A Phase Ib/II Study of Fisogatinib(BLU-554) in Subjects With Hepatocellular Carcinoma

A Muti-center, Open-label, Multiple-dose Phase Ib/II Study to Assess the Safety, Tolerability, Pharmacokinetics, Anti-tumor Efficacy of Fisogatinib(BLU-554) in Combination With CS1001 in Subjects With Locally Advanced or Metastatic Hepatocellular Carcinoma (HCC)

This study will evaluate the safety, tolerability, pharmacokinetic and efficacy of fisogatinib (formerly known as BLU-554) in combination with CS1001 in patients with locally advanced or metastatic hepatocellular carcinoma (HCC)

Phase Ib: participants received 400 mg Fisogatinib (BLU-554) once daily (QD), in combination with 1200mg fixed dose Sugemalimab (CS1001) once every 3 weeks (Q3W). Every 21 days (3 weeks) will be considered as one cycle.

Phase Ib: participants received 600 mg Fisogatinib (BLU-554) QD, in combination with 1200mg fixed dose Sugemalimab (CS1001) Q3W. Every 21 days (3 weeks) will be considered as one cycle.

Phase II: participants received 600 mg Fisogatinib (BLU-554) QD, in combination with 1200mg fixed dose Sugemalimab (CS1001) Q3W. Every 21 days (3 weeks) will be considered as one cycle.

Number of DLT (Dose-limiting toxicity) During the Administration of BLU-554 in Combination with CS1001. All toxicity or adverse events (AEs) are graded according to NCI-CTCAE 5.0. Any AE occurring during C1 (21 days) that is not clearly caused by something other than investigational drug.

An AE was any untoward medical occurrence after clinical study subjects receive study drug. An SAE was any event that meets any the following criteria: death, life-threatening; inpatient hospitalization or prolongation, persistent or significant disability/incapacity;congenital malformation/birth defects and significant medical events. AE and SAE were graded by CTCAE version 5.0 by severity, from Grade 1 mild to Grade 5 death related AE.

Safety and tolerance assessments continued for the duration of treatment. AEs and SAEs will be collected from time of signature of main informed consent, throughout the treatment period and including the follow-up period, up to approximate 22 months.

Per Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1 .1) for target lesions and assessed by MRI/ CT: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), > =30% decrease in the sum of the longest diameter of target lesions; Objective Response (OR) = CR + PR. Percentage of subjects who achieve objective tumor response (CR or PR) will be summarized.

Imaging (CT or MRI) assessments per RECIST v1.1 will be performed within 28 days prior to the first dose (baseline assessment), every 9 weeks during the first year of the study, and every 12 weeks thereafter. Up to 22 months.

Disease control rate (DCR) is defined as the proportion of participants who achieve complete response (CR), partial response (PR), and stable disease (SD) based on Response Evaluation Criteria In Solid Tumors (RECIST)v1.1. Per Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1 .1) for target lesions and assessed by MRI/ CT: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), > =30% decrease in the sum of the longest diameter of target lesions. Stable disease(SD) is defined as a tumor that does not meet the criteria for progression or for response.

Imaging (CT or MRI) assessments per RECIST v1.1 will be performed within 28 days prior to the first dose (baseline assessment), every 9 weeks during the first year of the study, and every 12 weeks thereafter. Up to 22 months.

Duration of response for responders (CR or PR) is defined as the time interval between the date of the earliest qualifying response and the date of PD or death for any cause (whichever occurs earlier). For subjects who are alive without progression following the qualifying response, duration of response will be censored on the date of last evaluable tumor assessment or last follow-up for progression of disease.

Imaging (CT or MRI) assessments per RECIST v1.1 will be performed within 28 days prior to the first dose (baseline assessment), every 9 weeks during the first year of the study, and every 12 weeks thereafter. Up to 22 months.

Per Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1 .1) for target lesions and assessed by MRI/ CT: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), > =30% decrease in the sum of the longest diameter of target lesions; Objective Response (OR) = CR + PR. Percentage of subjects who achieve objective tumor response (CR or PR) will be summarized.

Imaging (CT or MRI) assessments per RECIST v1.1 will be performed within 28 days prior to the first dose (baseline assessment), every 9 weeks during the first year of the study, and every 12 weeks thereafter. Up to 22 months.

Overall survival is defined as the time interval between the date of the first investigational product dose to the date of death from any cause

Subject should be followed from time of registration till the time of subject death. Up to 22 months.

Imaging (CT or MRI) assessments by FGF19 protein and PD-L1 protein level will be performed within 28 days prior to the first dose (baseline assessment), every 9 weeks during the first year of the study, and every 12 weeks thereafter. Up to 22 months.

Imaging (CT or MRI) assessments by FGF19 protein and PD-L1 protein level will be performed within 28 days prior to the first dose (baseline assessment), every 9 weeks during the first year of the study, and every 12 weeks thereafter. Up to 22 months.

