weeks

• Pathological response according to central pathological revision, according to pathological response criteria

  At 6 weeks

• Pathologic response rate according to central revision of the marked index lymph node

  At 6 weeks, prior surgery

• RFS at 24 months in patients achieving pCR or pnCR in their marked index lymph node and did not undergo CLND. RFS will be calculated from date of resection of the marked lymph node.

  24 months

• RFS at 24 months in patients with pNR and being subsequently treated with adjuvant nivolumab+optional radiotherapy (or dabrafenib/trametinib if BRAFV600E pos. and treatment is approved). RFS will be calculated from day of resection of marked lymph node.

  24 months

Secondary Outcomes (5)

• Recurrence Free Survival

  3 years after treatment initiation

• Description of late adverse events using CTCAE 4.03

  Up to 3 years after treatment initiation until new treatment

• Description of associations of mutational load, RNA tumor signatures, and tumor educated platelet signatures with tumor immune infiltrates and response

  At 6 weeks

• Response rate according to RECIST 1.1 at week 6

  At 6 weeks

• RFS at 2, 3 and 5 years

  Up to 5 years after treatment

Other Outcomes (6)

• EFS at 2, 3 and 5 years

  Up to 5 years after treatment

• DMFS at 2, 3 and 5 years

  Up to 5 years after treatment

• OS at 2, 3 and 5 years

  Up to 5 years after treatment

Study Arms (4)

Arm A: 2 courses ipi 3 + nivo 1

EXPERIMENTAL

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.

Drug: Ipilimumab; Drug: Nivolumab; Procedure: Surgery; Procedure: Blood for PBMCs; Procedure: Biopsies

Arm B: 2 courses ipi 1 + nivo 3

EXPERIMENTAL

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.

Drug: Ipilimumab; Drug: Nivolumab; Procedure: Surgery; Procedure: Blood for PBMCs; Procedure: Biopsies

Arm C: 2 courses ipi 3 + 2 courses nivo 3

EXPERIMENTAL

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.

Drug: Ipilimumab; Drug: Nivolumab; Procedure: Surgery; Procedure: Blood for PBMCs; Procedure: Biopsies

PRADO extension cohort

EXPERIMENTAL

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

Drug: Ipilimumab; Drug: Nivolumab; Procedure: Surgery; Procedure: Blood for PBMCs; Procedure: Biopsies

Interventions

Ipilimumab DRUG

Arm A: 2 courses ipi 3 + nivo 1; Arm B: 2 courses ipi 1 + nivo 3; Arm C: 2 courses ipi 3 + 2 courses nivo 3; PRADO extension cohort

Nivolumab DRUG

Arm A: 2 courses ipi 3 + nivo 1; Arm B: 2 courses ipi 1 + nivo 3; Arm C: 2 courses ipi 3 + 2 courses nivo 3; PRADO extension cohort

Surgery PROCEDURE

Surgery will be done at 6 weeks

Arm A: 2 courses ipi 3 + nivo 1; Arm B: 2 courses ipi 1 + nivo 3; Arm C: 2 courses ipi 3 + 2 courses nivo 3; PRADO extension cohort

Blood for PBMCs PROCEDURE

Blood will be taken for translational research on PBMCs

Arm A: 2 courses ipi 3 + nivo 1; Arm B: 2 courses ipi 1 + nivo 3; Arm C: 2 courses ipi 3 + 2 courses nivo 3; PRADO extension cohort

Biopsies PROCEDURE

Biopsies will be taken during screening and at relapse.

Arm A: 2 courses ipi 3 + nivo 1; Arm B: 2 courses ipi 1 + nivo 3; Arm C: 2 courses ipi 3 + 2 courses nivo 3; PRADO extension cohort

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• 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.

