JAB-21822 in Combination With Cetuximab in Patients With Advanced CRC and Other Solid Tumors With KRAS G12C Mutation

Study Overview
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Brief Summary
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This study is to evaluate the safety, tolerability, pharmacokinetics and antitumor activity of JAB-21822 in combination with cetuximab in patients with advanced colorectal cancer，advanced small intestine cancer and advanced appendiceal cancer with KRAS p.G12C mutation.

Detailed Description
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The primary objective of this study is to evaluate the safety and tolerability of JAB-21822 in combination with cetuximab to determine the MTD and RP2D during Dose Escalation phase; then to evaluate preliminary antitumor activity when JAB-21822 is administered in combination with cetuximab during Dose Expansion phase in patients with advanced colorectal cancer，advanced small intestine cancer and advanced appendiceal cancer with KRAS p.G12C mutation.

Official Title
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A Phase Ib/II Trial of JAB-21822 in Combination With Cetuximab in Patients With Advanced Colorectal Cancer, Small Intestine Cancer and Appendiceal Cancer With KRAS G12C Mutation

Conditions
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Advanced Colorectal Cancer, Small Intestinal Cancer, Appendiceal Cancer

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must be able to provide an archived tumor sample Histologically or cytologically confirmed advanced colorectal cancer, advanced small intestinal cancer and advanced appendiceal cancer with KRAS p.G12C mutation Must have received at least 1 prior standard therapy Must have at least 1 measurable lesion per RECIST v1.1 Must have adequate organ function Must be able to swallow and retain orally administered medication Exclusion Criteria: Has brain metastases, except if treated and no evidence of radiographic progression or hemorrhage for at least 28 days Active infection requiring systemic treatment within 14 days Active HIV, HBV or HCV Any severe and/or uncontrolled medical conditions LVEF<50% assessed by ECHO QT interval >470 msec

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: Phase 1b Dose Escalation<br>Dose escalation of JAB-21822 to determine maximum tolerated dose of JAB-21822 in combination with cetuximab. | Drug: JAB-21822<br>* JAB-21822 administered orally as a tablet.<br>Drug: Cetuximab<br>* Cetuximab administered as an intravenous (IV) infusion.<br>|
| Experimental: Phase 2 Dose Expansion, Cohort 1<br>Enrollment into the dose expansion cohort is for eligible participants with KRAS P.G12C mutant advanced colorectal cancer. | Drug: JAB-21822<br>* JAB-21822 administered orally as a tablet.<br>Drug: Cetuximab<br>* Cetuximab administered as an intravenous (IV) infusion.<br>|
| Experimental: Phase 2 Dose Expansion, Cohort 2<br>Enrollment into the dose expansion cohort is for eligible participants with KRAS P.G12C mutant advanced small intestinal cancer and advanced appendiceal cancer. | Drug: JAB-21822<br>* JAB-21822 administered orally as a tablet.<br>Drug: Cetuximab<br>* Cetuximab administered as an intravenous (IV) infusion.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Escalation phase: Number of participants with dose-limiting toxicities (DLTs) | A DLT is defined as the clinically significant treatment related adverse event (TRAE) or abnormal laboratory values assessment during the first 21 days of (Cycle 1) and excludes events that are deemed clearly related to underlying disease, progression, or intercurrent illness. | At the end of Cycle 1 (each cycle is 21 days) | 
| Dose Expansion phase: Overall response rate (ORR) | ORR is defined as the percentage of participants with complete response (CR) or partial response (PR) per RECIST v 1.1. | Up to 4 years - from baseline to RECIST confirmed Progressive Disease | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Escalation and Dose Expansion phase: Number of participants with adverse events | Patients will be assessed for incidence and severity of adverse events (AEs) according to NCI-CTCAE criteria. | Up to 4 years | 
| Dose Escalation and Dose Expansion phase: Peak Plasma Concentration (Cmax) | Cmax of JAB-21822 will be measured by using plasma PK samples. | Up to 4 years | 
| Dose Escalation and Dose Expansion phase: Area under the plasma concentration versus time curve (AUC) | AUC of JAB-21822 will be measured by using plasma PK samples. | Up to 4 years | 
| Dose Expansion phase: Duration of response ( DOR ) | DOR is defined as the time from the participant's initial objective response (CR or PR) to disease progression per CTCAE v1.1 or death due to any cause, whichever occurs first. | Up to 4 years | 
| Dose Escalation phase: Overall response rate (ORR) | The percentage of participants with complete response (CR) or partial response (PR) on RECIST v 1.1. | Up to 4 years | 
| Dose Expansion phase: Disease Control Rate ( DCR ) | DCR is defined as percentage of participants with complete response (CR), partial response (PR), or stable disease(SD) per CTCAE v1.1. | Up to 4 years | 
| Dose Expansion phase: Progression-free survival (PFS) | PFS is defined as the interval of time between the date of first treatment to the earliest date of disease progression per CTCAE v1.1 or death which occurs first. | Up to 4 years |