Study of ST-1898 in Advanced Renal Cell Carcinoma

Study Overview
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Brief Summary
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ST-1898 is a receptor tyrosine kinase (RTK) inhibitor for multi-targets, especially for VEGFR2, c-MET, AXL，PDGFRA，RET，KIT etc. This trial is to evaluate its safety, tolerability, pharmacokinetic, and efficacy in patients with advanced renal cell carcinoma (RCC). In phase Ib, the primary objectives are to assess the safety and tolerability, and to determine the maximum tolerated dose (MTD) of ST-1898 tablets in patients with advanced RCC. Secondary objectives are to assess the plasma concentration of ST-1898 and to evaluate the efficacy in patients with advanced RCC. In phase II, the primary objective is to assess the anti-tumor activities of ST-1898 tablets in patients with advanced RCC. The secondary objective is to evaluate the safety of ST-1898 tablets in patients with advanced RCC.

Official Title
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A Phase Ib/II Study of ST-1898 to Evaluate the Efficacy and Safety in Patients With Renal Cell Carcinoma (RCC)

Conditions
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Advanced Renal Cell Carcinoma

Intervention / Treatment
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* Drug: ST-1898 tablets


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age >= 18 years Life expectancy of three months or more Diagnosis of advanced renal cell carcinoma (RCC) by histopathology and medical imaging, standard treatment failure or no standard treatment regimen available With agreement to provide a tumor tissue specimen Has the ability to understand and willingness to sign a written ICF before the performance of any study-specific procedures on this protocol Has at least one measurable lesion as defined by RECIST version 1.1 Has an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1 Has adequate organ function defined as follows: Bone marrow : absolute neutrophil count ≥ 1,500/µL, Hgb level ≥ 90 g/L and platelet count (Plt) i. ≥ 90x109/µL without transfusion or growth factor support within 2 weeks prior to obtaining the hematology values at screening; Liver: transaminase levels (AST/ALT) ≤ 3.0 × upper limit of normal (ULN); total bilirubin i. (TBILI) ≤ 1.5 mg/dL in the absence of Gilbert's disease Kidney: Creatinine ≤1.5 ULN, protein in urine ≤1+, if ≥2+ but <1g within 24h Heart: LVEF≥50% Coagulation function: INR≤1.5×ULN，APTT≤1.5×ULN Women of child bearing potential must have a negative serum pregnancy test within 7 days before first study drug administration. Female patients of child bearing potential, or a male patients with a female partner of child-bearing potential (defined as all women physiologically capable of becoming pregnant), must agree to use a highly effective method of contraception during screening, during the period of drug administration and for 120 days after stopping study drug administration. Exclusion Criteria: Has received another anti-tumor therapy within two weeks or within 5 half-life of anti- tumor drug prior to the first dose Has had major surgery within 4 weeks before the first study drug administration (except tumor biopsy, puncture, invasive dental procedures such as tooth extraction, dental implants etc.) Current or previous severe retinopathy who, in the judgment of the Investigator or specialist, are not suitable for enrollment Has had any history of major cardiovascular event within 6 months prior to study drug administration including but not limited to : Serious arrhythmia or cardiac conduct abnormality , such as degree II-III atrioventricular block or ventricular arrhythmia needs to be treated QTc interval extension: male >450 ms, female >470 ms Acute coronary syndrome, stroke, deep vein thrombosis, pulmonary- thromboembolism, arterial thrombosis, congestive heart failure, aortic dissection etc. New York Heart Association Class ≥ II Has uncontrolled hypertension, as defined by a sustained blood pressure (BP) > 140/90 mHg with antihypertensive treatment Has brain metastases with symptoms or with evidence of progression Has Interstitial lung disease or radiation pneumonia requiring treatment by steroid Has a prior or concomitant invasive malignancy other than RCC with the exception of adequately treated non-melanoma skin cancer, breast cancer in situ ,cervical carcinoma in situ or superficial bladder cancer any other malignancy from which the patient has remained disease free within the past 5 years Has ≥ grade 3 hemorrhage/bleeding event within 6 months prior to study drug administration or currently ≥ grade 2 hemorrhage or event of high risk of hemorrhage ) including active gastritis/duodenal ulcer or esophageal varices Within 2 weeks prior to study drug administration, receiving chronic concomitant treatment with strong CYP3A4 inducers or CYP3A4 inhibitors Has not recovered from toxicities caused by prior therapy to CTCAE≤ Grade 1 (except for peripheral neuropathy becoming ≤Grade 2, alopecia, and other events judged tolerable by the Investigator and without safety risks). Active hepatitis B (asymptomatic hepatitis B carriers with HBV DNA < 2000 IU/mL are allowed to be enrolled), hepatitis C virus (HCV) antibody-positive and HCV-RNA- positive, or other active hepatitis, clinically significant moderate-to-severe cirrhosis, are allowed to receive prophylactic antiviral therapy other than interferon. Has acute bacterial, viral or fungal infections, requiring systemic anti-infective treatment. HIV positive Pregnant or lactating females Drug or alcohol dependents Has significant disorder of neurology or mental disease or poorly compliance Unable to swallow oral medications or condition or conditions that in the judgment of the Investigator which severely interfere with gastrointestinal absorption, such as dysphagia, intestinal obstruction, etc. Clinically uncontrollable third interstitial effusion that, in the judgment of the Investigator, is unsuitable for enrollment. Has a history of other serious systemic disease, or any other reason that might interfere with participation in trial or interfere with interpretation of trial results, in the judgement of the Investigator, that are not qualified to participate in this trial.

