Efficacy and Safety of TT-00420 (Tinengotinib) Tablets Versus Chemotherapy in Patients With Advanced Intrahepatic Cholangiocarcinoma Harboring FGFR2 Fusions/Rearrangements or Mutations

A Phase III, Randomized Controlled, Open-Label, Multicenter Clinical Study Evaluating the Efficacy and Safety of TT-00420 Tablets Versus Chemotherapy in Patients With Surgically Unresectable Advanced or Metastatic Intrahepatic Cholangiocarcinoma Harboring FGFR2 Fusions/Rearrangements or Mutations, Who Have Progressed or Relapsed After Prior First-Line Systemic Therapy

This is an open-label, randomized, controlled, multicenter, phase III clinical study designed to evaluate the efficacy and safety of TT-00420 tablets as monotherapy versus chemotherapy in subjects with unresectable advanced or metastatic intrahepatic cholangiocarcinoma harboring FGFR2 gene fusions/rearrangements or mutations, who have experienced recurrence or progression after prior first-line systemic chemotherapy.

Approximately 138 subjects will be enrolled. Eligible subjects will be randomized in a 2:1 ratio to one of the two arms: Arm A (TT-00420 tablet monotherapy) or Arm B (chemotherapy).

Inclusion Criteria:

1. ≥ 18 years of age at the time of signing the informed consent form (ICF).

2. Histologically or cytologically confirmed intrahepatic cholangiocarcinoma.

3. Subjects diagnosed with stage III or IV intrahepatic cholangiocarcinoma according to the American Joint Committee on Cancer (AJCC) 8th Edition (2018) staging system, and assessed by the investigator as not eligible for curative surgical resection.

4. Subjects who have experienced recurrence or progression after receiving only one prior line of systemic chemotherapy combined with immunotherapy (PD-1/PD-L1 inhibitor), with or without targeted therapy. Sequential immunotherapy following the completion of chemotherapy cycles is also considered part of the first-line combined regimen. First-line systemic chemotherapy is defined as gemcitabine/capecitabine with or without a platinum-based agent.

   Note: Recurrence within 6 months after completion of adjuvant or neoadjuvant therapy will be considered as a line of systemic therapy. Local treatments do not count as systemic therapy.

5. The presence of FGFR2 gene fusion/rearrangement or mutation must be confirmed by detection using tumor tissue samples provided by the patient and analyzed by a central laboratory.

6. At least one radiographically measurable lesion must be present according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.

7. ECOG ≤ 1.

8. Subjects must have adequate organ and bone marrow function.

Exclusion Criteria:

1. Subjects with a history of prior treatment with TT-00420 tablets.
2. Subjects with a known severe allergic reaction to any agent in the study and for whom no alternative study treatment is available.
3. Subjects receiving corticosteroid therapy for CNS metastases are also ineligible.
4. Concurrent active malignancy requiring active treatment. Malignancies diagnosed >5 years ago without the need for treatment, as well as cured localized tumors such as basal cell carcinoma of the skin, carcinoma in situ of the cervix, or papillary thyroid carcinoma, are allowed.
5. Administration of other anti-tumor drugs prior to randomization with an interval of ≤ 5 half-lives or 14 days (whichever is shorter), or failure to recover from adverse events of prior therapies (except for adverse events of ≤ Grade 1, or ≤ Grade 2 events judged by the investigator as not constituting a safety risk).
6. Prior radiation therapy (large-field radiotherapy within 4 weeks, or local palliative radiotherapy within 2 weeks, before randomization), or failure to recover from related adverse events, is excluded. However, initiation of the investigational drug during the washout period is permitted with sponsor approval, if the investigator believes it is in the subject's best interest based on a favorable benefit-risk assessment.
7. Subjects who have undergone major surgery within 4 weeks prior to randomization, or who have not recovered from related adverse events (with the exception of ≤ Grade 1 events or non-risk Grade 2 events per investigator's judgment), are excluded.
8. Subjects with uncontrolled hypertension (defined as blood pressure of ≥ 150 mm Hg systolic and/or ≥ 90 mm Hg diastolic despite adequate treatment with antihypertensive medications at screening).