Clinical Study of ICP-192 in Solid Tumors Patients

A Phase I/IIa, Multicenter, Open-Label Study to Assess the Safety, Tolerability, Pharmacokinetics of ICP-192 in Patients With Advanced Solid Malignancies

Open-label, non-randomized, Phase I/IIa, dose-escalating, dose-extension, first-in-man study.

The study consisted of a screening period, a treatment period with 21 days of repeated treatment per cycle (duration treatment with ICP-192), and a follow-up period (28 days after last dose). The recruited patients receive a single dose on day 1, then after a 3-day washout period, repeated dosing will be followed. The starting dose is 2 mg, QD, and dose escalation will follow accelerated titration and modified 3+3 dose-finding schema. The dose-limiting toxicity (DLT) assessment period consisted of Cycle 0 (single dose and washout period) and Cycle 1 (21-day cycle).

Inclusion Criteria:

1. An unresectable or metastatic advanced malignant solid tumor confirmed by histopathology that has failed to respond to known treatment or has recurred;Subjects who progress under standard treatment, are intolerant to standard treatment, or do not have standard treatment (dose escalation phase)

2. Tissue or cell pathology confirmed unresectable, recurrent or metastatic (AJCC version 8 TNM staging IV (2017), biliary tract malignant tumor, or intolerance to first-line chemotherapy failure (twice (defined as reduction still cannot tolerate) first-line chemotherapy, neoadjuvant/progress/adjuvant chemotherapy after 6 months recurrence can be selected (dose extension stage); - At least one evaluable disease according to RECIST1.1

3. FGFR2 translocation/fusion has been reported or FGFR2 translocation/fusion has been detected in central laboratory (dose extension phase);

4. Age ≥18 and ≤75

5. There is at least one evaluable lesion according to RECIST1.1 criteria

6. ECOG strength score is 0-1 (dose escalation stage), and ECOG strength score is 0-2 (dose expansion stage).

7. The expected survival time is more than 3 months

8. The organ function level must meet the following requirements (subject to the upper limit of normal value in the clinical trial center):

   A) bone marrow: absolute count of neutrophils (ANC)≥1.5*109/L (1500/mm3), platelet ≥75*109/L, hemoglobin ≥9g/dL; B) coagulation function: international standardized ratio of prothrombin time and partial thrombin time <1.5 times the upper limit of normal value; C) liver: serum bilirubin ≤1.5 times the upper limit of normal value (tumor involvement in the liver ≤2.5 times the upper limit of normal value), aspartic aminotransferase (AST) and alanine aminotransferase (ALT)≤3 times the upper limit of normal value (AST and ALT≤5 times the upper limit of normal value in the case of liver metastasis); D) serum creatinine ≤1.5 times the upper limit of normal value, or creatinine clearance ≥70mL/min (calculated according to the Cockroft-gult formula).

9. Volunteer to enroll and sign informed consent to follow the treatment protocol and visit plan.

Exclusion Criteria:

• Previous treatment with FGFR small molecule inhibitors or antibody drugs.
• Anti-cancer therapy, such as chemotherapy (except for oral fluorouracil), immunotherapy, hormonal, targeted therapy, or investigational agents within four weeks of the first dose of ICP-192, oral fluorouracil agents within two weeks of the first dose of ICP-192.
• Major surgery within 6 weeks of the first dose of ICP-192.
• Blood phosphate persistently above ULN with intervene therapy within two weeks of the first dose of ICP-192.
• Significant GI disorder(s) that could interfere with the absorption, metabolism, or excretion of ICP-192.
• Central nervous system (CNS) metastasis
• Current clinically significant cardiovascular disease including:
• Any class 3 or 4 cardiac disease such as arrhythmia, congestive heart failure or myocardial infarction defined by the New York Heart Association Functional Classification, or left ventricular ejection fraction (LVEF) < 50%, Primary cardiomyopathy, clinical significant QTc prolong history or QTc>470ms (female) QTc>450ms (male)
• Known active bleeding within 2 months of screening or 6 months of bleeding history.
• According to the investigator's judgement, there are evidences of a serious or uncontrollable systemic disease (such as unstable or uncompensated respiratory, liver or kidney disease); or any unstable systemic disease (including active clinically serious infections, uncontrolled hypertension, liver and kidney or metabolic diseases)
• History of interstitial pneumonia, deep vein thrombosis, pulmonary embolism. Stroke or intracranial hemorrhage within 6 months before the first dose of ICP-192.
• History of organ transplantation and allogeneic hematopoietic stem cell transplantation.
• Any corneal or retinal abnormalities that may increase ocular toxicity, including but not limited to:
• History of central serous retinopathy (CSR) or retinal vein occlusion (RVO) disease or has related diseases;
• Active age-related macular degeneration (AMD);
• Diabetic retinopathy with macular edema;
• Uncontrollable glaucoma;
• Keratonosus, such as Keratitis, keratoconjunctivitis, keratopathy, corneal wear, inflammation or ulceration.
• Known active infection with HBV, HCV or HIV or any uncontrolled active systemic infection
• Any toxicities must recover to ≤ Grade 1 from prior anti-cancer therapy (excluding alopecia, nausea and vomiting).
• Lactating or pregnant women, or women who will not use contraception during the study and for 180 days after the last dose of study drug if sexually active and able to bear children.
• Investigators believe that the patients are not eligible for enrollment for the other reasons.