a Study to Evaluate the Safety and Efficacy of D-1553 Combined With IN10018 in KRAS G12C Mutant Solid Tumors

Study Overview
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Brief Summary
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This is a phase 1b/II, open-label study to evaluate the safety, tolerability, pharmacokinetics and antitumor activities of D-1553 in combination with IN10018 in subjects with locally advanced or metastatic solid tumor with KRAS G12C mutation.

Detailed Description
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This study includes 2 phases: Phase Ib-Dose Escalation and Phase II-Dose Expansion. Phase Ib-Dose Escalation part will enroll at least 6 subjects to identify the safety and RP2D of D1553 in combination with IN10018 in KRAS G12C mutant solid tumors. Phase II-Dose Expansion part contains 3 cohorts with cohort A to enroll advanced colorectal cancer (CRC) with KRAS G12C mutation, cohort B to enroll advanced non-small cell lung cancer (NSCLC) with KRAS G12C mutation, and cohort C to enroll other advanced solid tumors with KRAS G12C mutation. Phase II study is to evaluate the safety and antitumor activities of D-1553 in combination with IN10018 in KRAS G12C mutant solid tumors. The sample size in each cohort is estimated per Simon's 2-stage design. In Cohort A, when Simon's 2-stage study achieved statistical hypothesis, an open-label, randomized study will be conducted for factorial analysis to evaluate the contribution of IN10018 in the combination regimen.

Official Title
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A Phase 1b/II, Open-label Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Efficacy of D-1553 Combined With IN10018 in Subjects With Locally Advanced or Metastatic Solid Tumors With KRAS G12C Mutation

Conditions
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Solid Tumor

Intervention / Treatment
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* Drug: D1553
* Drug: IN10018（Ifebemtinib）


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men or women aged ≥ 18 years at the time of signing the informed consent form. Subjects with pathologically confirmed locally advanced or metastatic solid tumors. Confirmed positive KRAS G12C mutation in tumor tissue or other biospecimens (only for phase1b) containing cancer cells or DNA. Tumor types in different phases and cohorts: 1) Phase 1b: subjects with locally advanced or metastatic solid tumors who have progressed on or failed in standard therapy, and no standard treatment is available. 2) Phase II Cohort A: subjects with locally advanced or metastatic CRC. 3) Phase II Cohort B: subjects with locally advanced or metastatic NSCLC. 4) Phase 2 Cohort C: subjects with other locally advanced or metastatic solid tumors. Has measurable lesions at baseline according to RECIST 1.1 criteria. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Adequate bone marrow, liver, renal, and coagulation function within 7 days prior to the first dose. Exclusion Criteria: Prior KRAS G12C inhibitors treatment. Have known symptoms of spinal cord compression, instable or symptomatic central nervous system (CNS) metastases, and/or carcinomatous meningitis. Have a history of stroke or other serious cerebrovascular diseases within 12 months prior to the first dose. Have had interstitial lung disease or any active infection requiring systemic treatment within 14 days prior to the first dose. Has a history of severe cardiovascular disease such as acute myocardial infarction, severe/unstable angina, QTc prolongation, or poorly controlled hypertension. Haven't recovered from toxicity due to prior antitumor therapy Pregnant or lactating women. Malignant neoplasms other than study disease within 5 years prior to enrollment.

