First-In-Human Phase I Trial of Ningetinib ( CT053PTSA ) in the Patients With Advanced Solid Tumors

This is a dose-escalation study. The primary purpose is to determine the dose limiting toxicity (DLT), maximum tolerated dose (MTD) and recommend doses and regimen of CT053PTSA for further studies.

Inclusion criteria

• A. Subjects with advanced solid tumors confirmed by histologically or cytologically that are refractory to current treatment or for which there is not a current standard of care B. Toxicity recovered to NCI CTCAE v.4.0 Grade ≤1 from previous treatments (chemotherapy, radiotherapy or surgery) C. ECOG performance status (PS) 0 or 1 D. Life expectancy of ≥ 12 weeks E. Adequate organ function

• Hemoglobin > 9 g/dL (SI Units: 90 g/L) without transfusion support or growth factors; Platelet count ≥ 100 × 10^9/L; Absolute neutrophil count (ANC) ≥ 1.5 × 10^9/L without growth factor support.
• AST/SGOT and/or ALT/SGPT≤ 2.5 × upper limit of normal (ULN) or ≤ 5.0× ULN if liver metastases are present; serum bilirubin ≤ 1.5×ULN
• Serum creatinine ≤ 1.5×ULN
• Blood potassium≥ 3.0 mmol/L; serum calcium≥2.0 mmol/L
• Fasting serum triglyceride level≤5.7 mmol/L
• Asymptomatic abnormal serum amylase≤1.5×ULN
• Serum lipase≤ ULN
• INR≤ 1.5×ULN；APTT≤ 1.5×ULN； PT ≤ 1.5×ULN

Exclusion criteria

• Chemotherapy, immunotherapy, radiotherapy, or major surgery within 4 weeks prior to study treatment
• Nitrosourea, anthracyclinea and mitomycin chemotherapy within 6 weeks prior to study treatment
• Had received live vaccine within 4 weeks prior to study treatment
• Had received any investigational agent from other clinical study within 4 weeks prior to study treatment or are currently participating in other clinical trials
• Previous treatment with any other c-MET inhibitor or HGF inhibitor
• Symptomatic, untreated or unstable central nervous system metastases
• Spinal cord compression, carcinomatous meningitis or leptomeningeal diseaseonly (patient are only permitted if treated, asymptomatic and stable for at least 4 weeks prior to start of study treatment)
• Patients with hypertension that can't be well controlled by drugs (systolic blood pressure> 140 mmHg or diastolic blood pressure> 90 mmHg)
• Doppler ultrasound evaluation：Left ventricular ejection fraction < 50%
• Grade ≥ 2 of arrhythmia (assessed by NCI CTCAE 4.0), or symptomatic bradycardia, or male with QTCF > 450 ms or female with QTCF > 470 ms, or patients with a history of torsion or congenital QT prolonged syndrome long QT syndrome
• Certain factors that would preclude adequate absorption of CT053PTSA (eg. unable to swallow, chronic diarrhea, intestinal obstruction)
• Significant hemoptysis within 2 months prior to enrollment, or a daily hemoptysis volume is 2.5 ml or above
• Patients with evidence of bleeding tendency, including the following cases: gastrointestinal bleeding, hemorrhagic gastric ulcer, fecal occult blood ++ and above; or melena or hematemesis within 2 months; or visceral bleeding that may occur considered by investigator
• History of immunodeficiency, or other acquired or congenital immunodeficiency, or history of organ transplantation
• Any disease of the following bellowed within 12 months prior to administration: Myocardial infarction, severe angina, or unstable angina, coronary or peripheral artery bypass graft, congestive heart failure, or cerebrovascular events (including transient ischemic attack)
• Pulmonary embolism within 6 months prior to administration
• Active infection of hepatitis B, hepatitis C, or infection of HIV
• Undergone a bone marrow or solid organ transplant.
• Patients with severe retinopathy or exfoliation in the investigator's judgment
• Patients need to be supplemented with stem cells before receiving large dose chemotherapy (except for myeloma or lymphoma)
• History of thyroid dysfunction, and the thyroid function cannot be maintained at the normal range with drugs.
• Anticoagulants, vitamin K antagonists, other anti-tumor drugs and drugs that prolong the QT interval are not allowed.
• Serious electrolyte imbalance in the investigator's judgment
• Pregnant or lactating woman
• Any other reason the investigator considers the patient is not suitable to participate in the study