Phase 1 Study to Evaluate the Safety, Pharmacokinetics and Pharmacodynamics of H3B-6527 in Participants With Advanced Hepatocellular Carcinoma

Hepatocellular Carcinoma Clinical Trial

Official title:

An Open-Label Multicenter Phase 1 Study to Evaluate the Safety, Pharmacokinetics and Pharmacodynamics of H3B-6527 in Subjects With Advanced Hepatocellular Carcinoma

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02834780
• Other study ID #: H3B-6527-G000-101
• Secondary ID: 2016-001915-19
• Status: Completed
• Phase: Phase 1
• Start date: December 28, 2016
• Est. completion date: February 23, 2022

Study information

• Verified date: July 2021
• Source: Eisai Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of H3B-6527, and to assess the safety, tolerability and pharmacokinetics of H3B-6527.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 128
• Est. completion date: February 23, 2022
• Est. primary completion date: February 23, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion criteria:

1. Participants with hepatocellular carcinoma.

2. Must have had at least one prior standard-of-care therapy, unless contraindicated.

3. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.

4. Must be willing to undergo a biopsy up to 8 weeks before administration of H3B-6527 on Cycle 1 Day 1 for part 2 (dose expansion).

5. Adequate bone marrow and organ function.

Exclusion criteria:

1. Uncontrolled significant active infections, except hepatitis B virus (HBV) or hepatitis C virus (HCV).

2. Known human immunodeficiency virus infection.

3. Presence of gastric or esophageal varices requiring active treatment.

4. Previous treatment with a selective FGF19-FGFR4 targeted therapy.

5. Females of childbearing potential, or males who have not had a successful vasectomy, who are unable or unwilling to follow adequate contraceptive measures.

6. Hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption.

Related Conditions & MeSH terms

• Advanced Hepatocellular Carcinoma
• Carcinoma
• Carcinoma, Hepatocellular
• Hepatic Cancer
• Hepatic Carcinoma
• Hepatocellular Carcinoma
• Liver Cancer
• Liver Neoplasms

Intervention

Drug:
• H3B-6527
H3B-6527 by mouth once or twice daily at specified doses.

Locations

Country	Name	City	State
Belgium	Universitair Ziekenhuis Gent	Gent
Belgium	UCL Cliniques universitaires Saint-Luc	Woluwe-Saint-Lambert	Brussels
Canada	Cross Cancer Institute	Edmonton	Alberta
Canada	Jurvanski Cancer Center	Hamilton	Ontario
France	Institut Bergonié	Bordeaux
France	Centre Oscar Lambret	Lille
France	Hôpital Haut-Lévêque - CHU de Bordeaux	Pessac
France	Centre Eugène Marquis	Rennes
Italy	IRCCS Istituto Scientifico Romagnolo per lo studio e la cura dei tumori - U.O. di Oncologia Medica	Meldola
Italy	IRCCS Ospedale San Raffaele S.r.l. - PPDS	Milano
Italy	Azienda Ospedaliero Universitaria - Policlinico di Modena	Modena
Korea, Republic of	Asan Medical Center	Seoul
Russian Federation	Altay Regional Oncology Center	Barnaul	Altay, Re
Russian Federation	Russian Oncology Research Center n a N N Blokhin	Moscow
Russian Federation	Omsk Regional Oncology Center	Omsk
Russian Federation	City Clinical Oncology Dispensary	Saint Petersburg
Russian Federation	Railway Clinical Hospital JSC RZhD	Saint Petersburg
Singapore	National University Cancer Insitute	Singapore
Spain	Hospital Universitario de Badajoz	Badajoz
Spain	Hospital Universitario Vall d'Hebron	Barcelona
Spain	General Universitario Gregorio Maranon	Madrid
Spain	Hospital Universitario HM Sanchinarro	Madrid
Spain	START Madrid FJD, Hospital Universitario Fundacion Jimenez Diaz	Madrid
Spain	Clínica Universidad de Navarra	Pamplona	Navarra
Spain	Hospital Universitario Marques de Valdecilla	Santander	Cantabria
Spain	Hospital Universitario Virgen del Rocio	Sevilla
Taiwan	Taichung Veterans General Hospital	Taichung
Taiwan	National Cheng Kung University Hospital	Tainan
United Kingdom	Sarah Cannon Research Institute UK - SCRI - PPDS	London
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Northwestern Unversity	Chicago	Illinois
United States	University of Cincinnati Cancer Institute	Cincinnati	Ohio
United States	Simmons Comprehensive Cancer Center	Dallas	Texas
United States	University of Texas Southwestern Medical Center	Dallas	Texas
United States	Barbara Ann Karmanos Cancer Institute	Detroit	Michigan
United States	Duke University Cancer Center	Durham	North Carolina
United States	John theurer Cancer Center at Hackensack University Medical Center	Hackensack	New Jersey
United States	USC/Norris Comprehensive Cancer Center	Los Angeles	California
United States	Hoag Memorial Hospital Presbyterian	Newport Beach	California
United States	UC Irvine Medical Center	Orange	California
United States	University of Pennsylsvania - Perelman Cancer Center for Advanced Medicine	Philadelphia	Pennsylvania
United States	McGuire VA Medical Center	Richmond	Virginia
United States	UCLA Medical Center	Santa Monica	California
United States	Georgetown Unversity Lombardi Comprehensive Cancer Center	Washington	District of Columbia

