A Study to Assess Safety, Tolerability, and Pharmacokinetics of ABSK121-NX in Patients With Advanced Solid Tumors

Eligibility Criteria

• 1. Patients should understand, sign, and date the written informed consent form prior to screening
• 2. Male or female age 18 years or older
• 3. Patients with histologically confirmed locally-advanced or metastatic solid tumors who have progressed on, or are intolerant of standard therapy, or for whom no standard therapy exists, or reject standard therapy
• 1. Patients must have the following FGFR genetic alterations based on central laboratory tests or existing test reports of tumor tissue and/or blood:
• 1. Urothelial carcinoma (UC): pre-specified FGFR3 mutations (R248C, S249C, G370C, Y373C) or FGFR2/3 fusions (partner gene is previously described or in frame), or
• 2. Intrahepatic Cholangiocarcinoma (iCCA): FGFR2 fusions or rearrangements which containing an intact kinase domain as follows:
• 2. Patients must have at least one measurable target lesion according to RECIST 1.1
• 1. Urothelial carcinoma: pre-specified FGFR3 mutations (R248C, S249C, G370C, Y373C) or FGFR2/3 fusions (partner gene is previously described or in frame)
• 2. Cholangiocarcinoma: FGFR2 fusions or rearrangements which containing an intact kinase domain as follows:
• * FGFR2 fusions: FGFR2 rearrangements with a literature-derived known partner gene regardless of strand or frame, or FGFR2 rearrangements in the same 5' to 3' orientation and in frame with a novel partner gene
• * FGFR2 rearrangements: FGFR2 rearrangements with one breakpoint in the hotspot region (intron 17-exon 18) and the other breakpoint in an intergenic region or within another gene, or intragenic duplication of the kinase domain (exon 9-17)
• 3. Other tumor types: solid tumors harboring FGFR1-4 alterations including activating mutations, fusions or rearrangements and amplifications, e.g., advanced/metastatic gastric cancer (GC) or gastroesophageal junction (GEJ) carcinoma harboring the FGFR2 amplifications, or iCCA patients or UC patients with other FGFR alterations not mentioned above, are also allowed
• 4. ECOG performance status 0 or 1
• 5. Life expectancy ≥3 months
• 6. 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:
• 1. Absolute neutrophil count (ANC) ≥1.5×109/L (without the use of hematopoietic colony-stimulating growth factors (e.g. G-CSF, GM-CSF, M-CSF) within 7 days before testing)
• 2. Platelet count (PLT) ≥100×109/L (without transfusion within 14 days before testing)
• 3. Hemoglobin (Hb) ≥90 g/L (without transfusion within 7 days before testing)
• 4. Total bilirubin (TBIL) ≤1×ULN
• 5. Aspartate transaminase (AST) and alanine transaminase (ALT) ≤2.5×ULN
• 6. Creatinine clearance (Crcl) ≥60 mL/min based on Cockcroft-Gault formula
• 7. Electrolyte: magnesium within 0.85 to 1.25 × institutional normal limits, sodium ≥130 mmol/L, potassium within institutional normal limits 7. For patients participating exploration of food effect:
• 1. be able to eat a standardized high-fat, high caloric meal within 30 minutes
• 2. be able to fast for 10 hours
• 1. Known allergy or hypersensitivity to any component of the investigational product
• 2. RDE-confirmation in Escalation part: Prior treatment with any FGFR inhibitors
• 3. Expansion part:
• 1. Previously FGFR-inhibitors naive cohorts in UC or iCCA patients: Prior treatment with any FGFR inhibitors
• 2. Other solid tumors cohort: Prior treatment with any FGFR inhibitors
• 4. Has a known additional malignancy that is progressing or has required active treatment.
