A Phase I Study to Evaluate the Safety, Pharmacokinetics and Efficacy of SY-5007 in Patients With Advanced Solid Tumors
Study Details
Study Description
Brief Summary
This is a phase I, open-label, single-arm, first-in-human study designed to evaluate the safety, tolerability, pharmacokinetics (PK) and preliminary anti-tumor activity of SY-5007 administered orally to participants with advanced solid tumors, including RET-fusion positive NSCLC or RET-mutant medullary thyroid cancer (MTC) or other RET- altered advanced solid tumor.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 1 |
Detailed Description
The study consists of 2 parts, a dose-escalation part and an expansion part. Both parts will enroll patients with RET-fusion positive NSCLC or RET-mutant MTC or other RET- altered advanced solid tumor. Dose-escalation study phase is designed to determine the DLTs (Dose-limiting toxicity) and recommended phase II dose (RP2D) and to characterize the safety, tolerability, and pharmacokinetics (PK) profile of SY-5007. Dose-expansion study phase is designed to evaluate the antitumor activity of SY-5007 in patients.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Dose-escalation and Dose-expansion SY-5007 will be given orally in ascending doses (escalation cohort), until the DLT or RP2D is reached. Up to 7-17 patients will then be enrolled in the expansion cohort at the recommended doses. |
Drug: SY-5007
a RET selective Inhibitor
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Determine the dose-limiting toxicities (DLT) during the first 28-day cycle of SY-5007 treatment [Dose-escalation Cycle 1 (each cycle is 28 days)]
Maximum Tolerated Dose (MTD) and/or recommended phase 2 dose (RP2D) in Cycle 1
- Number of patients with adverse events and serious adverse events [Up to 24 months]
Characterization of the safety and tolerability
Secondary Outcome Measures
- Overall Response Rate (ORR) as assessed by RECIST 1.1 criteria [Up to 24 months]
Preliminary measure of anti-tumor activity of SY-5007
- Duration of response (DOR) [Up to 24 months]
Preliminary measure of anti-tumor activity of SY-5007
- Progression Free Survival (PFS) [Up to 24 months]
Preliminary measure of anti-tumor activity of SY-5007
- Pharmacokinetics (Cmax) for SY-5007 [Protocol-defined time points during Cycles 1 of treatment (each cycle is 28 days)]
Defined as maximum observed plasma concentration
- Pharmacokinetics (Tmax) for SY-5007 [Protocol-defined time points during Cycles 1 of treatment (each cycle is 28 days)]
Defined as time to maximum plasma concentration
- Pharmacokinetics (t½) for SY-5007 [Protocol-defined time points during Cycles 1 of treatment (each cycle is 28 days)]
Defined as the apparent plasma terminal phase disposition half-life
- Pharmacokinetics (Cl/F) for SY-5007 [Protocol-defined time points during Cycles 1 of treatment (each cycle is 28 days)]
Defined as oral dose clearance
Eligibility Criteria
Criteria
Inclusion Criteria:
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Male or female, At least 18 years of age.
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Eastern Cooperative Oncology Group (ECOG) performance status score of 0 to 1.
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Estimated life expectancy >12 weeks.
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Patients must have at least one assessable lesion in dose-escalation part and one measurable lesion in dose-expansion part per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
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Dose-escalation Part: patients must have histological or cytological confirmed advanced solid tumours with RET alteration (fusion or mutation) and have progressed after standard therapy, or no standard or available curative therapy exists.
Dose-expansion Part: Patients with advanced tumor must have histological or cytological confirmed RET alteration, including NSCLC patients with RET-fusion or MTC patients with RET-mutation or other patients with RET alteration, and either have progressed after standard therapy or no standard/ available curative therapy exists.
- Patients must have adequate organ function as defined in the below:
Hepatic function:
Serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≤ 3 times the upper limit of normal (ULN) if no hepatic metastases are present, or otherwise ≤ 5 times ULN, Total serum bilirubin (TBIL) ≤ 1.5 times ULN.
