A Phase I Study of SY-4835 in Patients With Advanced Solid Tumors
Study Details
Study Description
Brief Summary
This is a phase 1, open-label, single-arm, first-in-human study to evaluate the safety, tolerability, pharmacokinetics (PK) and anti-tumor activity of SY-4835 administered orally in patients with advanced solid tumors.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 1 |
Detailed Description
This study is a first-in-human phase I study of SY-4835, a potent WEE1 inhibitor, in patients with advanced solid tumor. Dose-escalation study is conducted to evaluate primary endpoints and secondary endpoints including the maximum tolerated dose (MTD), Dose-limiting toxicity (DLT), pharmacokinetics (PK) parameters and recommended phase II dose (RP2D), and the safety, tolerability and pharmacokinetics (PK) profiles of SY-4835 are characterized in this study.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Dose-escalation The study is conducted to evaluate the safety, tolerability, pharmacokinetics (PK) and anti-tumor activity of SY-4835. |
Drug: SY-4835
WEE1 inhibitor
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Adverse events (AE), serious adverse events (SAEs), suspected unexpected serious adverse reaction (SUSAR), physical examination, etc. (CTCAE 5.0 standard) [Up to 24 months]
Characterization of the safety and tolerability
- Tolerability: Ratio of Dose reductions or interruptions [Up to 24 months]
Characterization of the safety and tolerability
- Incidence rate of dose limiting toxicities (DLTs) [cycle 1 (each cycle is 21 days)]
Maximum Tolerated Dose(s) (MTD(s)) and recommended phase 2 dose (RP2D(s))
Secondary Outcome Measures
- Pharmacokinetics (Cmax) for SY-4835 [Cycle 1 (each cycle is 21 days)]
Defined as maximum observed plasma concentration
- Pharmacokinetics (Tmax) for SY-4835 [Cycle 1 (each cycle is 21 days)]
Defined as time to maximum plasma concentration
- Pharmacokinetics (AUC0-t) for SY-4835 [Cycle 1 (each cycle is 21 days)]
Defined as area under the single-dose plasma concentration-time curve from Hour 0 to the last quantifiable measurable plasma concentration
- Pharmacokinetics (t½) for SY-4835 [Cycle 1 (each cycle is 21 days)]
Defined as the apparent plasma terminal phase disposition half-life
- Overall Response Rate (ORR) as assessed by RECIST 1.1 criteria [Up to 24 months]
Preliminary measure of anti-tumor activity of SY-4835
- Progression Free Survival (PFS) [Up to 24 months]
Preliminary measure of anti-tumor activity of SY-4835
- Disease control rate (DCR) [Up to 24 months]
Preliminary measure of anti-tumor activity of SY-4835
- Duration of response (DOR) [Up to 24 months]
Preliminary measure of anti-tumor activity of SY-4835
Eligibility Criteria
Criteria
Inclusion Criteria:
- For inclusion in this study, patients must fulfil the following criteria:
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Must understand andvoluntarily sign the informed consent form, willing to follow and able to complete all study procedures.
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Male or female (age of 18~75 years old ).
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Eastern Collaboration Oncology Group (ECOG) performance status (PS) scored of 0-1.
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Estimated life expectancy ≥3 months.
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Histological or cytological confirmation of a advanced solid tumor, that failed to respond to standard therapy, progressed despite standard therapy, or for which standard therapy does not exist.
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At least 1 measureable lesion for solid tumors assessed using RECIST 1.1.
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Patients must have adequate organ function as defined below (no supportive treatment for the following parameters within 7 days prior to testing):
Liver function:
Patients without hepatic metastasis, aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) ≤ 3 times institutional upper limit of normal (ULN), total bilirubin (TBIL) ≤ 1.5 times ULN; Patients with hepatic metastasis, AST, ALT ≤ 5 times ULN, TBIL ≤ 1.5 times ULN; Patients with hepatoma carcinoma, AST and ALT ≤ 5 times ULN, TBIL ≤ 2.5 times ULN.