Sponsors (2)

Lead Sponsor	Collaborator
H3 Biomedicine Inc.	Eisai Inc.

Countries where clinical trial is conducted

United States,  Belgium,  Canada,  France,  Italy,  Korea, Republic of,  Russian Federation,  Singapore,  Spain,  Taiwan,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Part 1, Dose Escalation Phase: Number of Participants With Dose-limiting Toxicities (DLTs) Based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03	DLTs were defined as any of the following toxicities: Hematology, gastrointestinal, renal, hepatic or nonhematologic toxicities occurring during Cycle 1 in Dose Escalation Phase only and judged by the investigator as related to study drug. This included any Grade 4: neutropenia that does not resolve to Grade less than or equal to (<=) 2 within 7 days, thrombocytopenia, anemia of any duration, diarrhea and/or vomiting irrespective of prophylaxis or appropriate treatment; Grade 3: thrombocytopenia requiring transfusion, thrombocytopenia and clinically significant bleeding, anemia if transfused or if lasting for more than 7 days, nausea, vomiting and/or diarrhea lasting more than 72 hours despite the use of optimal anti-emetic/antidiarrheal treatment, bilirubin, fatigue lasting less than 1 week, elevations in biochemistry laboratory values without associated clinical symptoms that last for <=7 days; Grade greater than or equal to (>=) 3 serum creatinine.	Cycle 1 (Cycle length = 21 days)
Primary	Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)	A TEAE was defined as an adverse event (AE) that emerges during treatment, having been absent at pretreatment (Baseline) or reemerges during treatment, having been present at pretreatment (Baseline) but stopped before treatment, or worsens in severity during treatment relative to the pretreatment state, when the AE was continuous. An SAE was any untoward medical occurrence that at any dose: Resulted in death, was life-threatening (that is, the participant was at immediate risk of death from the AE as it occurred; this does not include an event that, had it occurred in a more severe form or was allowed to continue, might have caused death), required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect (in the child of a participant who was exposed to the study drug).	From the first dose of study drug up to approximately 36.7 months
Primary	Number of Participants With Clinically Significant Change From Baseline in Laboratory Parameters	Laboratory assessment included hematology, coagulation, clinical chemistry, and urinalysis parameters.	From baseline up to approximately 36.7 months
Primary	Number of Participants With Clinically Significant Change From Baseline in Electrocardiogram (ECG) Parameters		From baseline up to approximately 36.7 months
Primary	Number of Participants With Clinically Significant Change From Baseline in Vital Sign Parameters		From baseline up to approximately 36.7 months
Secondary	Area Under the Plasma Concentration-time Curve From Time 0 Through the Last Measurable Point (AUC0-t) of H3B-6527		Part 1, Cycle 1 Day 1 and Day 8: 0-24 hours post-dose (for QD dosing) and 0-10 hours post-dose (for BID dosing); Part 2, Cycle 1 Day 8: 0-24 hours post-dose (for QD dosing) and 0-10 hours post-dose (for BID dosing) (Cycle 1 length = 21 days)
Secondary	Maximum Observed Plasma Concentration (Cmax) of H3B-6527		Part 1, Cycle 1 Day 1 and Day 8: 0-24 hours post-dose (for QD dosing) and 0-10 hours post-dose (for BID dosing); Part 2, Cycle 1 Day 8: 0-24 hours post-dose (for QD dosing) and 0-10 hours post-dose (for BID dosing) (Cycle 1 length = 21 days)