Bone marrow function (No blood transfusion or haematopoietic stimulating factor treatment within 10 days prior to testing):
Absolute neutrophil count (ANC) ≥ 1.5 x 10⁹/L; Platelets (PLT) count ≥ 75 x 10⁹/L; Hemoglobin (Hb) ≥ 85 g/L.
Renal function:
Creatinine clearance ≥ 50 mL/min.
Coagulation function:
Prothrombin time (PT) or International Normalized Ratio (INR) ≤ 1.5 times ULN.
Serum lipid:
Cholesterol ≤ 500mg/dL（12.92mmol/L）.
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Female patients with reproductive potential must have a negative serum pregnancy test within 7 days prior to the first dose, male and female patients of childbearing potential must be willing to completely abstain or agree to use an appropriate method of contraception during the entire study duration and for at least 3 months after the last dose of study medication.
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Willingness and ability to give informed consent and follow protocol procedures, and comply with follow-up visit requirements.
Exclusion Criteria:
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Dose-expansion Part: Patient's cancer has a known primary driver alteration other than RET. e.g. EGFR, ALK, ROS1, KRAS, etc.
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Dose-expansion Part: Patients previously treated with a selective RET inhibitor.
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Patients received systemic antitumor therapy, including chemotherapy, radiotherapy, biologic therapy, endocrine therapy, or immunotherapy within 3 weeks prior to the first dose, except for the following:
Nitrosoureas or mitomycin C within 6 weeks; Oral fluorouracils and small molecule drugs within 2 weeks or within 5 half-life periods of the drug (whichever is longer); Antitumour traditional Chinese medicine within 2 weeks.
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Patients received other unlisted clinical trial drugs or treatments within 4 weeks prior to the first dose.
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Patients underwent major organ surgery (excluding puncture biopsy) or had significant trauma within 4 weeks prior to the first dose.
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Adverse effects of previous anti-tumor therapy have not recovered to CTCAE 5.0 grade rating of ≤ grade 1 (except for toxicity judged by the investigator be of no safety risk, such as alopecia, grade 2 peripheral neurotoxicity, etc.)
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Patients have symptomatic central nervous system (CNS) metastases, meningeal metastases, or a primary CNS tumor that is associated with progressive neurological symptoms.
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Patients with active uncontrolled systemic bacterial, viral, or fungal infection despite optimal treatment (chronic disease screening not required).
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Active hepatitis (Hepatitis B: HBsAg-positive and HBV-DNA ≥ 2000 IU/ mL; Hepatitis B: HCV antibody-positive and HCV-RNA ≥ 1000 IU/ml), HIV antibody-positive; Active syphilis.
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Patients have a history of severe cardiovascular disease, including but not limited to:
Severe cardiac rhythm or conduction abnormalities, e.g. ventricular arrhythmia requiring clinical intervention, II-III degree atrioventricular block, etc.
Mean QT interval corrected using Fridericia's formula (QTcF)> 480ms at rest. Acute coronary syndrome, congestive heart failure, aortic coarctation, stroke or other grade 3 or higher cardiovascular or cerebrovascular events within 6 months prior to the first dose.
New York Heart Association (NYHA) ≥ class II heart failure or left ventricular ejection fraction (LVEF) < 50%.
Hypertension remains uncontrolled after aggressive antihypertensive therapy.
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Patients have been treated with any CYP3A inhibitors or inducers within 14 days prior to the first dose.
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Patients with malignancies other than tumors treated in this study (except: malignancies that are cured and have not recurred within 3 years prior to study entry; completely resected basal cell and squamous cell skin cancer; completely resected carcinoma in situ of any type).
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Patients are unable to swallow the drug orally, or has a condition that seriously affects gastrointestinal absorption in the judgment of the investigator.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Shanghai Pulmonary Hospital | Shanghai | Shanghai | China | 200433 |
| 2 | Tianjin People's Hospital | Tianjin | Tianjin | China | 300000 |
Sponsors and Collaborators
- Shouyao Holdings (Beijing) Co. LTD
Investigators
- Study Director: Yinghui Sun, PhD, Shouyao Holdings (Beijing) Co. LTD
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- SY-5007-I