A Study to Assess the Safety, Tolerability, and Pharmacokinetics of ABSK-011 in Patients With Advanced Solid Tumor

Study Overview
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Brief Summary
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This is an open-label phase 1 study with an escalation part and an expansion part.

Detailed Description
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The escalation part will evaluate the safety, tolerability, PK and recommended dose of expansion (RDE) of oral ABSK-011 in patients with advanced solid tumors. The expansion part of oral ABSK-011 at RDE will be followed for further evaluating safety and tolerability in patients with FGF19 overexpression advanced HCC. Preliminary antitumor activity will also be assessed.

Official Title
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A Phase 1, Open-Label Study of ABSK-011 to Assess Safety, Tolerability, and Pharmacokinetics in Patients With Advanced Solid Tumors

Conditions
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Advanced Liver Cancer

Intervention / Treatment
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* Drug: 60mg ABSK-011capsule
* Drug: 120mg ABSK-011capsule
* Drug: 180mg ABSK-011capsule
* Drug: 240mg ABSK-011capsule
* Drug: 320 mg ABSK-011capsule
* Drug: 400mg ABSK-011capsule


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female, age 18   75 (include both ends, or other age range required by local regulations or IRB). Escalation Part: Patients must have histological or cytological confirmed advanced solid tumors that have progressed on or intolerant to standard therapy or whom no standard therapy exists; and patients with advanced HCC must satisfy: BCLC stage B or C and Child-Pugh score 5 6 Patient must provide archived tissue sample or biopsy for FGF19 overexpression central lab testing Expansion Part: patients must have histological or cytological confirmed, BCLC stage B or C HCC, and have progressed on or intolerant to or have refused to receive or have no access to receive first line systemic therapy (by local guideline/regulation) and is unsuitable for other standard therapy(ies) (by local guideline/regulation) against HCC, and must satisfy: Patient must provide archived tissue sample or biopsy for FGF19 overexpression central lab testing, and the result must be positive Patient must have at least 1 measurable lesion (RECIST V1.1) Child-Pugh score 5 7 without hepatic encephalopathy, no clinically apparent ascites or require medical intervention ECOG performance status 0 1 Life expectancy ≥ 3 months Adequate organ function and bone marrow function as indicated by the following screening assessments performed within 14 days prior to the first dose of study drug (without blood transfusion or medication with stimulation factors within 14 days before 1st dose): Absolute neutrophil count (ANC) ≥1.5×109/L Platelet count (PLT) ≥75×109/L Hemoglobin (Hb) ≥80 g/L Total bilirubin (TBIL) ≤1.5×ULN Aspartate transaminase (AST) and alanine transaminase (ALT), ≤3×ULN (for patient with liver metastasis in escalation part or patient in expansion part: AST and AST ≤5×ULN) Serum creatinine (Cr) ≤1.5×ULN or creatinine clearance (Crcl) ≥50 mL/min based on Cockcroft-Gault formula Patients with HBV infection should follow local clinical practice and anti-HBV therapy should be performed to ensure adequate viral suppression (HBV-DNA < 10000 IU/mL or equivalent copies/mL prior to enrollment). Patients are examined every cycle to monitor HBV-DNA levels. If virus reactivation occurred for patients without anti-viral treatment when enrolled, anti-HBV therapy will be started following local practice. Non-surgically sterilized male or female patients of childbearing potential must agree to use effective methods of birth control during the study and for up to 6 months after the last dose of