Clinical trial NCT04194801: A Phase Ib/II Study of Fisogatinib(BLU-554) in Subjects With Hepatocellular Carcinoma
Official title: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Hepatocellular Carcinoma
Lead sponsor: CStone Pharmaceuticals
Sponsor class: INDUSTRY
Collaborators: name: Blueprint Medicines Corporation
First posted: 2019-12-11
Enrollment: 26
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: 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)


Eligibility criteria: Inclusion criteria:

1. Voluntarily participate in the clinical study. Fully understand and get informed of this study and sign the Informed Consent Form (ICF).
2. ≥18 years of age on day of signing the informed consent.
3. Unresectable locally advanced or metastatic hepatocellular carcinoma as confirmed by histology or cytology.
4. 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.
5. 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.
6. At least one measurable lesion as evaluable by RECIST version 1.1.
7. Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0-1 point.
8. A-level Child-Pugh score.
9. Expected survival≥3 months.
10. For Phase Ib and II, fresh or archived tumor tissue should be provided for analysis in the central laboratory.
11. The function of the main organs was basically normal and met the requirements of the protocol.
12. For subject with HCV infection, HCV antiviral treatment with the locally approved and available HCV antiviral therapy can be received.
13. For subjects with HBV infection, HBV DNA ≤ 2,000 IU/ml at Screening.
14. 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:

1. tumor thrombus in the main portal vein (VP4) by imaging, involving the inferior vena cava or the heart.
2. Prior history of hepatic encephalopathy.
3. 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.
4. Active or documented gastrointestinal bleeding within 6 months (e.g. esophageal or gastric varices, ulcer bleeding).
5. 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.
6. Presence of meningeal metastasis or central nervous system (CNS) metastatic lesions.
7. Subject has clinically significant, uncontrolled cardiovascular disease.
8. History of definite interstitial lung disease or non-infectious pneumonia except that caused by local radiotherapy; history of active tuberculosis.
9. Any serious acute, chronic infections that require systemic antimicrobial, antifungal or antiviral therapy at screening, excluding viral hepatitis.
10. Malabsorption syndrome or inability to take the study drug orally for other reasons.
11. Had primary malignancies other than HCC within 5 years.
12. 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).
13. Previously received FGFR4 inhibitor treatment.
14. 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.
15. Requiring corticosteroids (dose equivalent to \> 10 mg/day of Prednisone) or other immunosuppressive drugs within 14 days prior to first dose for systemic therapy.
16. Use of traditional Chinese medicine with anti-liver cancer indication within 14 days prior to the first dose.
17. Subject has received potent CYP3A4 inhibitors and/or inducers within 2 weeks prior to first dose.
18. Concurrent HBV and HCV infection.
19. Subjects with known human immunodeficiency virus (HIV) infection.
20. Lactating women.
21. Subjects with a history of hypersensitivity or hypersensitivity to any of the components of the investigational drug.
22. Circumstances that in the opinion of the investigator would preclude participation in the study.
23. Subjects who are unwilling or unable to follow the study procedures as defined.
24. 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.
25. Subjects who have received prior allogeneic stem cell or solid organ transplantation.

Primary outcomes:
measure: Phase Ib: Patients With Event(s) of Dose-limiting Toxicity
timeFrame: Cycle 1 (21 days) of treatment
measure: Phase Ib: Safety and Tolerance
timeFrame: 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.
measure: Phase II: Objective Response Rate (ORR) Assessed by Investigator Based on RECIST Version 1.1
timeFrame: 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.
Secondary outcomes:
measure: Disease Control Rate Assessed by Investigator
timeFrame: 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.
measure: Duration of Response Assessed by Investigator
timeFrame: 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.
measure: Phase Ib: Objective Response Rate (ORR) Assessed by Investigator Based on RECIST Version 1.1
timeFrame: 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.
measure: Patients With Anti-CS1001 Antibody
timeFrame: Pre-dose of Cycle 1, 2, 4, 5, 7, 10, 13, 16 and every 8 cycles thereafter. Up to 22 months.
measure: Overall Survival
timeFrame: Subject should be followed from time of registration till the time of subject death. Up to 22 months.
measure: Disease Control Rate by PD-L1 Protein Level
timeFrame: 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.
measure: Objective Response Rate (ORR) by PD-L1 Protein Level
timeFrame: 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.
measure: Progression-free Survival Assessed by Investigator
timeFrame: 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.
measure: Time to Progression Assessed by Investigator
timeFrame: 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.
measure: Phase II: Safety and Tolerance
timeFrame: 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.
measure: Pharmacokinetic Parameters of Accumulation Ratio of Fisogatinib (BLU-554)
timeFrame: 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).
measure: Pharmacokinetic Parameters of Area Under the Serum Concentration-time Curve (AUC) of Fisogatinib (BLU-554)
timeFrame: 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).
measure: Pharmacokinetic Parameters of Clearance at Steady State (CLss) of Fisogatinib (BLU-554)
timeFrame: 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).
measure: Pharmacokinetic Parameters of Maximum Serum Concentration (Cmax) of Fisogatinib (BLU-554)
timeFrame: 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).
measure: Pharmacokinetic Parameters of Time to Maximum Serum Concentration (Tmax) of Fisogatinib (BLU-554)
timeFrame: 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).
measure: Pharmacokinetic Parameters of Accumulation Ratio of Sugemalimab (CS1001)
timeFrame: 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).
measure: Pharmacokinetic Parameters of Area Under the Serum Concentration-time Curve (AUC ) of Sugemalimab (CS1001)
timeFrame: 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).
measure: Pharmacokinetic Parameters of Clearance at Steady State (CLss) of Sugemalimab (CS1001)
timeFrame: 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).
measure: Pharmacokinetic Parameters of Maximum Serum Concentration (Cmax) of Sugemalimab (CS1001)
timeFrame: 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).
measure: Pharmacokinetic Parameters of Time to Maximum Serum Concentration (Tmax) of Sugemalimab (CS1001)
timeFrame: 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).
Other outcomes:
Locations:
city: Guangzhou
country: China
facility: Nanfang Hospital,
state: Guangdong
city: Harbin
country: China
facility: Harbin Medical University Cancer Hospital
state: Heilongjiang
city: Shanghai
country: China
facility: Shanghai East Hospital
state: Shanghai
Study officials:
References: