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

Stage III Skin Melanoma Clinical Trial

— OpACIN  

Official title:

Feasibility Study to Identify the Optimal Adjuvant Combination Scheme of Ipilimumab and Nivolumab in Stage III Melanoma Patients

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02437279
• Other study ID #: N14OPC
• Secondary ID: CA209-278NL51280
• Status: Active, not recruiting
• Phase: Phase 1
• Start date: November 24, 2016
• Est. completion date: June 2025

Study information

• Verified date: April 2022
• Source: The Netherlands Cancer Institute
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 20
• Est. completion date: June 2025
• Est. primary completion date: June 28, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Melanoma
• Stage III Skin Melanoma

Intervention

Procedure:
• Surgery of the tumor

Drug:
• Infusion with ipilimumab 3 mg/kg q3wks

• Infusion with nivolumab 1 mg/kg q3wks

Locations

Country	Name	City	State
Netherlands	Netherlands Cancer Institute	Amsterdam	NH

Sponsors (2)

Lead Sponsor	Collaborator
The Netherlands Cancer Institute	Bristol-Myers Squibb

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The alteration in magnitude of the neo-antigen specific T cell response in the time interval pre- to post-adjuvant therapy in peripheral blood	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).	12 weeks from baseline
Primary	Safety as measured by SUSARs.		12 weeks from baseline
Primary	The alteration in breadth of the neo-antigen specific T cell response in the time interval pre- to post-adjuvant therapy in peripheral blood	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).	12 weeks from baseline
Primary	Feasibility as measured adherence to the timelines in the study protocol.		12 weeks from baseline
Secondary	Recurrence Free Survival, as determined according to RECIST 1.1 criteria.		Until progression, median 10 months.
Secondary	Rate of adverse events and late adverse events		Until end of follow-up, median 3 years.
Secondary	Type of adverse events and late adverse events		Until end of follow-up, median 3 years.