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.
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).
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
6
KRAS G12C inhibitor
mTOR inhibitor
Local Institution - 019-104
Cleveland, Ohio, United States
Local Institution - 019-101
Nashville, Tennessee, United States
Local Institution - 019-102
Houston, Texas, United States
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: 1. Type, incidence, severity, timing, seriousness and relationship to study treatment of Adverse Events 2. Laboratory abnormalities, as measured by changes in lab results such as hematologic or chemistry parameters while on study treatment 3. Number of patients modifying or discontinuing study treatment due to an AE
Time frame: 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.
Time frame: 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.
Time frame: 30 months
Area under the plasma concentration versus time curve (AUC)
AUC - nab-sirolimus and adagrasib
Time frame: Up to 7 days
Time to achieve maximal plasma concentration
Tmax - nab-sirolimus and adagrasib
Time frame: Up to 1 days
Maximum observed plasma concentration
Cmax - nab-sirolimus and adagrasib
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Time frame: Up to 1 days
Terminal elimination half-life
t1/2 - nab-sirolimus
Time frame: 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.
1. Overall survival is defined as time from date of randomization to date of death due to any cause. 2. 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. 3. 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.
Time frame: 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.
Time frame: 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: 1. Type, incidence, severity, timing, seriousness and relationship to study treatment of Adverse Events 2. Laboratory abnormalities, as measured by changes in lab results such as hematologic or chemistry parameters while on study treatment 3. Number of patients modifying or discontinuing study treatment due to an AE,
Time frame: 30 months