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
- Registration Number
- NCT02988440
- Lead Sponsor
- Novartis Pharmaceuticals
- Brief Summary
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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 20
- 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
- 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description PDR001 + Sorafenib PDR001 PDR001 at 400 mg given intravenously every 4 weeks and sorafenib 400 mg taken orally once or twice per day (escalating doses) PDR001 + Sorafenib Sorafenib PDR001 at 400 mg given intravenously every 4 weeks and sorafenib 400 mg taken orally once or twice per day (escalating doses)
- Primary Outcome Measures
Name Time Method Number of participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) From baseline until 30 days of last dose of study treatment Incidence and severity of AEs and SAEs, including changes in laboratory vital signs and ECGs
Incidendence of Dose Limiting Toxicities (DLTs) During the first 8 weeks of treatment 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.
Dose interruptions Until end of treatment, assessed for a median time of 4 months Tolerability measured by the number of subjects who have interruptions of study treatment
Dose reductions Until end of treatment, assessed for a median time of 4 months Tolerability measured by the number of subjects who have reductions of study treatment
Dose intensity Until end of treatment, assessed for a median time of 4 months Tolerability measured by the dose intensity of study treatment
- Secondary Outcome Measures
Name Time Method Overall Response Rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 as per central radiology assessment by dose level Until end of treatment, assessed for a median time of 4 months 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
PDR001 trough concentration Pre-dose at Cycle 2, 3, 4, 6 , 8, 10, 12 on Day 1. Cycle=28 days Concentration of PDR001 in plasma
Maximum concentration (Cmax) of sorafenib Cycle 3 Day 1 Pre-dose, 1h, 3h and 8 h post-dose. Cycle=28 days The maximum (peak) observed plasma, drug concentration after single dose administration.
Time to reach maximum concentration (Tmax) of sorafenib Cycle 3 Day 1 Pre-dose, 1h, 3h and 8 h post-dose. Cycle=28 days The time to reach maximum (peak) plasma drug concentration after single dose administration (time)
Area under the plasma concentration-time curve of sorafenib from time zero to 8 hours after administration (AUC0-8) 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 time 't' where t is a defined time point after administration. t=8 hours (AUC0-8)
Area Under the Plasma Concentration-time Profile (AUCtau) of sorafenib Cycle 3 Day 1 Pre-dose, 1h, 3h and 8 h post-dose. Cycle=28 days Area under the plasma concentration-time curve from time zero to the end of the dosing interval tau at steady-state
Trial Locations
- Locations (2)
Karmanos Cancer Institute
🇺🇸Detroit, Michigan, United States
Novartis Investigative Site
🇨🇳Taipei, Taiwan