Study of Safety and Tolerability of PDR001 in Combination With Sorafenib and to Identify the Maximum Tolerated Dose and/or Phase 2 Dose for This Combination in Advanced Hepatocellular Patients

Study Overview
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Brief Summary
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A two part study to determine the maximum tolerated dose and/or recommended phase 2 dose of PDR001 in combination with sorafenib in patients with advanced hepatocellular carcinoma in first line. There will be a dose escalation part and a dose expansion part.

Official Title
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A Phase Ib Study of PDR001 in Combination With Sorafenib in Patients With Advanced Hepatocellular Carcinoma (HCC)

Conditions
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Hepatocellular Carcinoma

Intervention / Treatment
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* Drug: PDR001
* Drug: Sorafenib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed advanced (unresectable and/or metastatic) HCC Patients with advanced HCC not amenable for surgical or loco-regional treatment At least one measureable tumor lesion that that has not been previously locally Patients with current cirrhotic status of Child-Pugh class A only (5-6 points with total bilirubin < 2 mg/dL for dose-escalation) with no encephalopathy and no clinical ascites (ascites controlled by diuretics is also excluded in this study). Patient has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Patient must meet required laboratory values at the screening Normal electrocardiogram at screening Exclusion Criteria: Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC Invasion of the main portal vein and/or tumor involvement in more than 50% of the liver (applicable only for the dose-escalation part) Patients with Portal-caval shunts Prior or concomitant systemic anti-cancer treatment for advanced disease Systemic chronic steroid therapy (≥ 10mg/day prednisone or equivalent) or any immunosuppressive therapy 7 days prior to planned date for first dose of study treatment. Topical, inhaled, nasal and ophthalmic steroids are allowed. Cardiac or cardiac repolarization abnormality Patients with active Hepatitis B infection (HBsAg positive) that are not receiving antiviral treatment are excluded Patients with positive test for hepatitis C ribonucleic acid (HCV RNA) Loco-regional treatment within 4 weeks prior to initiation of study treatment.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: PDR001 + Sorafenib<br>PDR001 at 400 mg given intravenously every 4 weeks and sorafenib 400 mg taken orally once or twice per day (escalating doses) | Drug: PDR001<br>* PDR001 will be administered intravenously<br>Drug: Sorafenib<br>* Sorafenib is formulated as a tablet.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) | Incidence and severity of AEs and SAEs, including changes in laboratory vital signs and ECGs | From baseline until 30 days of last dose of study treatment | 
| Incidendence of Dose Limiting Toxicities (DLTs) | A dose-limiting toxicity (DLT) was defined as an adverse event or abnormal laboratory value assessed as unrelated to disease progression, inter-current illness, or concomitant medications that met certain criteria as defined in the protocol. | During the first 8 weeks of treatment | 
| Dose interruptions | Tolerability measured by the number of subjects who have interruptions of study treatment | Until end of treatment, assessed for a median time of 4 months | 
| Dose reductions | Tolerability measured by the number of subjects who have reductions of study treatment | Until end of treatment, assessed for a median time of 4 months | 
| Dose intensity | Tolerability measured by the dose intensity of study treatment | Until end of treatment, assessed for a median time of 4 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 as per central radiology assessment by dose level | Overall response rate (ORR) as per the independent central radiology assessment will be summarized descriptively by dose level. The overall response rate (ORR) is defined as the proportion of patients with best overall response of CR or PR. The best overall response is the best response recorded using the independent central radiology review based on RECIST 1.1 from start of treatment until disease progression, death, start of new therapy, withdrawal of consent or cut-off date, whichever occurs first | Until end of treatment, assessed for a median time of 4 months | 
| PDR001 trough concentration | Concentration of PDR001 in plasma | Pre-dose at Cycle 2, 3, 4, 6 , 8, 10, 12 on Day 1. Cycle=28 days | 
| Maximum concentration (Cmax) of sorafenib | The maximum (peak) observed plasma, drug concentration after single dose administration. | Cycle 3 Day 1 Pre-dose, 1h, 3h and 8 h post-dose. Cycle=28 days | 
| Time to reach maximum concentration (Tmax) of sorafenib | The time to reach maximum (peak) plasma drug concentration after single dose administration (time) | Cycle 3 Day 1 Pre-dose, 1h, 3h and 8 h post-dose. Cycle=28 days | 
| Area under the plasma concentration-time curve of sorafenib from time zero to 8 hours after administration (AUC0-8) | Area under the plasma concentration-time curve of sorafenib from time zero to time 't' where t is a defined time point after administration. t=8 hours (AUC0-8) | Cycle 3 Day 1 Pre-dose, 1h, 3h and 8 h post-dose. Cycle=28 days | 
| Area Under the Plasma Concentration-time Profile (AUCtau) of sorafenib | Area under the plasma concentration-time curve from time zero to the end of the dosing interval tau at steady-state | Cycle 3 Day 1 Pre-dose, 1h, 3h and 8 h post-dose. Cycle=28 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HCC, PDR001, Hepatocellular carcinoma, Hepatocellular carcinoma (HCC), liver cancer, immunotherapy liver, malignant hepatoma, Hepatocellular cancer, advanced hepatocellular carcinoma (HCC), advanced liver cancer, liver cancer progression, sorafenib, anti-PD1, first line