A Phase III, Randomized, Controlled, Global Multicenter Study to Evaluate the Efficacy and Safety of Oral Tinengotinib versus Physician’s Choice in Subjects with Fibroblast Growth Factor Receptor (FGFR) altered, Chemotherapy- and FGFR Inhibitor-Refractory/Relapsed Cholangiocarcinoma (FIRST-308)

Prior treatment

• Prior receipt of two or more FGFR inhibitors, either approved or investigational drugs.
• Subjects with uncontrolled hypertension (defined as blood pressure of ≥ 150 mmHg systolic and/or ≥ 90 mmHg diastolic despite adequate treatment with antihypertensive medications at screening).
• Prior receipt of both FOLFOX and FOLFIRI chemotherapy regimens.
• Subjects who have not recovered (grade ≤ 1 or at pretreatment baseline except tolerable grade 2 alopecia, fatigue/asthenia, and neuropathy due to trauma including chemotherapy) from adverse events (AEs) of prior therapy.
• Subjects with known brain or central nervous system (CNS) metastases that have radiologically or clinically progressed in the 28 days prior to initiation of therapy (e.g., evidence of new or enlarging brain metastasis or new neurological symptoms attributable to brain/CNS metastases, no adequate treatment with radiotherapy, symptomatic, requiring treatment with anticonvulsants). Subjects with asymptomatic brain/CNS metastases or treated brain/CNS metastases that have been clinically stable for 14 days on steroids without escalation of steroids are eligible for enrollment.
• Subjects with a known concurrent malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, carcinoma in situ of the cervix, or other noninvasive or indolent malignancy, including those that have previously undergone potentially curative therapy.
• Subjects who have received prior systemic therapy or investigational study drug ≤ 5 half-lives or 14 days, whichever is shorter, prior to starting the study drug.
• Concurrent anticancer therapy including chemo-, immune-, or radiotherapy. Hormone therapy may be allowed with Sponsor approval.
• Subjects who have received wide field radiotherapy ≤ 4 weeks or limited field radiation for palliation ≤ 2 weeks prior to starting the study drug or who have not recovered from AEs of prior therapy.
• Subjects who have undergone major surgery ≤ 4 weeks prior to starting the study drug or who have not recovered from AEs of prior therapy.

Other illness

• Subjects with a fistula, impairment of gastrointestinal function, or gastrointestinal disease that may significantly alter the absorption, metabolism, or excretion of tinengotinib.

Lab values

• Impaired cardiac function or significant diseases, including but not limited to any of the following: • History of congestive heart failure with New York Heart Association (NYHA) Class III or IV. • History of risk factors for Torsades de Pointes (TdP) including hypokalemia, or congenital long QT syndrome, or familial history of prolonged QT syndrome, etc. • QT interval with Fredericia’s correction (QTcF) ≥ 480 msec on screening electrocardiogram (ECG) (If QTcF measurement is not available, please consult with the cardiologist to exclude the risk of TdP). • Unstable angina pectoris ≤ 3 months prior to starting study drug. • Acute myocardial infarction or stroke ≤ 6 months prior to starting study drug. • Cardiac arrhythmia that is unstable requiring antiarrhythmic medical treatment (rate control medication, i.e. beta blockers, are permitted). Subjects with a pacemaker or well-controlled rhythm for at least 1 month prior to the first dose will be allowed.

• ≥ 18 years of age at the time of signing the informed consent form (ICF).
• Must agree to take sufficient contraceptive measures to avoid pregnancy (including male and female subjects) during the study and for at least 3 months after the end of treatment (EOT) for subjects randomized to the tinengotinib arm, and for at least 6 months after the EOT for subjects randomized to Physician’s Choice arm. (Note: for subjects who receive oxaliplatin to be at least 9 months for women of child-bearing potential and 6 months for men; for subjects who receive irinotecan to be at least 6 months for women of child-bearing potential and 3 months for men). Subjects will be considered to be of childbearing potential unless surgically sterile with a hysterectomy and/or bilateral oophorectomy or ≥ 12 months of amenorrhea.
• Life expectancy≥12 weeks.
• Able to understand and sign the ICF and comply with the protocol.
• Histologically or cytologically confirmed CCA/adenocarcinoma of biliary origin with radiological evidence of unresectable or metastatic disease.
• Documentation of presence FGFR2 fusion/rearrangement gene status
• Subjects must have received at least one line of prior chemotherapy and exactly one FGFR inhibitor.
• Radiographically measurable disease per RECIST v1.1, as confirmed by central imagining review (BICR). • At least one target lesion of ≥ 10 mm in the longest diameter for a non lymph node or ≥ 15 mm in the short-axis diameter for a lymph node using computed tomography (CT)/magnetic resonance imaging (MRI). If there is only one target lesion and it is a non-lymph node, it should have the longest diameter of ≥ 15 mm. • A target lesion must not be chosen from a previously irradiated area, unless it is a new lesion that appeared after completion of radiotherapy or show evidence of disease progression after completion of radiotherapy based on RECIST v1.1.
• Must agree to blood collection for liquid biopsy genomic testing.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
• Adequate organ function as evidenced by: • Absolute neutrophil count ≥ 1.5 × 109/L • Hemoglobin ≥ 9 g/dL • Platelet count ≥ 75 × 109/L • Aspartate aminotransferase (AST/SGOT) and alanine aminotransferase (ALT/SGPT) ≤ 2.5 × upper limit of normal (ULN) or ≤ 5.0 × ULN if liver metastases are present • Total bilirubin ≤ 1.5 × ULN; or < 2.5 × ULN if Gilbert syndrome or disease involving liver • Creatinine clearance >30 mL/min (Cockcroft Gault formula) • Adequate blood coagulation function as evidence by an international normalized ratio (INR) ≤ 1.5 unless subject is on anticoagulants