Phase Ib/II Study of INC280 + PDR001 or PDR001 Single Agent in Advanced HCC

Sponsor

Novartis Pharmaceuticals (Industry)

Overall Status

Completed

CT.gov ID

NCT02795429

Collaborator

(none)

Enrollment

Locations

Arms

60.3

Actual Duration (Months)

5.2

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study of INC280 and PDR001 is to characterize the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and antitumor activity of PDR001 administered i.v. as a single agent or in combination with INC280 administered orally in adult patients with advanced hepatocellular carcinoma (HCC).

Condition or Disease	Intervention/Treatment	Phase
Advanced Hepatocellular Carcinoma	Drug: PDR001 Drug: INC280	Phase 1/Phase 2

Study Design

Study Type:

Interventional

Actual Enrollment :

89 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase Ib/II, Open-label, Multi-center Study of INC280 in Combination With PDR001 or PDR001 Single Agent in Advanced Hepatocellular Carcinoma.

Actual Study Start Date :

Jun 15, 2016

Actual Primary Completion Date :

Jun 1, 2021

Actual Study Completion Date :

Jun 24, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: INC280+PDR001 PDR001 + INC280 treatment in Phase II	Drug: PDR001 PDR001 will be administered intravenously Drug: INC280 INC280 will be administered orally
Experimental: PDR001 single agent PDR001 single agent treatment in Phase II	Drug: PDR001 PDR001 will be administered intravenously

Arm

Intervention/Treatment

Experimental: INC280+PDR001

PDR001 + INC280 treatment in Phase II

Drug: PDR001

PDR001 will be administered intravenously

Drug: INC280

INC280 will be administered orally

Experimental: PDR001 single agent

PDR001 single agent treatment in Phase II

Drug: PDR001

PDR001 will be administered intravenously

Outcome Measures

Primary Outcome Measures

Number of participants with Dose Limiting Toxicities (DLTs) [During the first 2 cycles (42 days) of treatment (Phase Ib)]
To identify the Maximum Tolerated Dose (MTD)/Recommended Phase 2 Dose (RP2D).
Overall response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST v1.1) [From cycle 1, every 6 weeks up to cycle 12, then every 3 cycles until progression of disease per irRC or patient withdrawal, for up to 3 years (Phase II)]

Secondary Outcome Measures

Best overall response (BOR) [From cycle 1, every 6 weeks up to cycle 12, then every 3 cycles until progression of disease per irRC or patient withdrawal, for up to 3 years]
Duration of overall response (DOR) [Baseline, every 6 weeks until progression, for up to 3 years (Phase II)]
Time to response (TTR) [Baseline, every 6 weeks until response (Phase II), for up to 3 years]
Progression-free survival (PFS) [Baseline, every 6 weeks until progression for up to 3 years]
Time to progression (TTP) [Baseline, every 6 weeks until progression for up to 3 years]
Overall survival (OS) [Every 12 weeks until the end of study for up to 3 years]
Overall response rate (ORR) [Baseline, every 6 weeks until progression for up to 3 years (Phase Ib)]
Pharmacokinetics: Area under the plasma concentration versus time curve (AUC) (INC280) [Day 1 of the first 6 cycles]
PK: Area under the serum concentration versus time curve (AUC) (PDR001) [Days 1, 2, 3, 4, 8, 11 and 15 of Cycles 1 and 3, Day 1 of Cycles 2, 4, 5 and 6]
PK: Peak Plasma Concentration (Cmax) (INC280) [Day 1 of the first 6 cycles]
PK:Time of Maximum concentration observed (Tmax) (INC280) [Day 1 of the first 6 cycles]
PK: Peak Serum Concentration (Cmax) (PDR001) [Days 1, 2, 3, 4, 8, 11 and 15 of Cycles 1 and 3, Day 1 of Cycles 2, 4, 5 and 6]
PK: Time of Maximum concentration observed (Tmax) (PDR001) [Days 1, 2, 3, 4, 8, 11 and 15 of Cycles 1 and 3, Day 1 of Cycles 2, 4, 5 and 6]
Quantitation of tumor infiltrating lymphocytes (TILs) [Baseline, 6-9 weeks after start of study treatment (if feasible)]
Quantitation of TILs will be assessed by CD8 immunohistochemistry (IHC) within the tumor area
Programmed death ligand 1 (PD-L1) protein expression in tumor cells [Baseline, 6-9 weeks after start of study treatment (if feasible)]
Expression of PD-L1 will be measured on tumor cells by immunohistochemistry (IHC)

