A Trial Evaluating the Safety & Efficacy of Intra-Tumoral Ipilimumab in Combination With Intra-venous Nivolumab in Patients With Metastatic Melanoma

NCT02857569 | Completed Phase 1

• 2 other identifiers: 2015-005429-372015/2334
• Study Type: interventional
• Target: 90
• Locations: 1 country
• Sites: 1

Brief Summary

The study aims to evaluate the 6 month-treatment tolerance defined as the immune related grade 3-4 adverse event-free survival of the combination therapy IT ipilimumab + IV nivolumab. The IV ipilimumab + IV nivolumab (same doses than in Phase I) arm will be used as an internal control to interpret the results obtained in the IT ipilimumab arm.

Conditions

Stage III/IV Melanoma

Outcome Measures

Primary Outcomes (1)

• 6-months treatment-related grade 3-4 toxicity event-free survival (EFS).

  Assessed every 28 days after randomization up to 6 months

Study Arms (2)

Experimental IT Arm

EXPERIMENTAL

* ipilimumab: 0.3mg/kg IT injection every 3 weeks until complete response, eradication of all injectable sites, disease progression or toxicity, for a maximum of 4 doses (to compare back to back to IV standard of care and marketing authorization). * nivolumab: 1mg/kg, IV injection every 3 weeks during IT ipilimumab treatment period and 3mg/kg, IV injection every 2 weeks after IT ipilimumab treatment interruption. Treatment should be continued as long as clinical benefit is observed or until treatment is no longer tolerated by the patient for a maximum of 12 months.

Drug: Ipilimumab IT; Drug: Nivolumab IV

Standard Arm

ACTIVE COMPARATOR

* ipilimumab: 3mg/kg, IV injection every 3 weeks for a maximum of 4 doses as per standard of care and marketing authorization. * nivolumab: 1mg/kg, IV injection every 3 weeks during IV ipilimumab treatment period and 3mg/kg, IV injection every 2 weeks after IV ipilimumab treatment interruption. Treatment should be continued as long as clinical benefit is observed or until treatment is no longer tolerated by the patient for a maximum of 12 months.

Drug: Ipilimumab IV; Drug: Nivolumab IV

Interventions

Ipilimumab IT DRUG

Experimental IT Arm

Ipilimumab IV DRUG

Standard Arm

Nivolumab IV DRUG

Experimental IT Arm; Standard Arm

Eligibility Criteria

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

You may qualify if:

• Men and women \>/= 18 years of age
• Signed and dated written informed consent prior any study related procedure
• Histologically confirmed and clinically or radiologically progressing unresectable Stage III or Stage IV melanoma, as per AJCC staging system
• Patients with at least two lesions:
• At least one injectable tumor lesion (≥1cm3)
• At least one target lesion (measurable lesion as per RECIST 1.1)
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Treatment naïve subjects or patients relapsing after prior local or systemic anticancer therapy. Note that systemic anticancer therapy is permitted if it was completed at least 28 days or 5 times its half life (whichever is shorter) prior to the first study dose, and all related adverse events have either returned to baseline or stabilized.
• Measurable disease by CT or MRI per RECIST 1.1 criteria.
• Recent (less than 3 month) tumor tissue must be provided for patient stratification and biomarker analyses. In order to be equally randomized, a subject must be classified as PDL1 positive, PD-L1 negative, or PD-L1 indeterminate. If an insufficient amount of tumor tissue is available prior to the start of the screening phase, subjects must consent to allow the acquisition of additional tumor tissue for performance of biomarker analyses.
• Subjects with wild-type BRAF. BRAF-mutant can be included only if they have been treated with, or developed toxicity with or refused to be treated with BRAF-and/or MEK-targeted therapy in front-line
• Prior radiotherapy must have been completed at least 2 weeks prior to study drug administration.
• Screening laboratory values must meet the following criteria and should be obtained within 14 days prior to randomization:
• WBC \>/= 2000/μL
• Neutrophils \>/= 1500/μL

You may not qualify if:

• Active brain metastases or leptomeningeal metastases. Subjects with brain metastases or leptomeningeal disease are eligible if these lesions have been treated or if they are asymptomatic and there is no clinical evidence of progression within 28 days prior to first dose of study drug administration. CNS lesions should be monitored bu contrast enhanced MRI at disease assessment timepoints. Justification for allowing patient with CNS disease: whereas tumor-targeting antibodies have limited access to the central nervous system because of the blood brain barrier, immune targeted antibodies can generate a T-cell mediated anti-tumor immune response which I able to cross the blood brain barrier. Indeed, anti-CTLA-4 and anti PD-1 imAbs have shown their ability to induce tumor responses from metastatic sites all over the body, including in the brain
• Ocular melanoma. Distant metastatic relapse of ocular melanoma outside the CNS can be discussed with the study coordinator on a case by case basis.
• Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may increase the risk associated with study participation or study drug administration, impair the ability of the subject to receive protocol therapy, or interfere with the interpretation of study results.
• Prior malignancy active within the previous 3 years except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast.
• Subjects with active, known or suspected autoimmune disease. Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
• Subjects with a condition requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids, and adrenal replacement doses \> 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
• Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell costimulation or immune checkpoint pathways.
• Positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection.
• Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
• History of allergy to study drug components.
• History of severe hypersensitivity reaction to any monoclonal antibody.
• Pregnancy or breastfeeding
• Patients presenting coagulation abnormalities and/or patients requiring concomitant treatment with therapeutic doses of anticoagulants. Prophylactic low dose of anticoagulants for thrombo-embolic events is allowed. Prophylactic anticoagulants shall be stopped during 24h prior and after deep lesion biopsies/injections. No stopping rule for biopsies/injections of skin and sub-cutaneous lesions.

Sponsors & Collaborators

• Gustave Roussy, Cancer Campus, Grand Paris: lead

Study Sites (1)

Gustave Roussy

Villejuif, Val De Marne, 94805, France

Location

MeSH Terms

Interventions

Nivolumab

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 19, 2016
• First Posted: August 5, 2016
• Study Start: December 5, 2016
• Primary Completion: January 1, 2021
• Study Completion: May 20, 2022
• Last Updated: February 15, 2023

Record last verified: 2023-02

Data Sharing

• IPD Sharing: Will not share

Locations

FR (1)