Phase I Study of HRS-4642 in Patients With Advanced Solid Tumors Harboring KRAS G12D Mutation

Study Overview
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Brief Summary
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The study is being conducted to evaluate the safety and tolerability of HRS-4642 in patients with advanced solid tumors harboring KRAS G12D mutation.To estimate the maximum tolerated dose (MTD) and/or a biologically active dose (eg, recommended phase 2 dose [RP2D]) within investigated subject population groups

Official Title
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Phase I Study to Evaluate the Safety ,Tolerability, and Pharmacokinetics of HRS-4642 in Patients With Advanced Solid Tumors Harboring KRAS G12D Mutation

Conditions
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Advanced KRAS G12D Mutant Solid Tumors

Intervention / Treatment
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* Drug: HRS-4642


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must voluntarily agree to participate in the trial and sign a written informed consent form. Male or female ≥ 18 years old. Histologically confirmed diagnosis of advanced solid tumor harbouring with KRAS G12D mutation ECOG performance status of 0-1. With a life expectancy of ≥3 months. Have at least one measurable lesion. Adequate laboratory parameters during the screening period Exclusion Criteria: Previously received KRAS G12D inhibitors Priot radiotherapy within 28 days for non-thoracic radiation Prior anti-tumor chemotherapy (< 6 weeks if chemotherapy including nitrosoureas or mitomycin) within 4 weeks before the study drug administration Any unresolved AEs > Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 or inclusion/exclusion criteria level (The investigators determined that safe and controllable toxicity was excluded, such as alopecia and ≤ grade 2 peripheral neuropathy ). Central nervous system (CNS) metastases Major surgical therapy within 28 days prior to the date of signature of informed consent form, or expected major surgery during the study. Known history of hypersensitivity to any components of HRS-4642. Other factors that may affect the study results or lead to forced termination of the study early as judged by investigators.

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
Intervention Model: Single Group Assignment
Interventional Model Description: Single arm study of HRS-4642
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: HRS-4642<br>In Dose Escalation: HRS-4642 will be injected QW. Six dose levels are preset. In Dose Expansion: 1 to 2 dose cohorts will be selected for dose expansion stage. In Indication Expansion: Enrollment into the dose expansion cohorts may be from any eligible solid tumor type. | Drug: HRS-4642<br>* HRS-4642 will be administrated per dose level in which the patients are assigned.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety endpoints: adverse events(AEs), serious adverse events（SAEs）. | Assess safety and tolerability of HRS-4642 by way of adverse events (CTCAE v5.0). | 24 months | 
| Dose Limited Toxicity(DLT) | A DLT is defined as any event meeting the DLT criteria occurring within 21 days of first dose on Cycle 1 Day 1 (C1D1), excluding toxicities clearly related to disease progression or intercurrent illness | from day 1 to Day 21 | 
| Maximum tolerated dose (MTD) | Incidence and category of dose limiting toxicities (DLTs) during the first 21-day cycle of HRS-4642 treatment. | From Day 1 to Day 21 | 
| RP2D | RP2D will be determined on the basis of evaluation on safety, PK, efficacy data in dose escalation and dose expansion stages. | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Abnormal Laboratory Values |  | 24months. | 
| Number of subjects with clinically significant changes in ECOG, vital signs and physical examination. |  | 24months. | 
| Number of subjects with changes on ECG. |  | 24months. | 
| Efficacy endpoints: Overall response rate (ORR). | Evaluated by RECIST v1.1. | 24months. | 
| Efficacy endpoints: Duration of response (DoR). | Evaluated by RECIST v1.1 | 24 months. | 
| Efficacy endpoints: Disease control rate (DCR). | Evaluated by RECIST v1.1. | 24months. | 
| Efficacy endpoints: Progression free survival (DoR). | Evaluated by RECIST v1.1. | 24months. | 
| Efficacy endpoints: overall survival (OS). | Evaluated by RECIST v1.1 | 24minths | 
| Cmax. | Maximal plasma concentration. | 24 months. | 
| Tmax. | Time to Cmax. | 24 months | 
| AUC. | Area under the plasma concentration-time curve. | 24 months. | 
| t1/2. | Terminal-phase elimination half-life. | 24 months. | 
| Vz/F. | Apparent volume of distribution during terminal phase after non-intravenous administration. | 24 months. | 
| CL/F. | Apparent total clearance of the drug from plasma after oral administration. | 24 months. |