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

Study Overview
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Brief Summary
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This is a phase I, single-arm, single-center, open-label, dose-escalation Study evaluating the safety and efficacy of CT053PTSA in patients with Advanced Solid Tumors

Detailed Description
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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.

Official Title
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Safety, Tolerability, Pharmacokinetics and Preliminary Antitumor Activity of Ningetinib (CT053PTSA) in Patients With Advanced Solid Tumors: A Phase I, Single-arm, Single-center, Open-label, Dose-escalation Study

Conditions
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Advanced Solid Tumors

Intervention / Treatment
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* Drug: CT053PTSA


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CT053PTSA (dose escalation)<br>Patients were treated in 5 dose cohorts of 15 mg, 30 mg, 60 mg, 100 mg, and 150 mg QD capsules. Patients receive treatment with CT053PTSA once on Cycle 0 Day 1 following a 7-day treatment-free withdrawal period to observe the safety and pharmacokinetic of CT053PTSA. After that, Patients receive treatment with CT053PTSA per orally, beginning on Cycle 1 Day 1 for 28 day following a 7-day treatment-free withdrawal period to observe efficacy of CT053PTSA and determine to continue taking medicine or not. Each cycle had 28 days. | Drug: CT053PTSA<br>* CT053PTSA will be administered daily in fasting state<br>* Other names: Ningetinib;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) | The maximum tolerated dose (MTD) of the CT053PTSA will be determined according to incidence of dose-limiting toxicity (DLT) assessed by NCI CTCAE v4.0 | Cycle 0 Day 1 to Cycle 1 Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics (PK) of CT053PTSA_Cmax | To evaluate the Pharmacokinetics (PK) of CT053PTSA with Maximum observed plasma concentration (Cmax) | Cycle 0 Day 1 to Cycle 1 Day 28 | 
| Pharmacokinetics (PK) of CT053PTSA_Tmax | To evaluate the Pharmacokinetics (PK) of CT053PTSA with Time of maximum observed plasma concentration (Tmax). | Cycle 0 Day 1 to Cycle 1 Day 28 | 
| Pharmacokinetics (PK) of CT053PTSA_AUC | To evaluate the Pharmacokinetics (PK) of CT053PTSA with Area under the plasma concentration time curve (AUC). | Cycle 0 Day 1 to Cycle 1 Day 28 | 
| Efficacy of CT053PTSA_ORR | To assess overall response rate (ORR) for patients treated CT053PTSA. | up to approximately 36 months | 
| Efficacy of CT053PTSA_DCR | To assess disease control rate (DCR) for patients treated CT053PTSA. | up to approximately 36 months |