Study of TT-00420 (Tinengotinib) in Subjects With Cholangiocarcinoma Who Failed or Relapsed to Chemotherapy and FGFR Inhibitor

A phase II, open-label, multicenter study to evaluate the efficacy and safety of oral TT-00420 (Tinengotinib) tablets in subjects with cholangiocarcinoma who failed or relapsed to prior treatment of chemotherapy and FGFR Inhibitor.

Approximately 50 subjects will be enrolled. Eligible subjects will receive tinengotinib 10 mg QD orally as the initial dose level in 21-day cycles until confirmed disease progression, intolerable toxicity, death, or withdrawal of consent.

Eligibility Criteria:
Inclusion Criteria:

1. ≥ 18 years of age at the time of signing the informed consent form (ICF).
2. Histologically or cytologically confirmed CCA/adenocarcinoma of biliary origin with radiological evidence of unresectable or metastatic disease.
3. Subjects must have received one or two lines of prior systemic chemotherapy.
4. Documentation of FGFR2 gene alteration and must have failed to prior treatment of exactly one FGFR inhibitor.
5. At least one measurable lesion as defined by RECIST V1.1 criteria for solid tumors.
6. ECOG≤ 1.
7. Adequate organ and bone marrow function(without receiving any hematopoietic growth factor, blood or platelet therapy within 14 days before the first dose).
8. Must agree to take sufficient contraceptive methods to avoid pregnancy during the study and until at least 3 months after ceasing study treatment.
9. Able to sign informed consent and comply with the protocol.

Exclusion Criteria:

1. Subjects with concomitant brain or central nervous system (CNS) metastases and imaging or clinically confirmed progression within 28 days prior to the start of treatment. Brain or central nervous system metastases that not treated with corticosteroids and remain stable within 14 days prior to screening are eligible for enrollment.
2. 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.
3. 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 or who have not recovered (grade ≤ 1 or at pretreatment baseline except tolerable grade 2 alopecia, fatigue/asthenia, and neuropathy due to trauma) from adverse events (AEs) of prior therapy.
4. Concurrent anticancer therapy including chemo-, immune-, or radiotherapy. Hormone therapy may be allowed with Sponsor approval.
5. 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.
6. Subjects who have underwent major surgery or have not recovered from adverse events of surgery within the 4 weeks prior to initiation of the investigational drug (grade ≤ 1 or at pretreatment baseline except tolerable grade 2 alopecia, fatigue/asthenia, and neuropathy due to trauma).
7. Impaired cardiac function or significant diseases.
8. Subjects who have received stable doses of antihypertensive drugs for at least 1 week with uncontrolled hypertension under at screening period (defined as blood pressure of ≥ 150 mm Hg systolic and/or ≥ 90 mm Hg diastolic despite adequate treatment with antihypertensive medications at screening).
9. Subjects who have severe gastrointestinal disease or gastrointestinal dysfunction that may lead to absorption, metabolism or excretion of the study drug, enrollment eligibility will be based on the investigator's judgment (including but not limited to total gastrotomy, short bowel syndrome).
10. Subjects who have bleeding disorders or thrombotic disorders or therapeutic anticoagulant therapy requiring INR monitoring.
11. Subjects who have received a strong CYP3A inhibitor and inducer before starting the study drug, within an interval of ≤ 2 weeks or 5 half-lives (whichever is shorter); (except topical ketoconazole).
12. Tested positive for the human immunodeficiency virus (HIV).
13. Subjects who have an active HBV infection.
14. Subjects who are pregnant or breastfeeding.
15. Subjects who are unable to swallow or tolerate oral medication.
16. The investigator determines that he or she is not eligible for study participation for any clinical or laboratory abnormalities, or any reason that could confuse the study results, interfere with participants' safe participation and compliance with the trial procedure.