A Study of HS-10516 in Patients With Advanced Clear Cell Renal Cell Carcinoma

Study Overview
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Brief Summary
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The aim of the Phase Ia portion is to identify the maximum tolerated dose or maximum acceptable dose MTD/MAD of HS-10516. The phase Ib portion will evaluate the preliminary efficacy of HS-10516 in ccRCC.

Detailed Description
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This is a Phase Ia/Ib open label multicenter study of HS-10516 in Chinese patients aged 18 years or older with advanced clear cell renal cell carcinoma who have failed or are unavailable/intolerant to standard of care. HS-10516 as a single agent, is administrated orally once daily. The aim of phase Ia, a dose escalation study, is to identify the MTD/MAD of HS-10516. The goal of Phase Ib, a dose expansion study, is to evaluate the safety, pharmacokinetics and antitumor efficacy of HS-10516.

Official Title
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A Phase Ia/Ib Study of HS-10516 to Investigate the Safety, Tolerance, Pharmacokinetic and Efficacy in Patients With Advanced Clear Cell Renal Cell Carcinoma

Conditions
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Renal Cell Carcinoma

Intervention / Treatment
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* Drug: HS-10516


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female from 18 to 75 year-old Histologically confirmed locally advanced or metastasis clear cell renal cell carcinoma whose standard treatment failed or proven unavailable or intolerant Has at least one non-CNS target lesion per RESIST v1.1 Has an Eastern Cooperative Oncology Group performance status of 0-1 Has a life expectancy of ≥ 12 weeks Should use adequate contraceptive measures throughout the study Females subject must not be pregnant at screening Has the ability to understand and willingness to sign a written informed consent before the performance of the study Exclusion Criteria: Received or being received treatment as follows: Hypoxia-induced factor inhibitors Traditional Chinese medicine indicated for tumors within 2 weeks prior to the first dose of study treatment. Cytotoxic chemotherapeutic drugs, investigational drugs or other systematic anti-tumor therapies within 3 weeks before the first dose of study treatment Colony-stimulating factors (CSFs) within 4 weeks before the first dose of study treatment Local radiotherapy within 2 weeks prior to the first dose of study treatment; more than 30% of bone marrow radiotherapy or large-area irradiation within 4 weeks before the first dose of study treatment. Major surgery within 4 weeks prior to the first dose of study treatment. Has a pulse oximetry reading less than 92% at screening, requires intermittent supplemental oxygen, or requires chronic supplemental oxygen Has failed to recover from a ≥ grade 2 adverse event due to prior anti-tumor therapy Has another malignancy or a history of another malignancy Has inadequate bone marrow reserve or organ dysfunction Has a clinically significant bleeding events or tendency within 1 month prior to the first dose of study treatment Has severe infections within 4 weeks prior to the first dose of study treatment Has digestive system diseases may influencing ADME of study drug Has a history of severe hypersensitivity reaction, or proven allergic to HS-10516 or its metabolics Has any disease or condition would compromise subject safety or interfere with study assessments by investigator's decision

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
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase Ia dose escalation<br>Participants will be assigned to pre-specified dose level to identify the MTD/MAD of HS-10516. | Drug: HS-10516<br>* Oral HIF-2α inhibitor<br>|
| Experimental: Phase Ib dose expansion arm<br>Participants will be assigned to the recommended dose level determined in Phase Ia to evaluate the safety, pharmacokinetics and antitumor efficacy of HS-10516 | Drug: HS-10516<br>* Oral HIF-2α inhibitor<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase Ia: MTD/MAD of HS-10516 | Maximum Tolerated Dose or Maximum Acceptable Dose determined by the Number of Participants with Dose Limiting Toxicity (DLT) events during the DLT monitoring period (first 35 days of dosing) in the Dose Escalation Phase | Approximately 2 months | 
| Phase Ib: Objective Response Rate (ORR) by Independent Review Committee (IRC) | ORR defined as the percentage of participants with a confirmed complete response (CR) or partial response (PR) based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. ORR will be assessed by IRC. | Approximately 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Number of Participants with Adverse Events | An adverse event (AE) is defined as any untoward medical occurrence in a patient and which does not necessarily have a causal relationship with this treatment. The investigator assessed the relationship of each event to the use of study drug as either probably related, possibly related, probably not related or not related. | Approximately 2 years | 
| Observed maximum plasma concentration (Cmax) of HS-10516 | Cmax will be obtained following administration of the first dose of HS-10516 during first 2 cycles. | Approximately 2 months | 
| Time to reach maximum plasma concentration (Tmax) of HS-10516 | Tmax will be obtained following administration of the first dose of HS-10516 during first 2 cycles. | Approximately 2 months | 
| Area under plasma concentration versus time curve from zero to last sampling time (AUC0-t) following the first dose of HS-10516 | Area under the plasma concentration versus time curve from time zero to the last sampling time when the concentration was no less than the lower limit of quantification (LLQ). AUC0-t was calculated according to the mixed log-linear trapezoidal rule. | Approximately 1 year | 
| ORR by investigators | ORR defined as the percentage of participants with a confirmed complete response (CR) or partial response (PR) based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. | Approximately 1 year | 
| Disease Control Rate (DCR) | DCR defined as the percentage of participants with a confirmed complete response (CR) or partial response (PR) or a stable disease (SD) of 8 weeks or longer based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. | Approximately 1 year | 
| Duration of Response (DoR) | DoR is defined as the time from the date of first documented CR or PR, assessed by investigator and based on RECIST v. 1.1, to the documented date of progressive disease (PD) or death, whichever occurred first. | Approximately 1 year | 
| Progression Free Survival (PFS) | PFS defined as the time from the date the participant started study drug to the date the participant experiences an event of disease progression or death. | Approximately 2 years | 
| Overall Survival (OS) | OS defined as the time from the date the participant started study drug to death for any reason. | Approximately 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Advanced Clear Cell Renal Cell Carcinoma, Kidney Cancer, Renal Cancer, Recurrent Renal Cell Carcinoma