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

H3B-6527

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.

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

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

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.

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).

Laboratory assessment included hematology, coagulation, clinical chemistry, and urinalysis parameters.

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.

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).

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).

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.

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.

Eisai Inc.

H3 Biomedicine Inc.

Participants received H3B-6527 300 mg capsule, orally, QD in 21-days cycle in fasted state during treatment phase in dose escalation phase until disease progression, development of unacceptable toxicity, withdrawal of consent, or termination of the participants from the study by the Sponsor.

Part 1, Dose Escalation Phase: H3B-6527 300 mg QD Fasted

Participants received H3B-6527 600 mg capsule, orally, QD in 21-days cycle in fasted state during treatment phase in dose escalation phase until disease progression, development of unacceptable toxicity, withdrawal of consent, or termination of the participants from the study by the Sponsor.

Part 1, Dose Escalation Phase: H3B-6527 600 mg QD Fasted

Participants received H3B-6527 600 mg capsule, orally, QD in 21-days cycle in fed state during treatment phase in dose escalation phase until disease progression, development of unacceptable toxicity, withdrawal of consent, or termination of the participants from the study by the Sponsor.

Part 1, Dose Escalation Phase: H3B-6527 600 mg QD Fed

Participants received H3B-6527 1000 mg capsule, orally, QD in 21-days cycle in fasted state during treatment phase in dose escalation phase until disease progression, development of unacceptable toxicity, withdrawal of consent, or termination of the participants from the study by the Sponsor.

Part 1, Dose Escalation Phase: H3B-6527 1000 mg QD Fasted

Participants received H3B-6527 1000 mg capsule, orally, QD in 21-days cycle in fed state during treatment phase in dose escalation phase until disease progression, development of unacceptable toxicity, withdrawal of consent, or termination of the participants from the study by the Sponsor.

Part 1, Dose Escalation Phase: H3B-6527 1000 mg QD Fed

Participants received H3B-6527 1400 mg capsule, orally, QD in 21-days cycle in fasted state during treatment phase in dose escalation phase until disease progression, development of unacceptable toxicity, withdrawal of consent, or termination of the participants from the study by the Sponsor.

Part 1, Dose Escalation Phase: H3B-6527 1400 mg QD Fasted

Participants received H3B-6527 1400 mg capsule, orally, QD in 21-days cycle in fed state during treatment phase in dose escalation phase until disease progression, development of unacceptable toxicity, withdrawal of consent, or termination of the participants from the study by the Sponsor.

Part 1, Dose Escalation Phase: H3B-6527 1400 mg QD Fed

Participants received H3B-6527 2000 mg capsule, orally, QD in 21-days cycle in fed state during treatment phase in dose escalation phase until disease progression, development of unacceptable toxicity, withdrawal of consent, or termination of the participants from the study by the Sponsor.

Part 1, Dose Escalation Phase: H3B-6527 2000 mg QD Fed

Participants received H3B-6527 500 mg capsule, orally, BID in 21-days cycle in fasted state during treatment phase in dose escalation phase until disease progression, development of unacceptable toxicity, withdrawal of consent, or termination of the participants from the study by the Sponsor.

Part 1, Dose Escalation Phase: H3B-6527 500 mg BID Fasted

Participants received H3B-6527 500 mg capsule, orally, BID in 21-days cycle in fed state during treatment phase in dose escalation phase until disease progression, development of unacceptable toxicity, withdrawal of consent, or termination of the participants from the study by the Sponsor.

Part 1, Dose Escalation Phase: H3B-6527 500 mg BID Fed

Participants received H3B-6527 700 mg capsule, orally, BID in 21-days cycle in fed state during treatment phase in dose escalation phase until disease progression, development of unacceptable toxicity, withdrawal of consent, or termination of the participants from the study by the Sponsor.

Part 1, Dose Escalation Phase: H3B-6527 700 mg BID Fed

Participants received H3B-6527 1000 mg capsule, orally, QD in 21-days cycle either in fasted or fed state during treatment phase in dose expansion phase until disease progression, development of unacceptable toxicity, withdrawal of consent, or termination of the participants from the study by the Sponsor.

Part 2, Dose Expansion Phase: H3B-6527 1000 mg QD

Participants received H3B-6527 500 mg capsule, orally, BID in 21-days cycle in fed state during treatment phase in dose expansion phase until disease progression, development of unacceptable toxicity, withdrawal of consent, or termination of the participants from the study by the Sponsor.

Part 2, Dose Expansion Phase: H3B-6527 500 mg BID Fed

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Full analysis set included all participants who received at least 1 dose of the study drug.

Eisai Medical Information

DLT analysis set included all participants in Dose Escalation phase (Part 1) who must have completed safety assessments through pre-dose on Cycle 2 Day 1 and must have received at least 17 of 21 (approximately 80 percent \[%\]) study days within Cycle 1, unless due to a DLT. This outcome measure was planned to be analyzed for Part 1 only.

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

Participants with TEAEs

Participants with SAEs

Safety analysis set included all participants who received at least 1 dose of the study drug. This outcome measure was planned to be analyzed for Part 1 and Part 2.

Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

Cycle 1 Day 1

Cycle 1 Day 8

Participants received H3B-6527 1000 mg capsule, orally, QD in 21-days cycle in fasted state during treatment phase of dose escalation and expansion phases until disease progression, development of unacceptable toxicity, withdrawal of consent, or termination of the study by the Sponsor.

