Advanced Solid Tumors

Primary Objectives • To explore the MTD and/or the RP2D of TT-00434 in patients with advanced or recurrent malignant solid tumors; • To assess the safety and tolerability of TT-00434 in patients with advanced or recurrent malignant solid tumors; Secondary Objectives • To characterize the PK profiles of single and multiple-dose of TT-00434 in patients with advanced or recurrent malignant solid tumors • To preliminarily characterize the PD profiles of TT-00434 in patients with advanced or recurrent malignant solid tumors. • To preliminarily evaluate the anti-tumor activity of TT-00434 in patients with advanced or recurrent malignant solid tumors;

TT-00434

tablet

20, 100 mg

Primary Endpoint:
• Safety and tolerability of TT-00434 will be evaluated based on the frequency and attribute of DLT in the DLT evaluation period and the incidence of all AEs and serious adverse events (SAEs) during study period (including screening period, treatment period, and safety follow-up period) (according to NCI-CTCAE V5.0)

Secondary Endpoints:
• PK evaluation: Including but not limited to, Cmax, Tmax, AUC [AUC0-t, AUC0-τ], T1/2, CL and Ȝz.
• PD evaluation: PD parameters will be assessed by analyzing the change in serum phosphate levels relative to baseline level over time.
• Efficacy evaluations: CR, PR, SD, and disease progression will be evaluated, and objective response rate (ORR) (CR+PR) and disease control rate (DCR) (CR+PR+SD), PFS and OS will be determined according to RECIST version 1.1 criteria

1. Age ≥ 20 years.
2. Patients must have a histological or cytologically confirmed diagnosis of advanced or recurrent malignant solid tumors.
3. Patients have received all currently available standard treatments (unless the therapy is contraindicated, intolerable or unavailable due to any reasons).
4. Patients must have measurable or evaluable disease (according to RECIST 1.1, see Appendix A)
5. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 2.
6. Patients must have normal levels of total serum calcium and total phosphate.
7. Patients must have adequate organ and bone marrow function (patients must not have received any hematopoietic growth factors, transfusion, or platelet within 1 week before the first dose).
• Complete blood count:
◼ Absolute Neutrophil Count (ANC) ≥ 1.5 × 109/L
◼ Hemoglobin (Hgb) ≥ λ g/dl
◼ Platelets (Plt) ≥ 75 × 109/L
• Liver function:
◼ AST and ALT ≤ 2.5 × Upper Limit of Normal (ULN) or ≤ 5.0 × ULN for subjects with original HCC or CCA or liver metastases
◼ Total bilirubin ≤ 1.5 × ULN, or direct bilirubin < ULN for patients with total bilirubin levels >1.5 × ULN
◼ For HCC and CCA patients: Child Pugh Class A or Class B (Score ≤ 7)
• Renal function:
◼ Serum creatinine ≤ 1.5 × ULN or calculated 24-hour clearance ≥ 50 mL/min (by Cockcroft Gault formula, see Appendix B)
• Negative serum pregnancy test within 72 hours before starting study treatment in all pre-menopausal women and women < 12 months after the onset of menopause
8. Must agree to take sufficient contraceptive methods to avoid pregnancy during the study and until at least 6 months after ceasing study treatment
9. Patients must have fully understood and voluntarily signed informed consent form (ICF) for this study

1. Patients who received other investigational products or devices in other clinical trials within 4 weeks before the first dose.
2. Patients who received anti-tumor therapy (except for mitomycin, nitrosourea, and fluorouracil oral drugs) within 4 weeks, or within 5-half-lives (which is longer) before the first dose, including but not limited to chemotherapy, radiotherapy (palliative radiotherapy is completed at least 2 weeks before the first dose can enrol), targeted therapy or immunotherapy.
NOTE: The last dose of mitomycin and nitrosourea should be at least 6 weeks before investigational product initiation; the last dose of oral fluorouracil should be at least 2 weeks before investigational product initiation
3. Patients who require the use of concomitant medications that prolong the QT/QTc interval (Appendix C)
4. Patients who have previous toxicity of anti-tumor therapy that has not recovered to Grade
1. (except for ≤ Grade 2 alopecia, chemotherapy-induced peripheral neurotoxicity, and ototoxicity).
5. Patients who received CYP3A4 strong inhibitors and/or inducers (Appendix D) within 2 weeks prior to the first dose and the patients who need to continue using these drugs.
6. Patients who have any of the following eye diseases/conditions:
1) history of retinal pigment epithelial detachment (RPED);
2) history of laser treatment or intraocular injection for macular degeneration;
3) history of dry or wet age-related macular degeneration;
4) history of retinal vein occlusion (RVO);
5) history of retinal degenerative diseases;
6) history of chorioretinal lesions
7. Patients who have gastrointestinal disorders that will affect oral administration or the Investigator judges that the absorption of TT-00434 will be interfered.
8. Patients underwent major surgery (except biopsy) within 4 weeks, or the surgical incision has not completely healed prior to the first dose.
9. Patients who have symptomatic brain metastases or spinal cord compression. For the patients, who have been previously treated for brain metastases, if the clinical condition is stable and imaging evidence does not show disease progression within 4 weeks prior to the first dose, and do not need corticosteroid treatment within 2 weeks prior to the first dose, can be enrolled.
10. Patients who have active bacterial or fungal infections (Common Terminology Criteria for Adverse Events [CTCAE]) Grade ≥ 2) that required systemic treatment within 2 weeks prior to the first dose.
11. Patients who have active HBV infection (HBV DNA copies ≥ ULN) and/or HCV infection (HCV RNA copies ≥ ULN)
12. Patients who test positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome.
13. Has received a live-virus vaccination within 30 days of planned first dose
NOTE: Seasonal flu vaccines are permitted.
14. Patients who have clinically significant cardiovascular diseases that occurred 6 months prior to first dose. Cardiovascular diseases include, but not limited to follows: acute myocardial infarction; severe/unstable angina; cerebrovascular accident or transient ischemic attack; congestive heart failure (New York Heart Association [NYHA] > Class II, see Appendix
E); arrhythmias that require antiarrhythmic treatment except for beta blockers or digoxin; repeated ECG with QTc interval > 450 ms; high blood pressure that cannot be controlled by any antihypertensive drugs (systolic blood pressure > 160 mm Hg, diastolic blood pressure > 100 mmHg).
15. Known or suspected drug hypersensitivity to any ingredients of TT-00434 tablets.
16. Female patients in pregnancy or lactation. Male patients or female patients at reproductive ages who are unwilling to receive effective contraceptive measures.
17. Patients who are judged by the Investigator to be unsuitable for this study