• 5. Has persistent phosphate level \>ULN during screening (within 14 days prior to the first dose of study treatment) and despite medical management
• 6. Unable to swallow capsules or tablets or malabsorption syndrome, disease significantly affecting GI function, or resection of the stomach or small bowel, symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction. If any of these conditions exist, the site should discuss with the sponsor to determine patient eligibility
• 7. Previous anti-cancer therapy, including chemotherapy (chemotherapy with nitrosourea or mitomycin received ≤ 6 weeks prior to initiation of study treatment), radiotherapy, molecular targeted therapy, antibody therapy or other investigational drugs received ≤4 weeks; endocrine therapy ≤2 weeks or ≤5 half-lives (whichever is shorter) prior to initiation of study treatment
• 8. Major surgery within 4 weeks of the first dose of study drug. Note that all surgical wounds must be healed and free of infection or dehiscence
• 9. 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 alopecia, vitiligo and grade 2 peripheral neurotoxicity
• 10. Potent inhibitors or inducers of CYP3A4 within 2 weeks before the first dose of study treatment (3 weeks for St John's Wort). Refer to https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers for a list of drugs
• 11. Active central nervous system (CNS) metastases including presence of cerebral edema, requirement for systemic steroid treatment, disease progression due to intracranial lesions, leptomeningeal metastasis, and other clinical symptoms related to CNS metastases
• 12. Impaired cardiac function or clinically significant cardiac disease, including any one of the following:
• 1. New York Heart Association class III or IV heart disease, active ischemia or any other uncontrolled cardiac condition such as angina pectoris, clinically significant cardiac arrhythmia requiring therapy, uncontrolled hypertension or congestive heart failure,
• 2. Baseline prolongation of the rate-corrected QT interval based on repeated demonstration of QTcF \>470 ms (average of screening triplicates) or history of long QT interval corrected (QTc) syndrome (Note: QTc interval corrected by Fridericia's formula),
• 3. Left ventricular ejection fraction (LVEF) \<50% or below the institutional lower limit of normal (whichever is higher)
• 13. Known acquired immunodeficiency syndrome (AIDS)-related illness, or positive test for HIV 1/2 antibody
• 14. Exclusion of hepatitis infection based on the following results and/or criteria:
• 1. Active hepatitis B infection: positive tests for hepatitis B surface antigen (HBsAg), or antibody to hepatitis B core antigen (anti-HBc). A patient with positive tests for HBsAg or anti-HBc but with HBV-DNA measurements lower than detectable (or per local practice) can be enrolled,
• 2. Active hepatitis C infection: positive Hepatitis C virus antibody. If positive antibody to hepatitis C Virus (anti-HCV) is detected, Hepatitis C virus RNA by polymerase chain reaction (PCR) is necessary. A patient with positive anti-HCV but with a negative test for HCV RNA can be enrolled
• 15. Any of the following ophthalmological criteria:
• 1. Current evidence or previous history of retinal pigment epithelial detachment (RPED) /Central serous retinopathy (CSR)
• 2. Previous laser treatment or intra-ocular injection for treatment of macular degeneration
• 3. Current evidence or previous history of dry or wet age-related macular degeneration
• 4. Current evidence or previous history of retinal vein occlusion (RVO)
• 5. Current evidence or previous history of retinal degenerative diseases (e.g., hereditary)
• 6. Diabetic retinopathy with macular edema
• 7. Current evidence or previous history of any other clinically relevant chorioretinal defect
• 8. Uncontrolled glaucoma or intraocular pressure \> 21 mmHg \[after intervention per local standard of care (SOC)\]
• 9. History of systemic disease or ophthalmologic disorders requiring chronic use of ophthalmic steroids
• 10. Evidence of any ongoing ophthalmologic abnormalities or symptoms that are acute (within 4 weeks prior to first dose) or actively progressing
• 11. Current evidence or previous history of corneal pathology such as keratopathy, corneal abrasion or ulceration, or current evidence of conjunctivitis
• 16. Patients with refractory/uncontrolled ascites or pleural effusion
• 17. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive human chorionic gonadotropin (hCG) laboratory test within 7 days prior to the start of study drug
• 18. Non-surgically sterilized male or female patients of childbearing potential must agree to use highly effective methods of birth control during the study and for approximately 6 months after the last dose of study drug. A condom is also required to be used by vasectomized men to prevent delivery of the drug via seminal fluid
• 19. Vaccination with a live, attenuated vaccine within 4 weeks prior to the first dose of study treatment except for administration of inactivate vaccines (e.g., COVID-19 vaccines, inactivated influenza vaccines)
• 20. Any other clinically significant comorbidities, such as uncontrolled pulmonary disease, active infection, or any other condition, 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
• 21. Planned major surgery during study treatment