study drug. Non-surgically sterilized female patients of childbearing potential must in non-lactation period, and have a negative β-HCG test result within 7 days before first administration. Patient should understand, sign, and date the written voluntary informed consent form prior to any protocol-specific procedures performed. Patient should be able and willing to comply with study visits and procedures as per protocol. Exclusion Criteria: Known allergy or hypersensitivity to any component of the investigational drug product. Previous treatment with FGFR4 or pan-FGFR pathway inhibitors (pan-FGFR inhibitors should be confirmed with the sponsor). Has a known second primary malignancy required active treatment. Has a known active central nervous system (CNS) metastases (if stable disease after treatment, free from or daily dexamethasone <10 mg or other equivalent glucocorticoids can be enrolled). Liver tumor volume accounts for ≥50% of the whole liver. Inability to take oral medication or other factors significant preclude adequate absorption of oral medication, such as previously received total gastrectomy, residual gastric dysfunction after subtotal gastrectomy, short bowel syndrome after small bowel resection, active diarrhea required drug treatment, etc. Severe irritable bowel syndrome requires drug therapy. Prior organ transplantation requires anti-rejection drug therapy. Previous anti-cancer therapy prior to initiation of study treatment: major surgery (except palliative therapy), radiotherapy (bone-marrow exposure >30%), routine chemotherapy <4 weeks (chemotherapy with nitrosourea or mitomycin <6 weeks); oral chemotherapy, endocrine therapy, molecular targeted therapy or immunotherapy within ≤ 5 half-life or ≤ 4 weeks (whichever is shorter). Prior toxicities from chemotherapy, radiotherapy, and other anti-cancer therapies, including immunotherapy that have not regressed to Grade ≤1 severity (CTCAE v5.0) with the exception of which inclusion criteria allowed, alopecia, vitiligo and neurotoxicity Grade ≤2 that investigator believe don't affect safety assessment. Concomitant use of strong inhibitors or inducers of CYP3A4 (include grapefruit juice, grapefruit hybrids, pomegranates, starfruit, pomelos, Seville oranges or juice or products) within at least 14 day prior to the first dose of the study drug. Impaired cardiac function or clinically significant cardiac disease, including any one of the following: New York Heart Association class III or IV congestive heart failure, unstable angina, or myocardial infarction within 6 months before administration of the study drug; Clinically significant cardiac arrhythmia requiring active therapy; Uncontrolled hypertension; Left ventricle ejection fraction<50% Prolongation of QTcF (average of three times of examine, male > 450 ms, female > 470 ms) (Note: QTc interval corrected by Frederica's formula) at screening, and other ECG abnormalities with clinical significant by the judge of the investigator. Active infection or unexplained fever > 38.5℃. Active or record of gastrointestinal bleeding within 6 months (e.g. esophageal varices or ulcer bleeding). Patients with active HCV infection (HCV-RNA>103 copies/mL or following local clinical practice) and require concomitant anti-HCV therapy during the study; or HBV HCV co-infection. History of immunodeficiency, including HIV serum test positive, or other acquired/congenital immunodeficiency disease, or active tuberculosis. Any other clinically significant comorbidities, such as respiratory, metabolic, congenital, endocrine or central nervous system disease, or any other medical conditions, mental disturbances or social determinants, which in the judgment of the Investigator, could compromise compliance with the protocol, interfere with the interpretation of study results, or predispose the patient to safety risks

