Advanced Cancer, Malignant Neoplastic Disease, Metastatic Cancer, NSCLC, Solid Tumor, Adult
Conditions
Keywords
KRAS, NSCLC, Adagrasib, KRAS G12C, mTOR, nab-sirolimus, Fyarro, ABI-009
Brief summary
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
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).
Interventions
DRUGAdagrasib
KRAS G12C inhibitor
DRUGnab-Sirolimus
mTOR inhibitor
Sponsors
Aadi Bioscience, Inc.
Mirati Therapeutics Inc.
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1: Safety and tolerability in the study population. | 30 months | 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 |
| Phase 1: Maximum tolerated dose (MTD) and Recommended Phase 2 Dose (RP2D) | 30 months | Evaluate safety and assess number of patients with dose-limiting toxicity to determine the MTD/RP2D. |
| Phase 2: Objective Response Rate (ORR) using Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) (Phase 2) | 30 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Terminal elimination half-life | Up to 7 days | t1/2 - nab-sirolimus |
| Phase 1 and 2: Evaluate efficacy endpoints characterized by overall survival, progression-free survival, and duration of response in the study population. | 30 months | 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. |
| Area under the plasma concentration versus time curve (AUC) | Up to 7 days | AUC - nab-sirolimus and adagrasib |
| Phase 2: Safety and tolerability in the study population. | 30 months | 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, |
| Phase 1: Objective Response Rate (ORR) using Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) | 30 months | 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 to achieve maximal plasma concentration | Up to 1 days | Tmax - nab-sirolimus and adagrasib |
| Maximum observed plasma concentration | Up to 1 days | Cmax - nab-sirolimus and adagrasib |
Countries
United States
Outcome results
None listed