Parts 1 and 2, Dose Escalation + Expansion Phase: H3B-6527 1000 mg QD Fasted

Participants received H3B-6527 1000 mg capsule, orally, QD in 21-days cycle in fed state during treatment phase of dose escalation and expansion phases until disease progression, development of unacceptable toxicity, withdrawal of consent, or termination of the study by the Sponsor.

Parts 1 and 2, Dose Escalation + Expansion Phase: H3B-6527 1000 mg QD Fed

Participants received H3B-6527 500 mg capsules, orally, BID in 21-days cycle in fed state during treatment phase of dose escalation and expansion phases until disease progression, development of unacceptable toxicity, withdrawal of consent, or termination of the study by the Sponsor.

Parts 1 and 2, Dose Escalation + Expansion Phase: H3B-6527 500 mg BID Fed

Pharmacokinetic (PK) analysis set: Participants who received at least 1 dose of study drug and had at least 1 evaluable plasma concentration. 'Overall Number of participants analyzed' signifies those who were evaluable for this outcome measure; 'Number analyzed' signifies participants who were evaluable at given timepoints. As planned, PK data was collected and reported together due to same dose and food conditions in Part 1 and 2 for H3B-6527 1000 mg (QD fed and fasted) and 500 mg (BID fed).

Area Under the Plasma Concentration-time Curve From Time 0 Through the Last Measurable Point (AUC0-t) of H3B-6527

PK analysis set: Participants who received at least 1 dose of study drug and had at least 1 evaluable plasma concentration. 'Overall Number of participants analyzed' signifies those who were evaluable for this outcome measure; 'Number analyzed' signifies participants who were evaluable at given timepoints. As planned, PK data was collected and reported together due to same dose and food conditions in Part 1 and 2 for H3B-6527 1000 mg (QD fed and fasted) and 500 mg (BID fed).

Maximum Observed Plasma Concentration (Cmax) of H3B-6527

Time of Maximum Observed Plasma Concentration (Tmax) of H3B-6527

Participants with hepatocellular carcinoma (HCC) received H3B-6527 1000 mg capsule, orally, QD in 21-days cycle either in fasted or fed state during treatment phase in dose expansion phase until disease progression, development of unacceptable toxicity, withdrawal of consent, or termination of the participants from the study by the Sponsor.

Participants with HCC received H3B-6527 500 mg capsule, orally, BID in 21-days cycle in fed state during treatment phase in dose expansion phase until disease progression, development of unacceptable toxicity, withdrawal of consent, or termination of the participants from the study by the Sponsor.

Full analysis set included all participants who received at least 1 dose of the study drug. Here, "overall number of participants analyzed" signifies participants who were evaluable for this outcome measure. This outcome measure was planned to be analyzed for Part 2 only.

Part 2, Dose Expansion Phase: Objective Response Rate (ORR) Based on Modified Response Evaluation Criteria in Solid Tumors (mRECIST) v1.1

Participants with HCC received H3B-6527 1000 mg capsule, orally, QD in 21-days cycle either in fasted or fed state during treatment phase in dose expansion phase until disease progression, development of unacceptable toxicity, withdrawal of consent, or termination of the participants from the study by the Sponsor.

Full analysis set included all participants who received at least 1 dose of the study drug. Here, overall number of participants analyzed "N" included the participants who had CR or PR. This outcome measure was planned to be analyzed for Part 2 only.

Part 2, Dose Expansion Phase: Duration of Response (DOR) Based on Modified Response Evaluation Criteria in Solid Tumors (mRECIST) v1.1

Part 2, Dose Expansion Phase: Progression-free Survival (PFS) Based on Modified Response Evaluation Criteria in Solid Tumors (mRECIST) v1.1

Part 2, Dose Expansion Phase: Overall Survival (OS)

Full analysis set included all participants who received at least 1 dose of the study drug. Here, "overall number of participants analyzed" signifies participants who had CR or PR. This outcome measure was planned to be analyzed for Part 2 only.

Part 2, Dose Expansion Phase: Time to Response (TTR) Based on Modified Response Evaluation Criteria in Solid Tumors (mRECIST) v1.1

Hematology

Clinical Chemistry

Urinalysis

Coagulation

Number of Participants With Clinically Significant Change From Baseline in Laboratory Parameters

Number of Participants With Clinically Significant Change From Baseline in Electrocardiogram (ECG) Parameters

Number of Participants With Clinically Significant Change From Baseline in Vital Sign Parameters

Participants received H3B-6527 300 milligram (mg) capsule, orally, once daily (QD) in 21-days cycle in fasted state during treatment phase in dose escalation phase until disease progression, development of unacceptable toxicity, withdrawal of consent, or termination of the participants from the study by the Sponsor.

Participants received H3B-6527 500 mg capsule, orally, twice a day (BID) in 21-days cycle in fasted state during treatment phase in dose escalation phase until disease progression, development of unacceptable toxicity, withdrawal of consent, or termination of the participants from the study by the Sponsor.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Phase 1 Study to Evaluate the Safety, Pharmacokinetics and Pharmacodynamics of H3B-6527 in Participants With Advanced Hepatocellular Carcinoma	NCT02834780	Advanced Hepato... Hepatocellular ... Liver Cancer Liver Neoplasms Hepatic Cancer Hepatic Carcino...	H3B-6527	18 Years -	Eisai Inc.
Phase 1 Study to Evaluate the Safety, Pharmacokinetics and Pharmacodynamics of H3B-6527 in Participants With Advanced Hepatocellular Carcinoma	NCT02834780	Advanced Hepato... Hepatocellular ... Liver Cancer Liver Neoplasms Hepatic Cancer Hepatic Carcino...	H3B-6527	18 Years -	Eisai Inc.

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