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Other
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Dose escalation study: 60mg QD, 12mg QD, 180mg QD, 240mg QD, 32mg QD，400mg QD. Expansion study will recruit 20 subject in RDE dose level.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ABSK011 60mg cohort<br>60mg cohort：1 patient will first receive a single dose ABSK-011 (run-in period) at Day -2 and be followed by a 1-day off (2 days in all for run-in period) to access the PK of single-dose. Then, the patient will continuously receive ABSK-011 once daily (QD) in repeated 28-day cycles. | Drug: 60mg ABSK-011capsule<br>* Three 20mg capsules,QD for oral administration<br>* Other names: FGFR4 inhibitor;|
| Experimental: ABSK011 120mg cohort<br>all patients will first receive a single dose ABSK-011 (run-in period) at Day -2 and be followed by a 1-day off (2 days in all for run-in period) to access the PK of single-dose. Then, patients will continuously receive ABSK-011 once daily (QD) in repeated 28-day cycles. Dose escalation will employ a 3+3 design except for the patient in the accelerated titration cohort. | Drug: 120mg ABSK-011capsule<br>* One 20mg capsule and one 100mg capsule,QD for oral administration<br>* Other names: FGFR4 inhibitor;|
| Experimental: ABSK011 180mg cohort<br>all patients will first receive a single dose ABSK-011 (run-in period) at Day -2 and be followed by a 1-day off (2 days in all for run-in period) to access the PK of single-dose. Then, patients will continuously receive ABSK-011 once daily (QD) in repeated 28-day cycles. Dose escalation will employ a 3+3 design except for the patient in the accelerated titration cohort. | Drug: 180mg ABSK-011capsule<br>* One 100mg capsule and four 20mg capsules,QD for oral administration<br>* Other names: FGFR4 inhibitor;|
| Experimental: ABSK011 240mg cohort<br>all patients will first receive a single dose ABSK-011 (run-in period) at Day -2 and be followed by a 1-day off (2 days in all for run-in period) to access the PK of single-dose. Then, patients will continuously receive ABSK-011 once daily (QD) in repeated 28-day cycles. Dose escalation will employ a 3+3 design except for the patient in the accelerated titration cohort. | Drug: 240mg ABSK-011capsule<br>* Two 100mg capsules and two 20mg capsules,QD for oral administration<br>* Other names: FGFR4 inhibitor;|
| Experimental: ABSK011 320mg cohort<br>all patients will first receive a single dose ABSK-011 (run-in period) at Day -2 and be followed by a 1-day off (2 days in all for run-in period) to access the PK of single-dose. Then, patients will continuously receive ABSK-011 once daily (QD) in repeated 28-day cycles. Dose escalation will employ a 3+3 design except for the patient in the accelerated titration cohort. | Drug: 320 mg ABSK-011capsule<br>* Three 100mg capsule and one 20mg capsule,QD for oral administration<br>* Other names: FGFR4 inhibitor;|
| Experimental: ABSK011 400mg cohort<br>all patients will first receive a single dose ABSK-011 (run-in period) at Day -2 and be followed by a 1-day off (2 days in all for run-in period) to access the PK of single-dose. Then, patients will continuously receive ABSK-011 once daily (QD) in repeated 28-day cycles. Dose escalation will employ a 3+3 design except for the patient in the accelerated titration cohort. | Drug: 400mg ABSK-011capsule<br>* Four 100mg capsules,QD for oral administration<br>* Other names: FGFR4 inhibitor;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of DLT | Incidence of dose-limiting toxicities (DLTs) in Cycle 1 | From the starting dosing of study drug to the end of Cycle 1 (each cycle is 28 days) in escalation Part | 
| Incidence and severity of AEs, AESIs and SAEs | Incidence and severity of adverse events (AEs), adverse events of special interest (AESIs) and serious adverse events (SAEs) (Common Terminology Criteria for Adverse Events, CTCAE 5.0) | 30 days after last administration, an average of one half year | 
| dose reduction or discontinuation | dose reduction or discontinuation of study drug due to toxicity | through study completion, an average of one half year | 
| physical examinations changes from baseline | BMI | through study completion, an average of one half year | 
| ECOG performance status | ECOG performance status | through study completion, an average of one half year | 
| electrocardiograms (ECGs) | QTc | through study completion, an average of one half year | 
| echocardiograms changes from baseline | EF% | through study completion, an average of one half year | 
| vital signs changes from baseline | Temperature | through study completion, an average of one half year | 
| vital signs changes from baseline | pulse | through study completion, an average of one half year | 
| vital signs changes from baseline | blood pressure | through study completion, an average of one half year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax | maximum observed concentration (Cmax) | the end of Cycle 1 Day15 (each cycle is 28 days) | 
| Tmax | time to maximum observed concentration (Tmax) | the end of Cycle 1 Day15 (each cycle is 28 days) | 
| AUC | area under the concentration-time curve (AUC) | the end of Cycle 1 Day15 (each cycle is 28 days) | 
| t1/2β | elimination half-life (t1/2β) | the end of Cycle 1 Day15 (each cycle is 28 days) | 
| Vz/F | apparent volume of distribution (Vz/F) | the end of Cycle 1 Day15 (each cycle is 28 days) | 
| CL/F | apparent oral clearance (CL/F) | the end of Cycle 1 Day15 (each cycle is 28 days) | 
| Css_max | maximum observed concentration of steady-state (Css_max) | the end of Cycle 1 Day15 (each cycle is 28 days) | 
| Css_min | minimum observed concentration of steady-state (Css_min) | the end of Cycle 1 Day15 (each cycle is 28 days) | 
| AUCss | area under the concentration-time curve of steady-state (AUCss) | the end of Cycle 1 Day15 (each cycle is 28 days) | 
| Rac | accumulation rate (Rac) | the end of Cycle 1 Day15 (each cycle is 28 days) | 
| ORR | Evaluate the preliminary antitumor activity in patients with FGF19 overexpression advanced HCC and in patients with other types of advanced solid tumor | throughout study completion, on average of half year | 
| DoR | Duration of response (DoR): time from [PR] or [CR] to disease progression | throughout study completion, on average of half year | 
| DCR | Disease control rate (DCR): DCR = [CR] +[PR] + stable disease [SD] | throughout study completion, on average of half year | 
| PFS | Progression-free survival (PFS): time from the first day receive study drug to disease progression or death | throughout study completion, on average of half year |