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

• ClinicalTrials.gov Identifier: NCT02795429
• Recruitment Status: Active, not recruiting
• First Posted: June 10, 2016
• Last Update Posted: January 13, 2021
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

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 (Clinical Trial)
• Actual Enrollment: 90 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: June 15, 2016
• Estimated Primary Completion Date: March 25, 2021
• Estimated Study Completion Date: March 25, 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

Outcome Measures

Primary Outcome Measures :

1. Number of participants with Dose Limiting Toxicities (DLTs) [ Time Frame: During the first 2 cycles (42 days) of treatment (Phase Ib) ]
   To identify the Maximum Tolerated Dose (MTD)/Recommended Phase 2 Dose (RP2D).
2. Overall response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST v1.1) [ Time Frame: 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 :

1. Best overall response (BOR) [ Time Frame: 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 ]
2. Duration of overall response (DOR) [ Time Frame: Baseline, every 6 weeks until progression, for up to 3 years (Phase II) ]
3. Time to response (TTR) [ Time Frame: Baseline, every 6 weeks until response (Phase II), for up to 3 years ]
4. Progression-free survival (PFS) [ Time Frame: Baseline, every 6 weeks until progression for up to 3 years ]
5. Time to progression (TTP) [ Time Frame: Baseline, every 6 weeks until progression for up to 3 years ]
6. Overall survival (OS) [ Time Frame: Every 12 weeks until the end of study for up to 3 years ]
7. Overall response rate (ORR) [ Time Frame: Baseline, every 6 weeks until progression for up to 3 years (Phase Ib) ]
8. Tiime to progression (TTP) [ Time Frame: Baseline, every 6 weeks until progression for up to 3 years ]
9. Pharmacokinetics: Area under the plasma concentration versus time curve (AUC) (INC280) [ Time Frame: Day 1 of the first 6 cycles ]
10. PK: Area under the serum concentration versus time curve (AUC) (PDR001) [ Time Frame: Days 1, 2, 3, 4, 8, 11 and 15 of Cycles 1 and 3, Day 1 of Cycles 2, 4, 5 and 6 ]
11. PK: Plasma concentration vs. time profiles (INC280) [ Time Frame: Day 1 of the first 6 cycles ]
12. PK:Serum concentration vs. time profiles (PDR001) [ Time Frame: Days 1, 2, 3, 4, 8, 11 and 15 of Cycles 1 and 3, Day 1 of Cycles 2, 4, 5 and 6 ]
13. PK: Peak Plasma Concentration (Cmax) (INC280) [ Time Frame: Day 1 of the first 6 cycles ]
14. PK:Time of Maximum concentration observed (Tmax) (INC280) [ Time Frame: Day 1 of the first 6 cycles ]
15. PK: Peak Serum Concentration (Cmax) (PDR001) [ Time Frame: Days 1, 2, 3, 4, 8, 11 and 15 of Cycles 1 and 3, Day 1 of Cycles 2, 4, 5 and 6 ]
16. PK: Time of Maximum concentration observed (Tmax) (PDR001) [ Time Frame: Days 1, 2, 3, 4, 8, 11 and 15 of Cycles 1 and 3, Day 1 of Cycles 2, 4, 5 and 6 ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. 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).
2. 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),.
3. ECOG Performance Status ≤ 1.
4. Willing and able to swallow and retain oral medication. Other protocol defined Inclusion criteria may apply.

Exclusion Criteria:

1. Use of any live vaccines within 4 weeks of initiation of study treatment.
2. History of severe hypersensitivity reactions to other monoclonal antibodies (mAbs).
3. Clinically significant pleural effusion that either required pleurocentesis or is associated with shortness of breath.
4. Active autoimmune disease or a documented history of autoimmune disease.
5. Clinically significant, uncontrolled heart diseases.

6. 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

Canada, Ontario

Novartis Investigative Site

Toronto, Ontario, Canada, M5G 2M9

Canada, Quebec

Novartis Investigative Site

Montreal, Quebec, Canada, H3T 1E2

China, Guangdong

Novartis Investigative Site

Guangzhou, Guangdong, China, 510515

China, Shanghai

Novartis Investigative Site

Shanghai, Shanghai, China, 200032

France

Novartis Investigative Site

Montpellier cedex 5, Herault, France, 34059

Novartis Investigative Site

Lille Cedex, France, 59037

Novartis Investigative Site

Toulouse Cedex 9, France, 31059

Germany

Novartis Investigative Site

Heidelberg, Germany, 69120

Novartis Investigative Site

Wuerzburg, Germany, 97080

Hong Kong

Novartis Investigative Site

Hong Kong, Hong Kong

Italy

Novartis Investigative Site

Milano, MI, Italy, 20132

Novartis Investigative Site

Rozzano, MI, Italy, 20089

Novartis Investigative Site

Modena, MO, Italy, 41124

Korea, Republic of

Novartis Investigative Site

Seoul, Korea, Republic of, 03080

Novartis Investigative Site

Seoul, Korea, Republic of, 03722

Taiwan

Novartis Investigative Site

Tainan, Taiwan, 70403

Novartis Investigative Site

Taipei, Taiwan, 10002

Sponsors and Collaborators

Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

More Information

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02795429
• Other Study ID Numbers: CINC280X2108; 2015-005417-76 ( EudraCT Number )
• First Posted: June 10, 2016
• Last Update Posted: January 13, 2021
• Last Verified: January 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Novartis ( Novartis Pharmaceuticals ):

Phase Ib/II; INC280; PDR001; checkpoint inhibitor; PD-1; Liver cancer

Additional relevant MeSH terms:

Carcinoma; Carcinoma, Hepatocellular; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Adenocarcinoma; Liver Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Liver Diseases