Adagrasib in Combination With Nab-Sirolimus in Patients With Advanced Solid Tumors and Non-Small Cell Lung Cancer With a KRAS G12C Mutation (KRYSTAL -19)

Study Overview
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Brief Summary
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This study will evaluate the safety, MTD and/or RP2D, PK, and clinical activity of the combination of adagrasib with nab-sirolimus in patients with advanced solid tumors/NSCLC with a KRAS G12C mutation.

Detailed Description
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This study will evaluate the safety and tolerability and clinical activity of adagrasib in combination with nab-sirolimus in patients with advanced solid tumors harboring a KRAS G12C mutation. The Phase 1 portion will enroll advanced solid tumors to establish the maximum tolerated dose (MTD) and/or to identify recommended Phase 2 combinatorial doses. The Phase 2 portion will enroll patients with NSCLC to further evaluate the safety/tolerability and clinical activity. Adagrasib is an orally available small molecule inhibitor of KRAS G12C. nab-Sirolimus is a nanoparticle albumin-bound (nab) form of sirolimus, and sirolimus is an inhibitor of mechanistic target of rapamycin kinase (mTOR, previously known as mammalian target of rapamycin).

Official Title
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A Phase 1/2 Trial of Adagrasib in Combination With Nab-Sirolimus in Patients With Advanced Solid Tumors and Non-Small Cell Lung Cancer With a KRAS G12C Mutation

Conditions
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Solid Tumor, Adult, NSCLC, Advanced Cancer, Metastatic Cancer, Malignant Neoplastic Disease

Intervention / Treatment
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* Drug: Adagrasib
* Drug: nab-Sirolimus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed diagnosis of solid tumor malignancy (Phase 1) or NSCLC (Phase 2) with KRAS G12C mutation Unresectable or metastatic disease No available treatment with curative intent Adequate organ function Measurable disease per RECIST 1.1. Exclusion Criteria: History of intestinal disease, inflammatory bowel disease, major gastric surgery, or other gastrointestinal conditions likely to alter absorption of study treatment or result in inability to swallow History of interstitial lung disease or radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease or pneumonitis Cardiac abnormalities

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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Escalation and Clinical Efficacy<br>Dose escalation of adagrasib and nab-Sirolimus to determine maximum tolerated dose in combination and evaluate the clinical efficacy of adagrasib in combination with nab-sirolimus in patients with solid tumors (Phase 1) and NSCLC (Phase 2) harboring a KRAS G12C mutation | Drug: Adagrasib<br>* KRAS G12C inhibitor<br>* Other names: Krazati;Drug: nab-Sirolimus<br>* mTOR inhibitor<br>* Other names: Fyarro;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1: Safety and tolerability in the study population. | Safety characterized by the following, as noted from first dose of study treatment to 28 days after last dose of study treatment: Type, incidence, severity, timing, seriousness and relationship to study treatment of Adverse Events Laboratory abnormalities, as measured by changes in lab results such as hematologic or chemistry parameters while on study treatment Number of patients modifying or discontinuing study treatment due to an AE | 30 months | 
| Phase 1: Maximum tolerated dose (MTD) and Recommended Phase 2 Dose (RP2D) | Evaluate safety and assess number of patients with dose-limiting toxicity to determine the MTD/RP2D. | 30 months | 
| Phase 2: Objective Response Rate (ORR) using Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) (Phase 2) | ORR evaluation of subjects treated with adagrasib in combination with nab-sirolimus in patients with NSCLC with KRAS G12C mutation (Study Population) will be completed. Objective response is the proportion of subjects that experience confirmed complete response (CR) or partial response (PR) based on RECIST v1.1 during the time period from first dose of study treatment until last dose of study treatment. | 30 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the plasma concentration versus time curve (AUC) | AUC - nab-sirolimus and adagrasib | Up to 7 days | 
| Time to achieve maximal plasma concentration | Tmax - nab-sirolimus and adagrasib | Up to 1 days | 
| Maximum observed plasma concentration | Cmax - nab-sirolimus and adagrasib | Up to 1 days | 
| Terminal elimination half-life | t1/2 - nab-sirolimus | Up to 7 days | 
| Phase 1 and 2: Evaluate efficacy endpoints characterized by overall survival, progression-free survival, and duration of response in the study population. | Overall survival is defined as time from date of randomization to date of death due to any cause. Progression-free survival is defined as the time from randomization to the date of Progressive Disease (PD) or death due to any cause,whichever occurs first. Duration of response defined as the time from date of the first documentation of objective tumor response (CR or PR) to the first documentation of either PD or death due to any cause, whichever occurs first. | 30 months | 
| Phase 1: Objective Response Rate (ORR) using Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) | ORR evaluation of subjects treated with adagrasib in combination with nab-sirolimus in patients with advanced solid tumors and NSCLC with KRAS G12C mutation (Study Population) will be completed. Objective response is the proportion of subjects that experience confirmed complete response (CR) or partial response (PR) based on RECIST v1.1 during the time period from first dose of study treatment until last dose of study treatment. | 30 months | 
| Phase 2: Safety and tolerability in the study population. | Safety characterized by the following, as noted from first dose of study treatment to 28 days after last dose of study treatment: Type, incidence, severity, timing, seriousness and relationship to study treatment of Adverse Events Laboratory abnormalities, as measured by changes in lab results such as hematologic or chemistry parameters while on study treatment Number of patients modifying or discontinuing study treatment due to an AE, | 30 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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KRAS, NSCLC, Adagrasib, KRAS G12C, mTOR, nab-sirolimus, Fyarro, ABI-009