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Optimal Neo-adjuvant Combination Scheme of Ipilimumab and Nivolumab (OpACIN-neo)

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ClinicalTrials.gov Identifier: NCT02977052
Recruitment Status : Recruiting
First Posted : November 30, 2016
Last Update Posted : November 6, 2018
Sponsor:
Collaborator:
Bristol-Myers Squibb
Information provided by (Responsible Party):
The Netherlands Cancer Institute

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.


Condition or disease Intervention/treatment Phase
Malignant Melanoma Stage III Drug: Ipilimumab Drug: Nivolumab Procedure: Surgery Procedure: Blood for PBMCs Procedure: Biopsies Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 110 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Multicenter Phase 2 Study to Identify of the Optimal Neo-Adjuvant Combination Scheme of Ipilimumab and Nivolumab (OpACIN-neo)
Study Start Date : November 2016
Estimated Primary Completion Date : June 2020
Estimated Study Completion Date : June 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Melanoma

Arm Intervention/treatment
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.
Drug: Ipilimumab
Drug: Nivolumab
Procedure: Surgery
Surgery will be done at 6 weeks

Procedure: Blood for PBMCs
Blood will be taken for translational research on PBMCs

Procedure: Biopsies
Biopsies will be taken during screening and at relapse.

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.
Drug: Ipilimumab
Drug: Nivolumab
Procedure: Surgery
Surgery will be done at 6 weeks

Procedure: Blood for PBMCs
Blood will be taken for translational research on PBMCs

Procedure: Biopsies
Biopsies will be taken during screening and at relapse.

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.
Drug: Ipilimumab
Drug: Nivolumab
Procedure: Surgery
Surgery will be done at 6 weeks

Procedure: Blood for PBMCs
Blood will be taken for translational research on PBMCs

Procedure: Biopsies
Biopsies will be taken during screening and at relapse.

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
Drug: Ipilimumab
Drug: Nivolumab
Procedure: Surgery
Surgery will be done at 6 weeks

Procedure: Blood for PBMCs
Blood will be taken for translational research on PBMCs

Procedure: Biopsies
Biopsies will be taken during screening and at relapse.




Primary Outcome Measures :
  1. 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. ]
  2. Response rate according to RECIST 1.1 [ Time Frame: At 6 weeks ]
  3. Pathological response according to central pathological revision, according to pathological response criteria [ Time Frame: At 6 weeks ]
  4. Pathologic response rate according to central revision of the marked index lymph node [ Time Frame: 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. [ Time Frame: 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. [ Time Frame: 24 months ]

Secondary Outcome Measures :
  1. Recurrence Free Survival [ Time Frame: 3 years after treatment initiation ]
  2. Description of late adverse events using CTCAE 4.03 [ Time Frame: 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 [ Time Frame: At 6 weeks ]
  4. Response rate according to RECIST 1.1 at week 6 [ Time Frame: At 6 weeks ]
  5. RFS at 2, 3 and 5 years [ Time Frame: Up to 5 years after treatment ]

Other Outcome Measures:
  1. EFS at 2, 3 and 5 years [ Time Frame: Up to 5 years after treatment ]
  2. DMFS at 2, 3 and 5 years [ Time Frame: Up to 5 years after treatment ]
  3. OS at 2, 3 and 5 years [ Time Frame: Up to 5 years after treatment ]
  4. Grade 3/4 immune-related adverse event rate according to CTCAE v4.03 within the first 12 weeks [ Time Frame: At 12 weeks ]
  5. • Surgical complication rates according to Clavien-Dindo surgical classification of only marked index lymph node resection vs. CLND [ Time Frame: At 12 weeks ]
  6. • Description of late adverse event (up to 3 years after treatment initiation) according to CTCAE v4.03 [ Time Frame: Up to 3 years after treatment ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02977052


Contacts
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Contact: Christian Blank-de Hoop, Prof. +31205122951 c.blank@nki.nl
Contact: Lisette Rozeman, MD +31205126281 l.rozeman@nki.nl

Locations
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Australia, New South Wales
Melanoma Institute Australia Recruiting
Sydney, New South Wales, Australia, 2060
Contact: Maria Gonzalez    +61299117300    Maria.Gonzalez@melanoma.org.au   
Principal Investigator: Georgina Long         
Austria
Medical University of Vienna Not yet recruiting
Vienna, Austria, 1090
Contact: Christoph Hoeller, Prof.       christoph.hoeller@meduniwien.ac.at   
Principal Investigator: Christoph Hoeller, Prof.         
Netherlands
Netherlands Cancer Institute Recruiting
Amsterdam, NH, Netherlands, 1066CX
Contact: Christian Blank-de Hoop, Prof.    +31205122951    c.blank@nki.nl   
Contact: Lisette Rozeman, MD    +31205126281    l.rozeman@nki.nl   
Sweden
Karolinska Institutet Recruiting
Stockholm, Sweden, S-171 76
Contact: Johan Hansson, Prof.       Johan.Hansson@ki.se   
Contact: Leia Ollmar       leia.ollmar@sll.se   
Principal Investigator: Johan Hansson, Prof.         
Sub-Investigator: Hanna Eriksson, MD PhD         
Sponsors and Collaborators
The Netherlands Cancer Institute
Bristol-Myers Squibb
Investigators
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Study Chair: Christian Blank, Prof. Medical oncologist/researcher

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: The Netherlands Cancer Institute
ClinicalTrials.gov Identifier: NCT02977052     History of Changes
Other Study ID Numbers: M16OPN
2016-001984-35 ( EudraCT Number )
CA209-701 ( Other Identifier: Bristol-Myers Squibb )
First Posted: November 30, 2016    Key Record Dates
Last Update Posted: November 6, 2018
Last Verified: November 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by The Netherlands Cancer Institute:
Melanoma
Ipilimumab
Nivolumab
Neo-adjuvant
Additional relevant MeSH terms:
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Melanoma
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas
Nivolumab
Ipilimumab
Antineoplastic Agents, Immunological
Antineoplastic Agents