Progression-free Survival is defined as the time from the date of first study dose to disease progression or death (whichever occurs first).

Imaging (CT or MRI) assessments per RECIST v1.1 will be performed within 28 days prior to the first dose (baseline assessment), every 9 weeks during the first year of the study, and every 12 weeks thereafter. Up to 22 months.

Time to Progression is defined as the time from the date of first study dose to disease progression. Subjects without event (no disease progression) will be censored at the date of "last tumor assessment".

Imaging (CT or MRI) assessments per RECIST v1.1 will be performed within 28 days prior to the first dose (baseline assessment), every 9 weeks during the first year of the study, and every 12 weeks thereafter. Up to 22 months.

An AE was any untoward medical occurrence after clinical study subjects receive study drug. An SAE was any event that meets any the following criteria: death, life-threatening; inpatient hospitalization or prolongation, persistent or significant disability/incapacity;congenital malformation/birth defects and significant medical events. AE and SAE were graded by CTCAE version 5.0 by severity, from Grade 1 mild to Grade 5 death related AE.

Safety and tolerance assessments continued for the duration of treatment. AEs and SAEs will be collected from time of signature of main informed consent, throughout the treatment period and including the follow-up period, up to approximate 22 months.

Pharmacokinetic(PK) parameters of accumulation ratio of Fisogatinib (BLU-554),Rac,AUC. Only participants with evaluable PK results were included in the analysis. Where data is not presented, the PK profiles were non-measurable. Results for Phase Ib and Phase II have been pooled for the same dosage.

For BLU554, Cycle 1 day 1( 0, 0.5 to 24 hour post dose) and Cycle 2 day 1( 0, 0.5 to 24 hour post dose).

Pharmacokinetic Parameters of Area Under the Serum Concentration-time Curve (AUC) of Fisogatinib (BLU-554)

Pharmacokinetic parameters of area under the serum concentration-time curve (AUC0-τ,ss, Time from 0 to 24h) of Fisogatinib (BLU-554). Only participants with evaluable PK results were included in the analysis. Where data is not presented, the PK profiles were non-measurable. Results for Phase Ib and Phase II have been pooled for the same dosage.

For BLU554, Cycle 1 day 1( 0, 0.5 to 24 hour post dose) and Cycle 2 day 1( 0, 0.5 to 24 hour post dose).

Pharmacokinetic Parameters of Clearance at Steady State (Clss) of Fisogatinib (BLU-554). Only participants with evaluable PK results were included in the analysis. Where data is not presented, the PK profiles were non-measurable. Results for Phase Ib and Phase II have been pooled for the same dosage.

For BLU554, Cycle 1 day 1( 0, 0.5 to 24 hour post dose) and Cycle 2 day 1( 0, 0.5 to 24 hour post dose).

PK Parameters of Cmax of Fisogatinib (BLU-554). Only participants with evaluable PK results were included in the analysis. Where data is not presented, the PK profiles were non-measurable. Results for Phase Ib and Phase II have been pooled for the same dosage.

For BLU554, Cycle 1 day 1( 0, 0.5 to 24 hour post dose) and Cycle 2 day 1( 0, 0.5 to 24 hour post dose).

PK Parameters of Tmax of Fisogatinib (BLU-554). Only participants with evaluable PK results were included in the analysis. Where data is not presented, the PK profiles were non-measurable. Results for Phase Ib and Phase II have been pooled for the same dosage.

For BLU554, Cycle 1 day 1( 0, 0.5 to 24 hour post dose) and Cycle 2 day 1( 0, 0.5 to 24 hour post dose).

PK Parameters of Rac, AUC of Sugemalimab (CS1001). Only participants with evaluable PK results were included in the analysis. Where data is not presented, the PK profiles were non-measurable. Results for Phase Ib and Phase II have been pooled for the same dosage.

For CS1001: Cycle 1 day 1(0, 0.5 to 504 hour post dose) and Cycle 4 day 1 (0, 0.5 to 504 hour post dose).

Pharmacokinetic Parameters of Area Under the Serum Concentration-time Curve (AUC ) of Sugemalimab (CS1001)

PK Parameters of (AUC 0-τ,ss ) of Sugemalimab (CS1001). Only participants with evaluable PK results were included in the analysis. Where data is not presented, the PK profiles were non-measurable. Results for Phase Ib and Phase II have been pooled for the same dosage.

For CS1001: Cycle 1 day 1(0, 0.5 to 504 hour post dose) and Cycle 4 day 1 (0, 0.5 to 504 hour post dose).

PK Parameters of CLss of Sugemalimab (CS1001). Only participants with evaluable PK results were included in the analysis. Where data is not presented, the PK profiles were non-measurable. Results for Phase Ib and Phase II have been pooled for the same dosage.

For CS1001: Cycle 1 day 1(0, 0.5 to 504 hour post dose) and Cycle 4 day 1 (0, 0.5 to 504 hour post dose).