Secondary	Time of Maximum Observed Plasma Concentration (Tmax) of H3B-6527		Part 1, Cycle 1 Day 1 and Day 8: 0-24 hours post-dose (for QD dosing) and 0-10 hours post-dose (for BID dosing); Part 2, Cycle 1 Day 8: 0-24 hours post-dose (for QD dosing) and 0-10 hours post-dose (for BID dosing) (Cycle 1 length = 21 days)
Secondary	Part 2, Dose Expansion Phase: Objective Response Rate (ORR) Based on Modified Response Evaluation Criteria in Solid Tumors (mRECIST) v1.1	ORR was defined as the percentage of participants achieving a best overall confirmed response of partial response (PR) or complete response (CR) (PR + CR), from the first dose date until disease progression/recurrence. Responses (PR or CR) were confirmed no less than 4 weeks after the initial response. CR was defined as the disappearance of all target lesions and non-target lesions. Any pathological lymph nodes (target or non-target) had to be reduced in the short axis to less than 10 millimeter (mm). PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. The tumor assessment was done using number of lesions based on modified RECIST v1.1 for assessing tumor burden up to 10 target lesions with up to 5 target lesions per organ.	From the first dose date until disease progression/recurrence or up to approximately 36.7 months
Secondary	Part 2, Dose Expansion Phase: Duration of Response (DOR) Based on Modified Response Evaluation Criteria in Solid Tumors (mRECIST) v1.1	DOR was defined as the time from the date of first documented CR or PR based on modified RECIST v1.1 until the first documentation of disease progression (PD) as determined by the investigator or death, whichever comes first. CR was defined as the disappearance of all target lesions and non-target lesions. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. PD was defined as at least a 20% increase in the sum of long diameter (LD) of target and non-target lesions as compared with the smallest sum of LD and the increase of LD was at least 5 mm (including new lesions).	From the date of first documented CR or PR up to approximately 36.7 months
Secondary	Part 2, Dose Expansion Phase: Progression-free Survival (PFS) Based on Modified Response Evaluation Criteria in Solid Tumors (mRECIST) v1.1	PFS was defined as the time from the first dose date to the date of the first documentation of PD as determined by the investigator or death (whichever occurs first). PD was defined as at least a 20% increase in the sum of LD of target and non-target lesions as compared with the smallest sum of LD and the increase of LD was at least 5 mm (including new lesions).	From the first dose date to the date of the first documentation of PD as determined by the investigator or death (whichever occurs first) up to approximately 36.7 months
Secondary	Part 2, Dose Expansion Phase: Overall Survival (OS)	OS was defined as the time from the first dose date to the date of death. OS was assessed using Kaplan-Meier method. The time of death was censored for participants who were without death information at the time of OS analysis.	From the date of first dose of study drug until date of death from any cause (up to approximately 36.7 months)
Secondary	Part 2, Dose Expansion Phase: Time to Response (TTR) Based on Modified Response Evaluation Criteria in Solid Tumors (mRECIST) v1.1	TTR was defined as the time from the first dose date to the date of first documented CR/PR. CR was defined as the disappearance of all target lesions and non-target lesions. Any pathological lymph nodes (target or non-target) had to be reduced in the short axis to less than 10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters.	From date of first dose of study drug until CR or PR (up to approximately 36.7 months)