Hepatocellular carcinoma
Conditions
Interventions
the third part:It is anticipated that patients will receive at least 1 cycle of BLU?554(subject will take 600mg qd)
no maximum treatment duration has been set. After C1, patients may continue to receive BLU?554 until precluded by toxicity, noncompliance, progressive disease, withdrawal of consent, death, or closure
Sponsors
The Chinese People's Liberation Army 81th Hospital
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Aged =18 years; 2. For Part 1, patient is willing to provide archived tumor tissue (if available) and willing to undergo pre-and on-treatment tumor biopsy (if considered safe and medically feasible by the treating Investigator); 3. Patient has confirmed diagnosis of HCC by histological examination or by noninvasive criteria according to the European Association for the Study of the Liver (EASL) or American Association for the Study of Liver Diseases (AASLD) guidelines (Bruix et al, 2005, Part 1, Part 2, and Part 3), or patient has relapsed or refractory solid tumor other than HCC that has evidence of aberrant FGF19/FGFR4 pathway activity (Part 1 enrichment cohorts ONLY). For Part 1 and Part 2, the patient has unresectable disease and has been previously treated with sorafenib, has declined sorafenib, or does not have access to sorafenib. For Part 3, the patient has not received prior treatment with a TKI. Prior immunotherapy may be allowed upon approval by Medical Monitor; 4. For Part 2 and Part 3, patient has at least one target lesion evaluable by RECIST, version 1.1. 5. For Part 2 and Part 3, all patients must have an FGF19 IHC result available. Only FGF19 IHC+ HCC patients will be eligible for Part 3; 6. Patient has Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1; 7. Patient has a Child-Pugh score of 5 or 6 points (Child-Pugh Class A) with no clinically apparent ascites (Refer to Appendix 1); 8. If patient has HCV infection, must have completed HCV antiviral therapy prior to the first dose of study drug if curative HCV antiviral therapy is indicated and available. In patients with HBV infection, treatment with antiviral therapy is not required prior to enrollment and treatment is permitted during the study, unless it is listed as a prohibited co-medication (see Appendix 3); 9. Patient or legal guardian provides informed consent to participate in the study.
Exclusion criteria
Exclusion criteria: 1. Patient has known central nervous system (CNS) metastases. If patient has had radiotherapy and/or surgery for CNS metastases, is stable neurologically and is not taking corticosteroids, the patient may be enrolled in Part 1 of the study only. Magnetic resonance imaging or CT scan of the brain is only required in those patients suspected to have CNS metastases; 2. Patient has any of the following within 14 days prior to the first dose of study drug: (1) Platelet count 5 × the upper limit of normal (ULN); (5) Total bilirubin >2.5 mg/dL; (6) International normalized ratio (INR) >2.3 or prothrombin time (PT) >6 seconds above control; (7) Estimated (Cockroft-Gault formula) or measured creatinine clearance 450 msec. Patient has a history of prolonged QT syndrome or Torsades de Pointes. Patient has a familial history of prolonged QT syndrome; 4. Patient has clinically significant, uncontrolled, cardiovascular disease including congestive heart failure Grade III or IV according to the New York Heart Association (NYHA) classification; myocardial infarction or unstable angina within the previous 6 months, uncontrolled hypertension, or clinically significant, uncontrolled arrhythmias, including bradyarrhythmias that may cause QT prolongation (e.g.,Type II second degree heart block or third degree heart block); 5. Patient has been confirmed diagnosis of human immunodeficiency virus (HIV); testing is not required; 6. Patient received any anti-cancer therapy within 14 days or 5 half-lives (whichever is shorter) prior to the first dose of study drug; 7. Patient has previously received treatment with a selective FGFR4 inhibitor; 8. Patient received neutrophil growth factor support within 14 days of the first dose of study drug; 9. Patient has received treatment with drugs that are strong CYP3A4 inhibitors and/or inducers within 2 weeks before the start of study drug administration. Please refer to Appendix 3 for a list of these drugs; 10. Patient has had a major surgical procedure within 15 days of the first dose of study drug (procedures such as central venous catheter placement, tumor needle biopsy, and feeding tube placement are not considered major surgical procedures); 11. Patient has undergone prior liver transplantation; 12. Patient has a history of another primary malignancy that has been diagnosed or required therapy within the past year. The following prior malignancies are not exclusionary: completely resected basal cell and squamous cell skin cancer, curatively treated localized prostate cancer, and completely resected carcinoma in situ of any site; 13. Patient is unwilling or unable to comply with scheduled visits, drug administration plan, laboratory tests, or other study procedures and study restrictions; 14. Women who are unwilling, if not postmenopausal or surgically sterile, to abstain from sexual intercourse or employ highly effective contraception during the study drug administration period and for at least 30 days after the last dose of study drug. Men who are unwilling, if not surgically sterile, to abstain from sexual intercourse or employ highly effective contraception during
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| MTD of BLU 554 on qd schedules;RP2D of BLU 554 on qd schedules;MTD of BLU 554 on bid schedules;RP2D of BLU 554 on bid schedules;the type of any AEs;the frequency of any AEs;the severity of any AEs;the timing of any AEs;the relationship to study drug of any AEs;serious adverse events (SAEs);changes in vital signs;ECGs;safety laboratory tests; | — |
Secondary
| Measure | Time frame |
|---|---|
| maximum plasma concentration (Cmax);time to maximum plasma concentration (tmax);area under the plasma concentration versus time curve from 0 to 24 hours (AUC0-24);area under the plasma concentration versus time curve from 0 to 12 hours (AUC0-12) for the bid dosing schedule only;area under the plasma concentration versus time curve from 0 to infinity (AUCinf);terminal half-life;apparent clearance (CL/F);accumulation ratio (R);FGF19 protein levels;FGF19 gene amplification status;changes in FGF19(Part 1 only);changes in cholesterol;changes in bile acid precursors (e.g., 7a hydroxy-4-cholesten-3-one [C4], Part 1 only);changes in alpha fetoprotein;changes in tumor Ki-67;changes in cleaved caspase-3 levels;Overall response rate, defined as the rate of complete response (CR) and partial response (PR);DOR( defined as the rate of CR and stable disease [SD]);CBR( defined as the rate of PR and stable disease [SD]);Progression free survival (PFS), defined as time from first dose to the time of disease progression, or death due to any cause, whichever occurs first (Part 2 and Part 3);Overall survival, defined as time from first dose to the time of death due to any cause (Part 3 only); | — |
Countries
China
Contacts
Public ContactLi Bo
West China Hospital, Sichuan University
Outcome results
None listed