A Phase I Study Evaluating Safety and Efficacy of Hepatic Intra-Arterial Administration of Ipilimumab in Combination With Intra-venous Nivolumab for Advanced Hepatocellular Carcinoma
Overview
- Phase
- Phase 1
- Intervention
- Nivolumab
- Conditions
- Hepatocellular Carcinoma
- Sponsor
- Gustave Roussy, Cancer Campus, Grand Paris
- Enrollment
- 27
- Locations
- 1
- Primary Endpoint
- Maximum Tolerated Dose (MTD)
- Status
- Recruiting
- Last Updated
- last year
Overview
Brief Summary
To determine the Maximum Tolerated Dose (MTD), and the recommended Phase 2 dose of HIA Ipilimumab in combination with IV Nivolumab by monitoring the Dose Limiting Toxicity (DLT) within 1 month after IA Ipilimumab administration in dose-escalation phase.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Adult Men and women ≥ 18 years old
- •Patient should understand, sign, and date the written informed consent form prior to any protocol-specific procedures performed.
- •Patient should be able to comply with treatment, PK, and pharmacodynamic sample collection and willing to comply with study visits and procedures as per protocol.
- •Patients must have pathological confirmation of HCC.
- •Patient should be considered as non resectable by Multidisciplinary Team and liver surgeon, and non-eligible for liver transplantation (advanced HCC, BCLC C).
- •Patient who progresses on, or is intolerant to, or has refused standard first line therapy and eligible for receiving IV infusion of Nivolumab and HIA administration of Ipilimumab
- •Patient with active intrahepatic HCC. Part of the disease should not have undergone local treatments (including chemoembolization, or percutaneous targeted therapies).
- •Patients with or without active viral infection (i.e., HCV, HBV) are eligible. Patients with active HBV/HCV are eligible provided they are adequately treated to control the disease.
- •Patients should have measurable disease as defined by mRECIST criteria for response assessment.
- •ECOG status of 0 or 1 (Appendix 2).
Exclusion Criteria
- •Patients with a prior malignancy are excluded, except those with prior malignancies treated more than 2 years previously (at the time of informed consent) with curative intent with no evidence of disease during the interval and who are considered by the Investigator to present a low risk for recurrence, will be eligible.
- •Patients with any active autoimmune disease or history of known or suspected autoimmune disease with the exception of patients with vitiligo, resolved/controlled asthma/atopy, controlled hypoadrenalism or hypopituitarism, and euthyroid patients with a history of Grave-Basedow"s disease (patients with controlled hyperthyroidism must be negative for thyroglobulin and thyroid peroxidase antibodies and thyroid stimulating immunoglobulin prior to inclusion).
- •A known or underlying medical condition that, in the opinion of the Investigator, could make the administration of study drug hazardous to the subject or could adversely affect the ability of the subject to comply with or tolerate study.
- •Requirement for daily supplemental oxygen
- •Any of the following within the 6 months prior to study entry: myocardial infarction, uncontrolled angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack.
- •A confirmed history of encephalitis, meningitis, or uncontrolled seizures in the year prior to informed consent.
- •Positive blood screen for human immunodeficiency virus (HIV) with acquired immunodeficiency syndrome (AIDS). Patients with controlled HIV infection under anti-retroviral therapy and normal CD4+ T-cell counts (\>500/mm3) could be considered eligible by the investigator if the patient fulfills the other inclusion/exclusion criteria.
- •Evidence of active infection that requires systemic antibacterial, antiviral, or antifungal therapy ≤ 7 days prior to inclusion.
- •Any other significant acute or chronic medical illness. Any other sound medical, psychiatric, and/or social reason as determined by the Investigator.
- •Subjects who are unable to undergo and/or tolerate venous AND arterial access (evaluated on pre-treatment imaging)
Arms & Interventions
Patients with hepatocellular carcinoma
1. Intravenous Nivolumab (1mg/kg) will be given every 6 weeks for a maximal period of 6 months within the study. 2. Ipilimumab, single intra-arterial (IA) injection per patient, at 3 dose-levels\*. * (D1) Starting dose : 50 mg; n=3 to 6 * (D2) 2nd dose-level : 100 mg; n=3 to 6 * (D3) Maximal tested dose : 150mg; n=3 to 6 (if no limiting toxicities) \*Dose level (D-1) : 25 mg will be tested if de-escalation is needed at D1 (\>1/3 DLT at D1)
Intervention: Nivolumab
Patients with hepatocellular carcinoma
1. Intravenous Nivolumab (1mg/kg) will be given every 6 weeks for a maximal period of 6 months within the study. 2. Ipilimumab, single intra-arterial (IA) injection per patient, at 3 dose-levels\*. * (D1) Starting dose : 50 mg; n=3 to 6 * (D2) 2nd dose-level : 100 mg; n=3 to 6 * (D3) Maximal tested dose : 150mg; n=3 to 6 (if no limiting toxicities) \*Dose level (D-1) : 25 mg will be tested if de-escalation is needed at D1 (\>1/3 DLT at D1)
Intervention: Ipilimumab
Outcomes
Primary Outcomes
Maximum Tolerated Dose (MTD)
Time Frame: 28 days
To determine the Maximum Tolerated Dose (MTD), and the recommended Phase 2 dose of HIA Ipilimumab in combination with IV Nivolumab by monitoring the Dose Limiting Toxicity (DLT) within 1 month after IA Ipilimumab administration in dose-escalation phase.