You may not qualify if:

• 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;
• Pregnant or nursing

Sponsors & Collaborators

• The Netherlands Cancer Institute: lead
• Bristol-Myers Squibb: collaborator

Study Sites (4)

Melanoma Institute Australia

Sydney, New South Wales, 2060, Australia

Location

Medical University of Vienna

Vienna, 1090, Austria

Location

Netherlands Cancer Institute

Amsterdam, North Holland, 1066CX, Netherlands

Location

Karolinska Institutet

Stockholm, S-171 76, Sweden

Location

Related Publications (9)

• Hoeijmakers LL, Dimitriadis P, Wijnen SCMA, Reijers ILM, Lopez-Yurda M, Menzies AM, Broeks A, Cornelissen S, Torres Acosta A, van der Wal A, Saw RPM, Versluis JM, van Houdt WJ, Wouters MW, Romano J, Rozeman EA, Grijpink-Ongering LG, Kapiteijn E, van der Veldt AAM, Suijkerbuijk KPM, Eriksson H, Hospers GAP, van der Hage JA, Grunhagen DJ, Witkamp AJ, Lijnsvelt JM, Klop WMC, Zuur CL, Bruining A, Al-Mamgani A, Pennington TE, Shannon KF, Ch'ng S, Colebatch AJ, Gonzalez M, Spillane AJ, Haanen JBAG, Rawson RV, Scolyer RA, van de Wiel BA, van Akkooi ACJ, Long GV, Blank CU. Neoadjuvant ipilimumab plus nivolumab in melanoma: 5-year survival and biomarker analysis from the phase 2 PRADO-trial. Nat Med. 2026 Jan 28. doi: 10.1038/s41591-025-04158-9. Online ahead of print.

  PMID: 41606118 DERIVED

• Fraterman I, Reijers ILM, Dimitriadis P, Broeks A, Gonzalez M, Menzies AMM, Lopez-Yurda M, Kapiteijn E, van der Veldt AAM, Suijkerbuijk KPM, Hospers GAP, Long GV, Blank CU, van de Poll-Franse LV. Association between pretreatment emotional distress and neoadjuvant immune checkpoint blockade response in melanoma. Nat Med. 2023 Dec;29(12):3090-3099. doi: 10.1038/s41591-023-02631-x. Epub 2023 Nov 13.

  PMID: 37957378 DERIVED

• Hoefsmit EP, Vollmy F, Rozeman EA, Reijers ILM, Versluis JM, Hoekman L, van Akkooi ACJ, Long GV, Schadendorf D, Dummer R, Altelaar M, Blank CU. Systemic LRG1 Expression in Melanoma is Associated with Disease Progression and Recurrence. Cancer Res Commun. 2023 Apr 20;3(4):672-683. doi: 10.1158/2767-9764.CRC-23-0015. eCollection 2023 Apr.

  PMID: 37089863 DERIVED

• Zijlker LP, van der Burg SJC, Blank CU, Zuur CL, Klop WMC, Wouters MWMJ, van Houdt WJ, van Akkooi ACJ. Surgical outcomes of lymph node dissections for stage III melanoma after neoadjuvant systemic therapy are not inferior to upfront surgery. Eur J Cancer. 2023 May;185:131-138. doi: 10.1016/j.ejca.2023.03.003. Epub 2023 Mar 7.

  PMID: 36989829 DERIVED

• Gorry C, McCullagh L, O'Donnell H, Barrett S, Schmitz S, Barry M, Curtin K, Beausang E, Barry R, Coyne I. Neoadjuvant treatment for stage III and IV cutaneous melanoma. Cochrane Database Syst Rev. 2023 Jan 17;1(1):CD012974. doi: 10.1002/14651858.CD012974.pub2.

