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

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

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

Study Overview

• Status: Completed
• Conditions: Advanced Solid Tumors
• Intervention / Treatment: Drug: CT053PTSA

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 1

Contacts and Locations

Study Locations

• China
  • Guangdong
    • Guangzhou, Guangdong, China, 510060
      • Sun Yat-sen University Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

1. 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.
2. 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
3. Serum creatinine ≤ 1.5×ULN
4. Blood potassium≥ 3.0 mmol/L; serum calcium≥2.0 mmol/L
5. Fasting serum triglyceride level≤5.7 mmol/L
6. Asymptomatic abnormal serum amylase≤1.5×ULN
7. Serum lipase≤ ULN
8. INR≤ 1.5×ULN；APTT≤ 1.5×ULN； PT ≤ 1.5×ULN

Exclusion Criteria:

1. Chemotherapy, immunotherapy, radiotherapy, or major surgery within 4 weeks prior to study treatment
2. Nitrosourea, anthracyclinea and mitomycin chemotherapy within 6 weeks prior to study treatment
3. Had received live vaccine within 4 weeks prior to study treatment
4. Had received any investigational agent from other clinical study within 4 weeks prior to study treatment or are currently participating in other clinical trials
5. Previous treatment with any other c-MET inhibitor or HGF inhibitor
6. Symptomatic, untreated or unstable central nervous system metastases
7. 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)
8. Patients with hypertension that can't be well controlled by drugs (systolic blood pressure> 140 mmHg or diastolic blood pressure> 90 mmHg)
9. Doppler ultrasound evaluation：Left ventricular ejection fraction < 50%
10. 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
11. Certain factors that would preclude adequate absorption of CT053PTSA (eg. unable to swallow, chronic diarrhea, intestinal obstruction)
12. Significant hemoptysis within 2 months prior to enrollment, or a daily hemoptysis volume is 2.5 ml or above
13. 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
14. History of immunodeficiency, or other acquired or congenital immunodeficiency, or history of organ transplantation
15. 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)
16. Pulmonary embolism within 6 months prior to administration
17. Active infection of hepatitis B, hepatitis C, or infection of HIV
18. Undergone a bone marrow or solid organ transplant.
19. Patients with severe retinopathy or exfoliation in the investigator's judgment
20. Patients need to be supplemented with stem cells before receiving large dose chemotherapy (except for myeloma or lymphoma)
21. History of thyroid dysfunction, and the thyroid function cannot be maintained at the normal range with drugs.
22. Anticoagulants, vitamin K antagonists, other anti-tumor drugs and drugs that prolong the QT interval are not allowed.
23. Serious electrolyte imbalance in the investigator's judgment
24. Pregnant or lactating woman
25. Any other reason the investigator considers the patient is not suitable to participate in the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: CT053PTSA (dose escalation); 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; CT053PTSA will be administered daily in fasting state; Other Names: Ningetinib

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Sunshine Lake Pharma Co., Ltd.

Study record dates

Study Major Dates

• Study Start (Actual): February 8, 2014
• Primary Completion (Actual): December 10, 2015
• Study Completion (Actual): December 10, 2015

Study Registration Dates

• First Submitted: September 16, 2020
• First Submitted That Met QC Criteria: September 30, 2020
• First Posted (Actual): October 8, 2020

Study Record Updates

• Last Update Posted (Actual): October 8, 2020
• Last Update Submitted That Met QC Criteria: September 30, 2020
• Last Verified: September 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms
• Other Study ID Numbers: PCD-DCT053-12-003

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No