Bone marrow function:
Absolute neutrophil count (ANC) ≥ 1.5×109/L; Platelets (PLT) count ≥ 75×109/L; Hemoglobin (HB) ≥ 80 g/L.
Renal function:
Creatinine clearance ≥ 45 mL/min or serum creatinine ≤ 1.5 times ULN.
Coagulation function:
Activated partial thromboplastin time (APTT) ≤ 1.5×ULN; International Normalized ratio (INR) ≤ 1.5×ULN.
- Women of childbearing age performed a serum pregnancy test within 7 days before the initiation of treatment, and agreed to adopt a reliable and effective contraceptive method during the trial and within 90 days after the final administration of the study drug.
Exclusion Criteria:
- Patients must not enrol in this study if any of the following exclusion criteria are fulfilled:
- Have received chemotherapy, radiotherapy, biotherapy, endocrine therapy, immunotherapy and other anti-tumor therapy within 3 weeks prior to the first use of the study drug, except for the following:
Nitrosourea or mitomycin C were used within 6 weeks prior to the first use of the study drug; Oral fluorouracil and small molecule targeted drugs were used within 2 weeks or within 5 half-lives prior to the first use of the study; Chinese medicines were used within 2 weeks prior to the first use of the study drug.
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Have received an unmarketed clinical investigational drug or treatment within 4 weeks prior to the first use of the study drug.
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Had major organ surgery (excluding needle biopsy) or had significant traumatism within 4 weeks prior to the first use of study drug.
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History of any WEE1 inhibitor treatment.
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With the exception of alopecia and ≤ Grade 2 peripheral neuropathy, any unresolved toxicities from prior treatment ≤ Grade 1 according to the Common Terminology Criteria for Adverse Events (CTCAE) at the time of starting study treatment.
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Evidence of central nervous system (CNS) metastases accompanied with clinical symptoms, or other evidence of uncontrolled CNS metastases judged by investigators that the patient should not participate in the study.
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Patients have serous effusion (such as pleural effusion, peritoneal effusion, pericardial effusion, etc.) with clinical symptoms, effusions will still increase after 2 weeks of conservative treatment (excluding drainage).
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Patients with active uncontrolled systemic bacterial, viral, or fungal infection despite optimal treatment.
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Active hepatitis B (HBsAg-positive and HBV-DNA ≥ 2000 IU/ mL), Hepatitis C virus infection (HCVAb-positive and HCV-RNA ≥ 1000 IU/ml); Human immunodeficiency virus antibody (HIV Ab) positive; Active syphilis.
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Have serious cardiovascular and cerebrovascular diseases, including but not limited to:
Severe arrhythmias or abnormal cardiac conduction, such as ventricular arrhythmias requiring clinical intervention, degree ii-iii atrioventricular block, etc; Mean resting corrected QT interval (QTcF) > 470 msec obtained from 3 electrocardiograms (ECGs); Had acute coronary syndrome, congestive heart failure, aortic dissection, or other grade 3 or higher cardio-cerebrovascular events within 6 months prior to the first use of study drug; Heart failure (New York Heart Association, NYHA) class ≥ II or left ventricular ejection fraction (LVEF) < 40 %; Hypertension remains uncontrolled after aggressive antihypertensive therapy. Uncontrolled hypertension was defined as systolic blood pressure > 185 mmHg and/or diastolic blood pressure > 110 mmHg measured on 3 repetitions at least 10 minutes apart.
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Prescription or non-prescription drugs known as moderate to strong inhibitors / inducers of CYP3A4 and CYP2D6 within 7 days prior to the first dose of study treatment.
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Patients with alcohol and/or drug dependence.
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Women who are breastfeeding.
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Patients suffering from conditions which are likely to adversely affect gastrointestinal motility.
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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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The investigator considers that the subject has a history of other serious systemic diseases or other reasons and is not suitable to participate in this clinical study.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine | Shanghai | Shanghai | China | 200127 |
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-4835-1