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

Study Overview
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Brief Summary
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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.

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

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

Intervention / Treatment
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* Drug: H3B-6527


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Participants with hepatocellular carcinoma. Must have had at least one prior standard-of-care therapy, unless contraindicated. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1. 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). Adequate bone marrow and organ function. Exclusion criteria: Uncontrolled significant active infections, except hepatitis B virus (HBV) or hepatitis C virus (HCV). Known human immunodeficiency virus infection. Presence of gastric or esophageal varices requiring active treatment. Previous treatment with a selective FGF19-FGFR4 targeted therapy. Females of childbearing potential, or males who have not had a successful vasectomy, who are unable or unwilling to follow adequate contraceptive measures. Hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: H3B-6527 (escalation and expansion)<br>Hepatocellular Carcinoma | Drug: H3B-6527<br>* H3B-6527 by mouth once or twice daily at specified doses.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | 
| 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 | 
| 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 | 
| Number of Participants With Clinically Significant Change From Baseline in Electrocardiogram (ECG) Parameters |  | From baseline up to approximately 36.7 months | 
| Number of Participants With Clinically Significant Change From Baseline in Vital Sign Parameters |  | From baseline up to approximately 36.7 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | 
| 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) | 
| 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) | 
| 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 | 
| 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 | 
| 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 | 
| 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) | 
| 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) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Advanced Hepatocellular Carcinoma, H3B-6527, Fibroblast growth factor receptor 4 (FGFR4), Fibroblast growth factor 19 (FGF19)