  PMID: 36648215 DERIVED

• Reijers ILM, Menzies AM, van Akkooi ACJ, Versluis JM, van den Heuvel NMJ, Saw RPM, Pennington TE, Kapiteijn E, van der Veldt AAM, Suijkerbuijk KPM, Hospers GAP, Rozeman EA, Klop WMC, van Houdt WJ, Sikorska K, van der Hage JA, Grunhagen DJ, Wouters MW, Witkamp AJ, Zuur CL, Lijnsvelt JM, Torres Acosta A, Grijpink-Ongering LG, Gonzalez M, Jozwiak K, Bierman C, Shannon KF, Ch'ng S, Colebatch AJ, Spillane AJ, Haanen JBAG, Rawson RV, van de Wiel BA, van de Poll-Franse LV, Scolyer RA, Boekhout AH, Long GV, Blank CU. Personalized response-directed surgery and adjuvant therapy after neoadjuvant ipilimumab and nivolumab in high-risk stage III melanoma: the PRADO trial. Nat Med. 2022 Jun;28(6):1178-1188. doi: 10.1038/s41591-022-01851-x. Epub 2022 Jun 5.

  PMID: 35661157 DERIVED

• Versluis JM, Reijers ILM, Rozeman EA, Menzies AM, van Akkooi ACJ, Wouters MW, Ch'ng S, Saw RPM, Scolyer RA, van de Wiel BA, Schilling B, Long GV, Blank CU. Neoadjuvant ipilimumab plus nivolumab in synchronous clinical stage III melanoma. Eur J Cancer. 2021 May;148:51-57. doi: 10.1016/j.ejca.2021.02.012. Epub 2021 Mar 15.

  PMID: 33735809 DERIVED

• Rozeman EA, Hoefsmit EP, Reijers ILM, Saw RPM, Versluis JM, Krijgsman O, Dimitriadis P, Sikorska K, van de Wiel BA, Eriksson H, Gonzalez M, Torres Acosta A, Grijpink-Ongering LG, Shannon K, Haanen JBAG, Stretch J, Ch'ng S, Nieweg OE, Mallo HA, Adriaansz S, Kerkhoven RM, Cornelissen S, Broeks A, Klop WMC, Zuur CL, van Houdt WJ, Peeper DS, Spillane AJ, van Akkooi ACJ, Scolyer RA, Schumacher TNM, Menzies AM, Long GV, Blank CU. Survival and biomarker analyses from the OpACIN-neo and OpACIN neoadjuvant immunotherapy trials in stage III melanoma. Nat Med. 2021 Feb;27(2):256-263. doi: 10.1038/s41591-020-01211-7. Epub 2021 Feb 8.

  PMID: 33558721 DERIVED

• Rozeman EA, Menzies AM, van Akkooi ACJ, Adhikari C, Bierman C, van de Wiel BA, Scolyer RA, Krijgsman O, Sikorska K, Eriksson H, Broeks A, van Thienen JV, Guminski AD, Acosta AT, Ter Meulen S, Koenen AM, Bosch LJW, Shannon K, Pronk LM, Gonzalez M, Ch'ng S, Grijpink-Ongering LG, Stretch J, Heijmink S, van Tinteren H, Haanen JBAG, Nieweg OE, Klop WMC, Zuur CL, Saw RPM, van Houdt WJ, Peeper DS, Spillane AJ, Hansson J, Schumacher TN, Long GV, Blank CU. Identification of the optimal combination dosing schedule of neoadjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma (OpACIN-neo): a multicentre, phase 2, randomised, controlled trial. Lancet Oncol. 2019 Jul;20(7):948-960. doi: 10.1016/S1470-2045(19)30151-2. Epub 2019 May 31.

  PMID: 31160251 DERIVED

MeSH Terms

Conditions

Melanoma

Interventions

Ipilimumab; Nivolumab; Surgical Procedures, Operative; Blood Specimen Collection; Biopsy

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Investigative Techniques; Cytodiagnosis; Cytological Techniques; Diagnostic Techniques, Surgical

Study Officials

• Christian Blank, Prof.

  Medical oncologist/researcher

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 21, 2016
• First Posted: November 30, 2016
• Study Start: November 24, 2016
• Primary Completion: January 3, 2020
• Study Completion: June 1, 2025
• Last Updated: November 15, 2023

Record last verified: 2023-11

Data Sharing

• IPD Sharing: Will not share

Locations

NL (1); AU (1); SE (1)