Overview
This is an open-label phase 1 study with an escalation part and an expansion part.
Description
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.
Eligibility
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:
1. Patient must provide archived tissue sample or biopsy for FGF19 overexpression
central lab testing, and the result must be positive
2. Patient must have at least 1 measurable lesion (RECIST V1.1)
3. Child-Pugh score 5~7 without hepatic encephalopathy, no clinically apparent
ascites or require medical intervention
3. ECOG performance status 0~1
4. Life expectancy ≥ 3 months
5. 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):
1. Absolute neutrophil count (ANC) ≥1.5×109/L
2. Platelet count (PLT) ≥75×109/L
3. Hemoglobin (Hb) ≥80 g/L
4. Total bilirubin (TBIL) ≤1.5×ULN
5. 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)
6. Serum creatinine (Cr) ≤1.5×ULN or creatinine clearance (Crcl) ≥50 mL/min based on
Cockcroft-Gault formula
6. 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.
7. 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.
8. 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:
1. Known allergy or hypersensitivity to any component of the investigational drug
product.
2. Previous treatment with FGFR4 or pan-FGFR pathway inhibitors (pan-FGFR inhibitors
should be confirmed with the sponsor).
3. Has a known second primary malignancy required active treatment.
4. 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).
5. Liver tumor volume accounts for ≥50% of the whole liver.
6. 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.
7. Severe irritable bowel syndrome requires drug therapy.
8. Prior organ transplantation requires anti-rejection drug therapy.
9. 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).
10. 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.
11. 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.
12. Impaired cardiac function or clinically significant cardiac disease, including any one
of the following:
1. 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;
2. Clinically significant cardiac arrhythmia requiring active therapy;
3. Uncontrolled hypertension;
4. Left ventricle ejection fraction<50%
5. 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.
13. Active infection or unexplained fever > 38.5℃.
14. Active or record of gastrointestinal bleeding within 6 months (e.g. esophageal varices
or ulcer bleeding).
15. 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.
16. History of immunodeficiency, including HIV serum test positive, or other
acquired/congenital immunodeficiency disease, or active tuberculosis.
17. 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