Phase 1/2a Study of JAB-21822 Plus JAB-3312 in Patients With Advanced Solid Tumors Harboring KRAS p.G12C Mutation

Study Overview
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Brief Summary
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This is a multicenter, open-label phase 1/2a study consisting of two parts: dose escalation phase and dose expansion phase. The objective of the dose escalation phase is to evaluate the safety, tolerability and pharmacokinetics of JAB-21822 in combination with JAB-3312 in patients with advanced solid tumors harboring KRAS p.G12C mutation and to determine the RP2D for the combination therapy. In the dose expansion phase, preliminary efficacy and safety of the combination therapy at the RP2D will be further explored in patients with specific cancer harboring KRAS p.G12C mutation.

Official Title
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A Phase 1/2a Clinical Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Antitumor Activity of JAB-21822 in Combination With JAB-3312 in Patients With Advanced Solid Tumors Harboring KRAS p.G12C Mutation

Conditions
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KRAS P.G12C, Non-small Cell Lung Cancer, Colorectal Cancer, Pancreatic Ductal Carcinoma

Intervention / Treatment
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* Drug: JAB-21822
* Drug: JAB-3312


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A written informed consent should be signed by a subject or his/her legal representative before any study-related procedures are performed; Subjects with histologically or cytologically confirmed locally advanced or metastatic advanced solid tumors who have failed or lack standard-of-care (SOC) or are unwilling to undergo or intolerant to SOC; those with solid tumors harboring KRAS p.G12C mutation are preferred; Expected survival ≥ 3 months; Subjects must have at least one measurable lesion as defined by RECIST v1.1. If no measurable lesion untreated with radiation is selected as the target lesion, a lesion treated with radiation ≥ 4 weeks before the first dose and with progression conformed by radiography may be selected as the target lesion; Eastern Cooperative Oncology Group(ECOG) performance status 0-1; The organ functions of subjects meet the criteria for the following laboratory parameters at screening; Subjects must be able to swallow oral medications without gastrointestinal abnormalities that significantly affect drug absorption Exclusion Criteria: Patients with previous (≤ 3 years) or current tumors of other pathological types, except for cured cervical carcinoma in situ, ductal carcinoma in situ of the breast, prostatic intraepithelial neoplasia, superficial non-invasive bladder cancer, stage I skin cancer (except melanoma); subjects without recurrence or metastasis for > 3 years after treatment, without current evidence of tumor, and without significant risk of recurrence of previous malignant diseases in the opinion of the study doctor may also be enrolled; Serious allergy to the investigational drug or excipients (such as microcrystalline cellulose, etc.); Patients with previous (≤ 6 months before the initiation of treatment) or current severe autoimmune diseases (including adverse reactions caused by previous anti- tumor immunotherapies), or autoimmune diseases requiring long-term systemic hormone therapy at immunosuppressive dose levels (prednisone > 10 mg/day or equivalent drugs); HIV, hepatitis B virus(HBV), or hepatitis C virus(HCV) positive; Previous (≤ 6 months prior to the first dose) or current evidence of the following diseases: acute myocardial infarction, unstable angina and cerebrovascular accident; Subjects who have impaired cardiac functions or clinically significant cardiac diseases; Pregnant or lactating women

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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose escalation<br> | Drug: JAB-21822<br>* KRAS G12C inhibitor<br>Drug: JAB-3312<br>* SHP2 inhibitor<br>|
| Experimental: Dose expansion<br> | Drug: JAB-21822<br>* KRAS G12C inhibitor<br>Drug: JAB-3312<br>* SHP2 inhibitor<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| recommended phase-2 dose (RP2D). | RP2D should be selected based on a comprehensive assessment of maximum tolerated dose(MTD), toxicity, pharmacokinetic(PK) profile, and efficacy data. | Approximately 2 years | 
| Number of participants with dose limiting toxicities | Dose-limiting toxicity (DLT) is defined as an adverse event (AE) or clinically significant abnormal laboratory value occurring in Cycle 1 (DLT assessment period), which is unrelated to progressive disease, concurrent disease, or concomitant medication but related to JAB-21822 and/or JAB-3312, and meets the criteria for DLT. | Approximately 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with AEs | All patients participating in this study will be assessed for incidence and severity of AEs and serious AEs, including changes in laboratory values, vital signs, electrocardiograms, cardiac imagings and ophthalmological assessments | Approximately 2 years | 
| Objective response rate (ORR) | ORR is defined as the proportion of participants with confirmed complete response or partial response | Approximately 2 years | 
| Progression-free survival (PFS) | Period of time from the start of treatment to tumor progression or death from any cause (whichever occurs first) based on RECIST v1.1 | Approximately 2 years |