PK Parameters of Cmax of Sugemalimab (CS1001). Only participants with evaluable PK results were included in the analysis. Where data is not presented, the PK profiles were non-measurable. Results for Phase Ib and Phase II have been pooled for the same dosage.

For CS1001: Cycle 1 day 1(0, 0.5 to 504 hour post dose) and Cycle 4 day 1 (0, 0.5 to 504 hour post dose).

PK Parameters of Tmax of Sugemalimab (CS1001). Only participants with evaluable PK results were included in the analysis. Where data is not presented, the PK profiles were non-measurable. Results for Phase Ib and Phase II have been pooled for the same dosage.

For CS1001: Cycle 1 day 1(0, 0.5 to 504 hour post dose) and Cycle 4 day 1 (0, 0.5 to 504 hour post dose).

Inclusion criteria: Voluntarily participate in the clinical study. Fully understand and get informed of this study and sign the Informed Consent Form (ICF). ≥18 years of age on day of signing the informed consent. Unresectable locally advanced or metastatic hepatocellular carcinoma as confirmed by histology or cytology. Stage B or C based on Barcelona Clinic Liver Cancer (BCLC) staging system; In case of Stage B, subject must be ineligible for surgery and/or local therapy, or has progressed after surgery and/or local therapy or refuses surgery and/or local treatment. For Phase Ib, subject has failed after or is unsuitable for the standard systemic therapy against HCC. For Phase II, subject has not previously received systemic therapy. At least one measurable lesion as evaluable by RECIST version 1.1. Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0-1 point. A-level Child-Pugh score. Expected survival≥3 months. For Phase Ib and II, fresh or archived tumor tissue should be provided for analysis in the central laboratory. The function of the main organs was basically normal and met the requirements of the protocol. For subject with HCV infection, HCV antiviral treatment with the locally approved and available HCV antiviral therapy can be received. For subjects with HBV infection, HBV DNA ≤ 2,000 IU/ml at Screening. For female subjects of childbearing potential, serum pregnancy test must be negative within 7 days prior to randomization. Except for female subjects who have been recorded as surgically sterilized or who are postmenopausal, female subjects of childbearing potential or male subjects and their partners must agree to use effective contraception from the signature of the informed consent form (ICF) until at least 6 months after the last dose of study drug. Exclusion criteria: tumor thrombus in the main portal vein (VP4) by imaging, involving the inferior vena cava or the heart. Prior history of hepatic encephalopathy. History of liver surgery and/or local treatment for HCC (intervention, ablation therapy, absolute alcohol injection, etc.) or radiotherapy, etc. within 4 weeks prior to first dose. Active or documented gastrointestinal bleeding within 6 months (e.g. esophageal or gastric varices, ulcer bleeding). Presence of ascites detected by physical examination or clinical symptoms caused by ascites during the screening period, or ascites that need for special treatment, such as repeated drainage, intraperitoneal drug infusion, etc. Presence of meningeal metastasis or central nervous system (CNS) metastatic lesions. Subject has clinically significant, uncontrolled cardiovascular disease. History of definite interstitial lung disease or non-infectious pneumonia except that caused by local radiotherapy; history of active tuberculosis. Any serious acute, chronic infections that require systemic antimicrobial, antifungal or antiviral therapy at screening, excluding viral hepatitis. Malabsorption syndrome or inability to take the study drug orally for other reasons. Had primary malignancies other than HCC within 5 years. Subject has had major surgery within 4 weeks prior to first dose (procedures such as central venous cannulation, biopsy, and feeding tube placement are not considered as major surgery). Previously received FGFR4 inhibitor treatment. Blood transfusion, use of hematopoietic stimulating factors [including G-CSF (granulocyte colony stimulating factor), GM-CSF (granulocyte-macrophage colony stimulating factor), EPO (erythropoietin) and TPO (thrombopoietin)] and human albumin preparations within 14 days prior to first dose. Requiring corticosteroids (dose equivalent to > 10 mg/day of Prednisone) or other immunosuppressive drugs within 14 days prior to first dose for systemic therapy. Use of traditional Chinese medicine with anti-liver cancer indication within 14 days prior to the first dose. Subject has received potent CYP3A4 inhibitors and/or inducers within 2 weeks prior to first dose. Concurrent HBV and HCV infection. Subjects with known human immunodeficiency virus (HIV) infection. Lactating women. Subjects with a history of hypersensitivity or hypersensitivity to any of the components of the investigational drug. Circumstances that in the opinion of the investigator would preclude participation in the study. Subjects who are unwilling or unable to follow the study procedures as defined. With the exception of alopecia, all toxicities from prior anticancer therapies and other therapies did not recover to ≤ Grade 1 (per CTCAE v5.0) prior to the first dose of study drug. Subjects who have received prior allogeneic stem cell or solid organ transplantation.