Study of ST-1898 in Locally Advanced or Metastatic Radioiodine-Refractory Differentiated Thyroid Cancer

ST-1898, a multi-targeted tyrosine kinase inhibitor, has demonstrated strong inhibitory activity for VEGFR2, c-MET, AXL, PDGFRA, RET, KIT, etc. The primary purpose of this study is to evaluate the efficacy of ST-1898 tablets in patients with locally advanced or metastatic RAIR-DTC after failure of at least first-line TKI systemic therapy. All subjects will receive ST-1898 180 mg orally once daily until disease progression or intolerable toxicity.


Eligibility Criteria:
Inclusion Criteria:

1. Age \>= 18 years
2. Life expectancy of twelve weeks or more
3. Histologically or cytologically confirmed locally advanced or metastatic DTC that cannot be removed by surgery or radiotherapy, including papillary thyroid cancer, follicular thyroid cancer, hurthle cell thyroid cancer or poorly differentiated thyroid cancer.
4. At least one measurable lesion according to RECIST 1.1
5. Participants must be radioiodine (131I)- refractory / resistant as defined by at least one of the following criteria:

   * One or more measurable lesions that do not demonstrate iodine uptake on any radioiodine scan.
   * One or more measurable lesions that has progressed as per RECIST 1.1 within 14 months of 131I therapy（3.7\~7.4 GBq or100\~200 mCi）,despite demonstration of radioiodine avidity at the time of that treatment by pre- or post-treatment scanning.
   * Cumulative activity of 131I of \> 22 GBq or 600 mCi, with the last dose administered at least 6 months prior to study entry
6. Patients with DTC must have "progressed on" after at least first-line TKI systemic therapy.
7. Tumor tissue sections available (Formalin fixed and paraffin-embedded wax chunks of tumor tissue or unstained specimen).
8. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
9. TSH-suppression therapy is well tolerated with thyroid stimulating hormone (TSH) \< 0.5 mU/L;
10. The patient has adequate organ and bone marrow function as follows:

    * Adequate bone marrow function (without transfusion or growth factor support within 2 weeks): hemoglobin ≥ 90 g/L, absolute neutrophil count (ANC) ≥ 1.5 ×109/L and platelets ≥ 90 × 109/L;
    * Adequate liver function: Bilirubin ≤ 1.5 × upper limit of normal (ULN); Alanine aminotransferase (ALT), and aspartate aminotransferase (AST) ≤ 3 × ULN (≤ 5 × ULN if participant has liver metastases);
    * Adequate renal function: Serum creatinine ≤1.5 ×ULN or creatinine clearance≥50 mL/min per the Cockcroft-Gault formula;
    * Adequate blood coagulation function: International Normalized Ratio (INR) ≤ 1.5 and Activated partial thromboplastin time (APTT) ≤1.5 ULN（except for the prophylactic use of anticoagulants）
    * Adequate cardiac function: Left ventricular ejection fraction (LVEF) ≥50%;
    * Participants having≤ 1 + proteinuria or ≥2+ proteinuria with urine protein \< 1 g/24 hour (h).
11. Ability to understand and the willingness to sign a written informed consent document. The results of routine examination during the corresponding window period before screening are acceptable.
12. Women with child-bearing potential and men must agree to use adequate contraception (e.g., hormonal contraceptives, male or female condom, or abstinence) during the course of the study and for at least 3 months following the last dose of study drug. Women with childbearing potential must have a negative serum pregnancy test within 7 days before first study treatment.

Exclusion Criteria:

1. Other histological subtypes of thyroid cancer (such as Anaplastic or medullary carcinoma of the thyroid).
2. Known hypersensitivity to any component of ST-1898 tablets.
3. Participants who have received any antitumor treatment within 4 weeks or 5 half-lives of the agent (contingent on the shorter time) prior to the first dose of study drug.
4. Patients who underwent major surgery, open biopsy or significant traumatic injury within 4 weeks prior to the first dose of study drug.
5. Serious non-healing wound/ulcer/bone fracture.
6. ≥ grade 3 bleeding episodes within 6 months prior to first dose of study treatment, or currently ≥ grade 2 hemorrhage, with high bleeding risks (such as coagulation disorders, tracheobronchial infiltration with significant bleeding, active gastritis/duodenal ulcer and esophageal varices)
7. Active hemoptysis or more than 0.5 teaspoon (2.5 mL) of hemoptysis per day within 2 months before first dose of study treatment
8. Subjects with antiplatelet agents treatment (low-dose aspirin ≤100 mg/day is permitted).
9. Current or previous severe retinopathy who, in the judgment of the Investigator or specialist, are not suitable for enrollment
10. Significant cardiovascular impairment, including but not limited to:

    1. Serious arrhythmia or cardiac conduct abnormality, such as degree II-III atrioventricular block or ventricular arrhythmia needs to be treated.
    2. QTcF interval extension (by the Fridericia formula): male \>450 ms, female \>480 ms
    3. Acute coronary syndrome, stroke, deep vein thrombosis, pulmonary- thromboembolism, arterial thrombosis, congestive heart failure, aortic dissection etc.
    4. New York Heart Association Class ≥ II
    5. Uncontrolled hypertension, as defined by a sustained blood pressure (BP) \> 140/90 mHg with two or more antihypertensive treatment.
11. Known brain metastasis or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks before first dose of study treatment. Eligible subjects must be neurologically asymptomatic and with a stable dose of corticosteroid treatment before first dose of study treatment.
12. Interstitial lung disease or radiation pneumonia in need of glucocorticoids intervention
13. Previous or currently malignant tumors (not including non-melanoma skin cancer, breast cancer or cervical cancer in situ, and superficial bladder transient cell carcinoma under control in the last 5 years)
14. Receiving chronic concomitant treatment of strong CYP3A4 inducers, CYP3A4 inhibitors or CYP3A4 substrate with a narrow therapeutic window within 2 weeks prior to study drug administration,
15. Prior treatment of cabozantinib or BRAF inhibitors.
16. Has not recovered from toxicities caused by prior therapy to CTCAE ≤Grade 1 (except for ≤Grade 2 peripheral neuropathy, alopecia, and other events judged tolerable by the Investigator and without safety risks).
17. Active hepatitis B (asymptomatic hepatitis B carriers with HBV DNA\< the lower limit of the reference range), hepatitis C virus (HCV) antibody-positive and HCV-RNA- positive, or other active hepatitis, clinically significant moderate-to-severe cirrhosis. Prophylactic antiviral therapy other than interferon are allowed.
18. Acute bacterial, viral or fungal infections (any infection requiring systemic treatment)
19. Females who are pregnant or breastfeeding.
20. Drug or alcohol dependents.
21. Significant disorder of neurology or mental disease or poorly compliance.
22. Subjects with oral administration impossible, or in the conditions of malabsorption as determined by the investigator, such as dysphagia and intestinal obstruction, etc..
23. Uncontrolled pleural effusion, pericardial effusion, abdominal effusion requiring frequent drainage or medical intervention (clinically significant recurrence requiring additional intervention within 2 weeks after intervention, excluding exudate cytology) before first dose of study treatment.
24. Any history of other serious systemic diseases, or any other reason that might interfere with participation in trial or interfere with interpretation of trial results, in the judgement of the Investigator, that are not qualified to participate in this trial.