Trial of Two Adagrasib Dosing Regimens in NSCLC With KRAS G12C Mutation (KRYSTAL 21)

Study Overview
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Brief Summary
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This study will evaluate the efficacy of two dosing regimens of adagrasib (600 mg BID versus 400 mg BID) in patients with NSCLC with KRAS G12C mutation.

Detailed Description
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849-021 is a phase 2 study of adagrasib monotherapy in which patients are randomized between two dosing regimens. The study will evaluate the efficacy of two dosing regimens of adagrasib (600 mg BID without regard to food versus 400 mg BID with food) in patients with NSCLC with KRAS G12C mutation and who have received prior treatment with a platinum-based regimen and immune checkpoint inhibitor therapy.

Official Title
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A Randomized Study of Two Dosing Regimens of Adagrasib in Patients With Previously Treated Non-Small Cell Lung Cancer With KRAS G12C Mutation

Conditions
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Advanced Cancer, Metastatic Cancer, Malignant Neoplasm of Lung

Intervention / Treatment
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* Drug: Adagrasib


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Are at least 18 years old (or old enough to legally make their own treatment decisions, according to local laws). Have advanced NSCLC or metastatic NSCLC (NSCLC that started in the lungs and then spread to other parts of the body) with the KRAS G12C mutation. Have had previous treatment with 1) chemotherapy that included a drug called cisplatin or a drug called carboplatin and 2) a type of drug called an immune checkpoint inhibitor. Have recovered from their prior treatment and blood tests are within a safe range. Key Exclusion Criteria: Have had previous treatment with a drug that targets KRAS G12C. Have cancer that can potentially be removed with surgery. Patients with brain lesions are not eligible if 1) any untreated brain lesions are > 2.0 cm in size 2) any brainstem lesions are present 3) ongoing steroid dosing >10 mg daily prednisone (or equivalent) and 4) poorly controlled (> 1/week) generalized or complex partial seizures or neurologic progression/instability due to brain lesions. Have certain medical conditions or need to take certain medications that, in the opinion of a trial doctor, could make it unsafe for them to participate or difficult to complete the trial assessments, or are pregnant.

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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Adagrasib 600mg BID<br>Adagrasib 600mg BID without regard to food | Drug: Adagrasib<br>* KRAS G12C inhibitor<br>* Other names: Krazati;|
| Experimental: Adagrasib 400mg BID<br>Adagrasib 400mg BID with food | Drug: Adagrasib<br>* KRAS G12C inhibitor<br>* Other names: Krazati;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) using Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). | ORR evaluation of subjects treated with adagrasib 600 mg BID without regard to food versus 400 mg BID with food having NSCLC with KRAS G12C mutation (Study Population) will be completed per blinded independent central radiology (BICR) review. 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 1st dose of adagrasib until last dose of adagrasib. | 30 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate Overall Survival (OS). | Overall survival is defined as time from date of randomization to date of death due to any cause. | 45 months | 
| Evaluate Progression Free Survival (PFS). | Progression-free survival is defined as time from date of randomization to date of first progression per RECIST 1.1 or death from any cause, whichever occurs first. | 30 months | 
| Evaluate Duration of Response (DOR). | 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 (per BICR review) or death due to any cause, whichever occurs first. | 30 months | 
| Safety and tolerability in the study population. | Safety characterized by number of participants with AEs, with abnormal laboratory test results and number of patients modifying or discontinuing study treatment due to an AE: 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 Adverse Event. | 30 months | 
| Population pharmacokinetic (PK) Model Derived Area Under the Curve During the Dosing Interval at Steady State (AUCtau,ss). | Sparse concentration data from this study will be pooled with other studies and analyzed using population PK methods to derive individual exposure parameters. Data for this Outcome Measure will not be reported here since ClinicalTrials.gov is designed for reporting results from only those participants who were enrolled in the study and described in the Participant Flow and Baseline Characteristics modules. | Pre-dose and 4-6 hours post dose; up to 6 months. | 
| Patient-reported symptoms during adagrasib administration from first dose to 28 days after last dose of adagrasib. | Patient reported outcomes (PROs) will be used to assess symptomatic toxicity of adagrasib using the NCI Patient Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) Measurement System. PRO items reflect the specific symptom 1) frequency, severity, interference with usual or daily activities, 2) amount, or 3) presence or absence. PRO-CTCAE responses are scored from 0 (low) to 4 (high), or 0/1 for absent/present, and scores for each attribute (frequency, severity and/or interference) are presented descriptively. | 30 months | 
| Patient -reported quality of life during adagrasib administration from first dose to End of Treatment visit. | Patient reported quality of life questionnaire will be used to assess five dimensions of patient health: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression using the 5-Level EQ-5D version (EQ-5D-5L) established by the EuroQol Group. This is presented descriptively, and patient responses correspond to a value of 1 (low) or 5 (high). Additionally, a one- page Visual Analog Scale (VAS) will be provided to patients so they may report their self-rated health from the best (100) and worst (0) health imaginable. | 30 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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KRAS G12C, Non-small cell lung cancer, Metastatic cancer, NSCLC