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Study to Identify the Optimal Adjuvant Combination Scheme of Ipilimumab and Nivolumab in Melanoma Patients (OpACIN)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02437279
Recruitment Status : Active, not recruiting
First Posted : May 7, 2015
Last Update Posted : October 19, 2020
Sponsor:
Collaborator:
Bristol-Myers Squibb
Information provided by (Responsible Party):
The Netherlands Cancer Institute

Tracking Information
First Submitted Date  ICMJE April 13, 2015
First Posted Date  ICMJE May 7, 2015
Last Update Posted Date October 19, 2020
Actual Study Start Date  ICMJE November 24, 2016
Actual Primary Completion Date June 28, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 4, 2015)
  • The alteration in magnitude of the neo-antigen specific T cell response in the time interval pre- to post-adjuvant therapy in peripheral blood [ Time Frame: 12 weeks from baseline ]
    To this purpose the immunogenic mutational load of each patient's melanoma will be determined by DNA and RNA sequencing from baseline biopsies (3x14g, 5ug tumor DNA). Proteasomal degradation and peptide presentation in HLA will be predicted in silico. MHC-tetramer staining containing the predicted peptides will be done as described before [2]. In addition, the effect of therapy on intratumoral T cell responses to obtain better insight into the mode of action of therapy will be analyzed. Identified neo-antigen specific T cells will be analyzed with respect to their phenotype and immunologic function (intracellular cytokine staining, lytic function as determined by CD107 staining, and coculture with APC presenting the cognate antigen).
  • Safety as measured by SUSARs. [ Time Frame: 12 weeks from baseline ]
  • The alteration in breadth of the neo-antigen specific T cell response in the time interval pre- to post-adjuvant therapy in peripheral blood [ Time Frame: 12 weeks from baseline ]
    To this purpose the immunogenic mutational load of each patient's melanoma will be determined by DNA and RNA sequencing from baseline biopsies (3x14g, 5ug tumor DNA). Proteasomal degradation and peptide presentation in HLA will be predicted in silico. MHC-tetramer staining containing the predicted peptides will be done as described before [2]. In addition, the effect of therapy on intratumoral T cell responses to obtain better insight into the mode of action of therapy will be analyzed. Identified neo-antigen specific T cells will be analyzed with respect to their phenotype and immunologic function (intracellular cytokine staining, lytic function as determined by CD107 staining, and coculture with APC presenting the cognate antigen).
  • Feasibility as measured adherence to the timelines in the study protocol. [ Time Frame: 12 weeks from baseline ]
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 4, 2015)
  • Recurrence Free Survival, as determined according to RECIST 1.1 criteria. [ Time Frame: Until progression, median 10 months. ]
  • Rate of adverse events and late adverse events [ Time Frame: Until end of follow-up, median 3 years. ]
  • Type of adverse events and late adverse events [ Time Frame: Until end of follow-up, median 3 years. ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study to Identify the Optimal Adjuvant Combination Scheme of Ipilimumab and Nivolumab in Melanoma Patients
Official Title  ICMJE Feasibility Study to Identify the Optimal Adjuvant Combination Scheme of Ipilimumab and Nivolumab in Stage III Melanoma Patients
Brief Summary This is a two-arm Phase 1b feasibility trial consisting of 20 patients receiving the combination of ipilimumab+nivolumab, either adjuvant, or split neo-adjuvant and adjuvant.
Detailed Description

Patients with stage III melanoma with palpable disease, naïve for CTLA-4/PD-1/PD-L1 immunotherapy, will be treated either post-surgery for 12 weeks with the combination of ipilimumab+nivolumab or in a split design for 6 weeks upfront surgery and for 6 weeks postsurgery. It is a two-arm Phase 1b feasibility trial consisting of 20 patients, 10 in each arm.

At different timepoints tumor biopsies and blood for PBMCs will be taken for translational research. Also scans will be done on specific timepoints.

The study will be held to determine safety, feasibility, and the immune-activating capacity of short-term combined neo-adjuvant and adjuvant ipilimumab + nivolumab. And to determine relapse free survival (RFS), any late adverse events, pharmacokinetics/pharmacodynamics, and the correlation between RFS and changes in neo-antigen specific T cell response.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Stage III Skin Melanoma
Intervention  ICMJE
  • Procedure: Surgery of the tumor
  • Drug: Infusion with ipilimumab 3 mg/kg q3wks
  • Drug: Infusion with nivolumab 1 mg/kg q3wks
Study Arms  ICMJE
  • Active Comparator: Arm A
    Post-surgery infusion for 12 weeks with the combination of ipilimumab+nivolumab
    Interventions:
    • Procedure: Surgery of the tumor
    • Drug: Infusion with ipilimumab 3 mg/kg q3wks
    • Drug: Infusion with nivolumab 1 mg/kg q3wks
  • Active Comparator: Arm B
    A split design 6 weeks upfront surgery and 6 weeks post-surgery infusion with the combination of ipilimumab+nivolumab
    Interventions:
    • Procedure: Surgery of the tumor
    • Drug: Infusion with ipilimumab 3 mg/kg q3wks
    • Drug: Infusion with nivolumab 1 mg/kg q3wks
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: May 4, 2015)
20
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 2021
Actual Primary Completion Date June 28, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Adults at least 18 years of age
  • World Health Organization (WHO) Performance Status 0 or 1
  • Histologically confirmed stage IIIB metastatic cutaneous melanoma, palpable disease (non-transit only) of the axilla or groin
  • Patient willing to undergo triple tumor biopsies during screening and in case of disease progression
  • No prior immunotherapy targeting CTLA-4, PD-1 or PD-L1
  • No immunosuppressive medications within 6 months prior study inclusion
  • Presence of at least two of the defined HLA alleles (Table 1, see appendix)
  • 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 contraception. 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 (ie, who are postmenopausal or surgically sterile as well as azoospermic men do not require contraception

Exclusion Criteria:

  • Distantly metastasized melanoma
  • 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 within this trial
  • Patients will be excluded if they are positive test for hepatitis B virus surface antigen (HBVsAg) 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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Netherlands
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02437279
Other Study ID Numbers  ICMJE N14OPC
CA209-278 ( Other Grant/Funding Number: BMS )
NL51280.031.14 ( Registry Identifier: CCMO register )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party The Netherlands Cancer Institute
Study Sponsor  ICMJE The Netherlands Cancer Institute
Collaborators  ICMJE Bristol-Myers Squibb
Investigators  ICMJE
Principal Investigator: Christian Blank, MD PhD The Netherlands Cancer Institute
PRS Account The Netherlands Cancer Institute
Verification Date October 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP