Hepatocellular Carcinoma
Conditions
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.
Interventions
DRUGNivolumab
Intravenous Nivolumab (1mg/kg) will be given every 6 weeks for a maximal period of 6 months within the study.
DRUGIpilimumab
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)
Sponsors
Gustave Roussy, Cancer Campus, Grand Paris
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Phase 1, Dose-Escalation (3+3 design), Open-label, single arm, single-center study, and expansion cohort. DLT will be captured within 1 month after HIA administration. 3 levels of dose of HIA ipilimumab will be tested. Starting by a dose 5 times lower than what is used for IV administration.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Adult Men and women ≥ 18 years old 2. Patient should understand, sign, and date the written informed consent form prior to any protocol-specific procedures performed. 3. 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. 4. Patients must have pathological confirmation of HCC. 5. Patient should be considered as non resectable by Multidisciplinary Team and liver surgeon, and non-eligible for liver transplantation (advanced HCC, BCLC C). 6. 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 7. Patient with active intrahepatic HCC. Part of the disease should not have undergone local treatments (including chemoembolization, or percutaneous targeted therapies). 8. 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. 9. Patients should have measurable disease as defined by mRECIST criteria for response assessment. 10. ECOG status of 0 or 1 (Appendix 2). 11. Life expectancy of ≥ 12 weeks at the time of informed consent per Investigator assessment. 12. Adequate organ function as defined by the following: 1. White blood cells (WBCs) ≥ 2000/mL 2. Neutrophils ≥ 1000/mL 3. Platelets ≥ 75 × 103/mL 4. Hemoglobin ≥ 8.0 g/dL 5. Creatinine \< 1.5 × ULN or creatinine clearance ≥ 40mL/min (Cockcroft-Gault formula) 6. ALT and AST ≤ 3 × ULN or \< 5 x ULN in case of liver metastasis 7. Lipase and amylase ≤ 1.5 × ULN 8. Total bilirubin ≤ 1.5 × ULN 9. Normal thyroid function, or stable on hormone supplementation per investigator assessment 13. Child-Pugh A, Without history of encephalopathy or clinically significant ascites 14. Women of childbearing potential (WOCBP) must have a negative urine or serum β-HCG pregnancy test within 14 days prior inclusion. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. Sexually active female patients must agree to use two methods of effective contraception, one of them being a barrier method, or to abstain from sexual activity during the study and for at least 5 months after last study drug administration or must refrain from heterosexual activity during this same period. 15. Sexually active males patients must agree to use condom during the study and for at least 7 months after the last study treatment administration. Also, it is recommended their women of childbearing potential partner use a highly effective method of contraception for the same duration. 16. Patients shall be eligible to undergo pre-treatment and on-treatment tumor biopsies. Patients who either do not consent to a pre-treatment tumor biopsy or do not have accessible lesions will not be eligible. 17. Resolved acute effects of any prior therapy to baseline severity or NCI CTCAE v5 Grade ≤1 except for AEs not constituting a safety risk by investigator judgment. 18. Patients must be affiliated to a social security system or beneficiary of the same
Exclusion criteria
1. 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. 2. 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-Basedows disease (patients with controlled hyperthyroidism must be negative for thyroglobulin and thyroid peroxidase antibodies and thyroid stimulating immunoglobulin prior to inclusion). 3. 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. 4. Requirement for daily supplemental oxygen 5. 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. 6. A confirmed history of encephalitis, meningitis, or uncontrolled seizures in the year prior to informed consent. 7. 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/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose (MTD) | 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. |
Countries
France
Contacts
Primary ContactLambros Tselikas, MD
Backup ContactThibault RAOULT
Outcome results
None listed