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Histologically or cytologically documented locally advanced recurrent or metastatic HCC or for patients with cirrhosis according to the American Association for the Study of Liver Diseases (AASLD) and Asian Pacific Association for the study of the liver (APASL) criteria. Current cirrhotic status of Child Pugh Class A (5-6 points), with no encephalopathy and/or clinically significant ascites (defined as requiring the use of diuretics or paracentesis treatment).
Patients must have received prior systemic sorafenib treatment for HCC with documented progression during or after discontinuation of sorafenib treatment (for France only: patients must have received at least 8 weeks of prior sorafenib treatment), or are intolerant to sorafenib (defined as documented Grade 3 or 4 adverse events that led to sorafenib discontinuation),.
ECOG Performance Status ≤ 1.
Willing and able to swallow and retain oral medication. Other protocol defined Inclusion criteria may apply.

Exclusion Criteria:

Use of any live vaccines within 4 weeks of initiation of study treatment.
History of severe hypersensitivity reactions to other monoclonal antibodies (mAbs).
Clinically significant pleural effusion that either required pleurocentesis or is associated with shortness of breath.
Active autoimmune disease or a documented history of autoimmune disease.
Clinically significant, uncontrolled heart diseases.
Patient having out of range laboratory values defined as:

Total bilirubin > 2 mg/dL, except for patients with Gilbert's syndrome who are excluded if total bilirubin > 3.0 x ULN or direct bilirubin > 1.5 x ULN
Alanine aminotransferase (ALT) > 5 x ULN
Aspartate aminotransferase (AST) > 5 x ULN
Coagulation: Prothrombin Time (PT) > 4 seconds more than the ULN or International Normalized Ratio (INR) > 1.7
Absolute neutrophil count (ANC) < 1.5 x 109/L
Platelet count < 75 x 109/L
Hemoglobin < 9 g/dL
Creatinine clearance (calculated using Cockcroft-Gault formula, or measured) < 45 mL/min
Asymptomatic serum amylase grade > 2 (1.5-2.0 x ULN). Patients with grade 1 or grade 2 serum amylase at the beginning of the study must be confirmed to have no signs or symptoms suggesting pancreatitis or pancreatic injury (e.g., elevated P-amylase, abnormal imaging findings of pancreas, etc.)
Serum lipase > ULN
Potassium, Magnesium, Phosphorus, total Calcium (corrected for serum albumin) outside of normal limits (patients may be enrolled if corrected to within normal limits with supplements during screening)

Other protocol-defined Exclusion criteria may apply.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Toronto	Ontario	Canada	M5G 2M9
2	Novartis Investigative Site	Montreal	Quebec	Canada	H3T 1E2
3	Novartis Investigative Site	Guangzhou	Guangdong	China	510515
4	Novartis Investigative Site	Shanghai	Shanghai	China	200032
5	Novartis Investigative Site	Montpellier cedex 5	Herault	France	34059
6	Novartis Investigative Site	Lille Cedex		France	59037
7	Novartis Investigative Site	Toulouse Cedex 9		France	31059
8	Novartis Investigative Site	Heidelberg		Germany	69120
9	Novartis Investigative Site	Wuerzburg		Germany	97080
10	Novartis Investigative Site	Hong Kong		Hong Kong
11	Novartis Investigative Site	Milano	MI	Italy	20132
12	Novartis Investigative Site	Rozzano	MI	Italy	20089
13	Novartis Investigative Site	Modena	MO	Italy	41124
14	Novartis Investigative Site	Seoul		Korea, Republic of	03080
15	Novartis Investigative Site	Seoul		Korea, Republic of	03722
16	Novartis Investigative Site	Tainan		Taiwan	70403
17	Novartis Investigative Site	Taipei		Taiwan	10002