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Malignant Melanoma Stage IIIPhase 2OpACIN-neoNCT02977052

Optimal Neo-adjuvant Combination Scheme of Ipilimumab and Nivolumab

A Phase 2 study testing Ipilimumab, Nivolumab and Surgery in people with Malignant Melanoma Stage III, run by The Netherlands Cancer Institute at 4 sites in 4 countries.

Unknown status

Status not confirmed. The sponsor has not verified this record for over two years, so it may be out of date.

Official record
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Trial 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… Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Malignant Melanoma Stage III
What is being tested?
Ipilimumab, Nivolumab and Surgery
Type of treatment
Surgery or procedure
Could I receive a placebo?
No, everyone receives an active treatment
How many people
186 participants
Where
4 sitesin 4 countries
Study dates
24 Nov 2016to Jun 2025
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
Show all 14Show fewer
  • 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.

Who cannot join

  • 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
Show all 15Show fewer
  • 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

Trial locations and contacts

4 sites in 4 countries.

4 sites in 4 countries

Australia1 site

  • Melanoma Institute Australia

    Sydney, New South Wales, 2060

Other trials in Australia

Austria1 site

  • Medical University of Vienna

    Vienna, 1090

Other trials in Austria

Netherlands1 site

  • Netherlands Cancer Institute

    Amsterdam, North Holland, 1066CX

Other trials in Netherlands

Sweden1 site

  • Karolinska Institutet

    Stockholm, S-171 76

Other trials in Sweden

About this study

Official title: Multicenter Phase 2 Study to Identify of the Optimal Neo-Adjuvant Combination Scheme of Ipilimumab and Nivolumab (OpACIN-neo)

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.

Being tested
Ipilimumab, Nivolumab, Surgery, Blood for PBMCs, Biopsies
Keywords
Melanoma, Ipilimumab, Nivolumab, Neo-adjuvant
Medical subject headings
Melanoma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • IpilimumabDrug

  • NivolumabDrug

  • SurgeryProcedure or surgery

    Surgery will be done at 6 weeks

  • Blood for PBMCsProcedure or surgery

    Blood will be taken for translational research on PBMCs

  • BiopsiesProcedure or surgery

    Biopsies will be taken during screening and at relapse.

Study groups in NCT02977052
Study groupRoleWhat they receive
Arm A: 2 courses ipi 3 + nivo 1ExperimentalPatients 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.
Receives: Drug: Ipilimumab; Drug: Nivolumab; Procedure: Surgery; Procedure: Blood for PBMCs; Procedure: Biopsies
Arm B: 2 courses ipi 1 + nivo 3ExperimentalPatients 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.
Receives: Drug: Ipilimumab; Drug: Nivolumab; Procedure: Surgery; Procedure: Blood for PBMCs; Procedure: Biopsies
Arm C: 2 courses ipi 3 + 2 courses nivo 3ExperimentalPatients 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.
Receives: Drug: Ipilimumab; Drug: Nivolumab; Procedure: Surgery; Procedure: Blood for PBMCs; Procedure: Biopsies
PRADO extension cohortExperimentalPatients 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
Receives: Drug: Ipilimumab; Drug: Nivolumab; Procedure: Surgery; Procedure: Blood for PBMCs; Procedure: Biopsies

What is being measured

The primary outcome is the main question the study is designed to answer.

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

    Measured: During the first 12 weeks.

  2. Response rate according to RECIST 1.1

    Measured: At 6 weeks

  3. Pathological response according to central pathological revision, according to pathological response criteria

    Measured: At 6 weeks

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

    Measured: At 6 weeks, prior surgery

  5. 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.

    Measured: 24 months

  6. 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.

    Measured: 24 months

Secondary outcomes (5)

  1. Recurrence Free Survival

    Measured: 3 years after treatment initiation

  2. Description of late adverse events using CTCAE 4.03

    Measured: Up to 3 years after treatment initiation until new treatment

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

    Measured: At 6 weeks

  4. Response rate according to RECIST 1.1 at week 6

    Measured: At 6 weeks

  5. RFS at 2, 3 and 5 years

    Measured: Up to 5 years after treatment

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted30 Nov 2016 (estimated)
  2. Study start24 Nov 2016
  3. Primary completion3 Jan 2020
  4. Study completionJun 2025 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Single group
Masking
None (open label)
Enrolment
186 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02977052
Sponsor's protocol ID
M16OPN
Other IDs
2016-001984-35, CA209-701, 2016
Acronym
OpACIN-neo
Status last verified
Nov 2023
First submitted
21 Nov 2016
Last updated
15 Nov 2023
Results posted
No
Data monitoring committee
Yes
Individual data sharing
No

Publications

  • 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 Mar;32(3):952-963. doi: 10.1038/s41591-025-04158-9. Epub 2026 Jan 28.

    PubMed 41606118

  • 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.

    PubMed 37957378

  • 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.

    PubMed 37089863

  • 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.

    PubMed 36989829

  • 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.

    PubMed 36648215

  • 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.

    PubMed 35661157

  • 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.

    PubMed 33735809

  • 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.

    PubMed 33558721

  • 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.

    PubMed 31160251

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Ipilimumab, Nivolumab and Surgery in people with Malignant Melanoma Stage III, run by The Netherlands Cancer Institute at 4 sites in 4 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 14 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: status not confirmed, as of the sponsor's last update on 15 Nov 2023. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 4 sites in Australia, Austria, Netherlands, Sweden. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the 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.). The study lists 6 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02977052, which also lists 9 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 15 Nov 2023.

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