Ages Eligible for Study
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Minimum Age: 18 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
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Sequential Assignment Escalation followed by Dose Expansion
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ST-1898 Phase Ib<br>Dose Escalation:participants will be administered orally at 100mg,140mg,160mg,180mg, 220mg,QD during the study, until disease progression or intolerable toxicity. | Drug: ST-1898 tablets<br>* Supplied as 5 mg and 40 mg tablets<br>|
| Experimental: ST-1898 Phase II<br>Dose Expansion: participants with advanced renal cell carcinoma will be dministered orally at recommended phase II dose from phase Ib once daily during the study, until disease progression or intolerable toxicity. | Drug: ST-1898 tablets<br>* Supplied as 5 mg and 40 mg tablets<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase Ib Dose Escalation：Maximum Tolerated Dose (MTD) | The MTD was defined as the highest dose level at which no more than 1 in 6 participants experienced a dose-limiting toxicity (DLT) during the first cycle (21days) of treatment. | Within the first cycle (21days) | 
| Phase Ib Dose Escalation: The Number and frequency of treatment-related adverse events (AEs) and treatment-related serious adverse events (SAEs) | The AEs and SAEs will be assessed according to the National Cancer Institute (NCI) CTCAE v5.0. | Approximately 18 months | 
| Phase II Expansion: Objective Response Rate (ORR) | ORR is defined as The percentage of participants who experience a CR or PR based on RECIST 1.1 (CR: Complete Response, Disappearance of all target lesions, PR: Partial Response, At least a 30% decrease in the sum of diameters of target lesions) | Approximately 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase Ib Dose Escalation: Plasma PK | To assess plasma pharmacokinetics (PK) of oral administration of ST-1898 in participants with advanced renal cell carcinoma | On Day 1, 8, 21 of Cycle 1 and Day 1 of Cycle 3, approximately 10 weeks | 
| Phase Ib Dose Escalation: ORR | Objective Response Rate (ORR) per RECIST 1.1 | Approximately 18 months | 
| Phase Ib Dose Escalation: DOR | DOR Duration of Response (DOR) per RECIST 1.1 | Approximately 18 months | 
| Phase Ib Dose Escalation: PFS | Progression-Free Survival (PFS) per RECIST 1.1 | Approximately 18 months | 
| Phase Ib Dose Escalation: DCR | Disease Control Rate (DCR) per RECIST 1.1 | Approximately 18 months | 
| Phase Ib Dose Escalation: OS | Overall Survival (OS) | Approximately 30 months | 
| Phase Ib Dose Escalation: TTP | Time to Progression（TTP）per RECIST 1.1 | Approximately 18 months | 
| Phase II Dose Expansion: DOR | DOR Duration of Response (DOR) per RECIST 1.1 | Approximately 18 months | 
| Phase II Dose Expansion: PFS | Progression-Free Survival (PFS) per RECIST 1.1 | Approximately 18 months | 
| Phase II Dose Expansion: DCR | Disease Control Rate (DCR) per RECIST 1.1 | Approximately 18 months | 
| Phase II Dose Expansion: OS | Overall Survival (OS) per RECIST 1.1 | Approximately 30 months | 
| Phase II Dose Expansion: OS12m | 12-Month survival rate（OS12m） | 12 months | 
| Phase II Dose Expansion: The Number and frequency of treatment-related adverse events and serious adverse events (SAEs) | The AEs and SAEs will be assessed according to the National Cancer Institute (NCI) CTCAE v5.0. | Approximately 18 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ST-1898, renal cell carcinoma