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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1b-Dose Escalation Part<br>To evaluate the safety and Recommended Phase 2 dose (RP2D) of D-1553 in combination with IN10018 in previously-treated solid tumors. | Drug: D1553<br>* D1553 orally taken，600mg twice a day<br>Drug: IN10018（Ifebemtinib）<br>* IN10018 orally taken once daily at approximately the same time each day<br>* Other names: BI 853520;|
| Experimental: Phase II Cohort A-previously-treated CRC with KRAS G12C mutation（Treatmnt Group）<br>To evaluate the safety and antitumor efficacy of D-1553 in combination with IN10018 in previously-treated CRCs with KRAS G12C mutation. | Drug: D1553<br>* D1553 orally taken，600mg twice a day<br>Drug: IN10018（Ifebemtinib）<br>* IN10018 orally taken once daily at approximately the same time each day<br>* Other names: BI 853520;|
| Active Comparator: Phase II Cohort A-previously-treated CRC with KRAS G12C mutation (Control Group)<br>To evaluate the safety and antitumor efficacy of D-1553 in previously-treated CRCs with KRAS G12C mutation. | Drug: D1553<br>* D1553 orally taken，600mg twice a day<br>|
| Experimental: Phase II Cohort B-treatment-naïve or previously-treated NSCLC with KRAS G12C mutation<br>To evaluate the safety and antitumor efficacy of D-1553 in combination with IN10018 in advanced NSCLCs with KRAS G12C mutation. | Drug: D1553<br>* D1553 orally taken，600mg twice a day<br>Drug: IN10018（Ifebemtinib）<br>* IN10018 orally taken once daily at approximately the same time each day<br>* Other names: BI 853520;|
| Experimental: Phase II Cohort C-other previously-treated solid tumors with KRAS G12C mutation<br>To evaluate the safety and antitumor efficacy of D-1553 in combination with IN10018 in other solid tumors with KRAS G12C mutation | Drug: D1553<br>* D1553 orally taken，600mg twice a day<br>Drug: IN10018（Ifebemtinib）<br>* IN10018 orally taken once daily at approximately the same time each day<br>* Other names: BI 853520;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recommended phase II dose (RP2D) of D1553 in combination with IN10018 in solid tumors with KRAS G12C mutation | Evaluate the number of patients with dose-limited toxicities (DLTs); Determine the RP2D of D1553 in combination with IN10018 in solid tumors with KRAS G12C mutation. | Through study completion, approximately 3 years | 
| Objective Response Rate (ORR) of D1553 in combination with IN10018 in solid tumors with KRAS G12C mutation | Defined as the proportion of subjects with complete response (CR) or partial response (PR). | Through study completion, approximately 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) of D1553 in combination with IN10018 in solid tumors with KRAS G12C mutation | Defined as the time from the first dose of study treatment to first documentation of disease progression or to death due to any cause, whichever comes first. | Through study completion, approximately 3 years | 
| Duration of Response (DoR) of D1553 in combination with IN10018 in solid tumors with KRAS G12C mutation | Defined as the time from start of the first documentation of CR or PR to the first documentation of disease progression or to death due to any cause, whichever comes first. | Through study completion, approximately 3 years | 
| Disease Control Rate (DCR) of D1553 in combination with IN10018 in solid tumors with KRAS G12C mutation | Defined as the proportion of patients with CR, PR, or stable disease (SD). | Through study completion, approximately 3 years | 
| Overall survival (OS) of D1553 in combination with IN10018 in solid tumors with KRAS G12C mutation | Defined as the time from the first dose of study treatment to the date of death due to any cause. | Through study completion, approximately 3 years | 
| Number of subjects with adverse event | The number of subjects who experienced AEs is presented. | Through study completion, approximately 3 years | 
| Plasma concentrations of D-1553 and IN10018 in solid tumors with KRAS G12C mutation | Plasma concentrations of D-1553 and IN10018 | Through study completion, approximately 3 years | 
| PK: Cmax of D-1553 and IN10018 | Maximum concentration (Cmax) | Through study completion, approximately 3 years | 
| PK: Cmin of D-1553 and IN10018 | Minimum concentration (Cmin) | Through study completion, approximately 3 years | 
| PK:t1/2 of D-1553 and IN10018 | Elimination half-life (t1/2). | Through study completion, approximately 3 years | 
| PK:CL/F of D-1553 and IN10018 | apparent clearance (CL/F) | Through study completion, approximately 3 years | 
| PK:Vd/F of D-1553 and IN10018 | Apparent volume of distribution (Vd/F) | Through study completion, approximately 3 years | 
| PK: AUC of D-1553 and IN10018 | Area under the concentration-time curve (AUC) | Through study completion, approximately 3 years |