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

Sponsor

Novartis Pharmaceuticals (Industry)

Overall Status

Completed

CT.gov ID

NCT02988440

Collaborator

(none)

Enrollment

Locations

Arm

34.3

Actual Duration (Months)

2.2

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Hepatocellular Carcinoma	Drug: PDR001 Drug: Sorafenib	Phase 1

Study Design

Study Type:

Interventional

Actual Enrollment :

20 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Apr 20, 2017

Actual Primary Completion Date :

Feb 27, 2020

Actual Study Completion Date :

Feb 27, 2020

Arms and Interventions

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

Arm

Intervention/Treatment

Other: PDR001 + Sorafenib

PDR001 at 400 mg given intravenously every 4 weeks and sorafenib 400 mg taken orally once or twice per day (escalating doses)

Drug: PDR001

PDR001 will be administered intravenously

Drug: Sorafenib

Sorafenib is formulated as a tablet.

Outcome Measures

Primary Outcome Measures

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

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Karmanos Cancer Institute	Detroit	Michigan	United States	48201
2	Novartis Investigative Site	Montreal	Quebec	Canada	H3T 1E2
3	Novartis Investigative Site	Essen		Germany	45147
4	Novartis Investigative Site	Hong Kong		Hong Kong
5	Novartis Investigative Site	Rozzano	MI	Italy	20089
6	Novartis Investigative Site	Kashiwa	Chiba	Japan	277 8577
7	Novartis Investigative Site	Yokohama city	Kanagawa	Japan	232 0024
8	Novartis Investigative Site	Pamplona	Navarra	Spain	31008
9	Novartis Investigative Site	Taipei		Taiwan	10002