Evaluate the safety and tolerability of sotorasib in adult subjects with KRAS p.G12C mutant advanced solid tumors. Estimate the maximum tolerated dose (MTD) and/or a recommended phase 2 dose (RP2D) in adult subjects with KRAS p.G12C mutant advanced solid tumors.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
713
Characterize the pharmacokinetics (PK) of sotorasib following administration as an oral Tablet formulation
Administered as an intravenous (IV) infusion
Administered as an oral hydrochloride (HCI) syrup
Primary: Number of subjects with treatment-emergent adverse events
Treatment-emergent adverse events will be a primary outcome measure for the following groups: * Phase 1 Dose Exploration Part 1 monotherapy * Phase 1 Dose Expansion Part 2 monotherapy * Phase 1 combination arm with sotorasib and anti PD-1/L1 * Phase 1 monotherapy treatment naïve advanced NSCLC * Phase 2 monotherapy dose comparison
Time frame: 24 Months
Primary: Number of subjects with treatment-related adverse events
Treatment-related adverse events will be a primary outcome measure for the following groups: * Phase 1 Dose Exploration Part 1 monotherapy * Phase 1 Dose Expansion Part 2 monotherapy * Phase 1 combination arm with sotorasib and anti PD-1/L1 * Phase 1 monotherapy treatment naïve advanced NSCLC
Time frame: 24 Months
Primary: Number of subjects with grade ≥3 treatment-emergent adverse events
Grade ≥3 treatment-emergent adverse events will be a primary outcome measure in the following group: \- Phase 2 monotherapy dose comparison
Time frame: 24 Months
Primary: Number of subjects with serious adverse events
Serious adverse events will be a primary outcome measure in the following group: \- Phase 2 monotherapy dose comparison
Time frame: 24 Months
Primary: Number of subjects with adverse events of interest
Adverse events of interest will be a primary outcome measure in the following group: \- Phase 2 monotherapy dose comparison
Time frame: 24 Months
Primary: Number of subjects with clinically significant changes in vital signs
Vital signs will be a primary outcome measure for the following groups: * Phase 1 Dose Exploration Part 1 monotherapy * Phase 1 Dose Expansion Part 2 monotherapy * Phase 1 combination arm with sotorasib and anti PD-1/L1 * Phase 1 monotherapy treatment naïve advanced NSCLC
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City of Hope National Medical Center
Duarte, California, United States
University of California Los Angeles
Los Angeles, California, United States
University of California at SF
San Francisco, California, United States
Sarcoma Oncology Research Center LLC
Santa Monica, California, United States
Rocky Mountain Cancer Centers
Denver, Colorado, United States
Sarah Cannon Research Institute at HealthONE
Denver, Colorado, United States
Smilow Cancer Hospital at Yale New Haven
New Haven, Connecticut, United States
Medical Oncology Hematology Consultants Helen F Graham Cancer Center
Newark, Delaware, United States
University of Florida Health
Gainesville, Florida, United States
AdventHealth Orlando Infusion Center
Orlando, Florida, United States
...and 123 more locations
Time frame: Baseline to 24 Months
Primary: Number of subjects with clinically significant changes in physical examination results
Physical examinations will be a primary outcome measure for the following groups: * Phase 1 Dose Exploration Part 1 monotherapy * Phase 1 Dose Expansion Part 2 monotherapy * Phase 1 combination arm with sotorasib and anti PD-1/L1
Time frame: Baseline to 24 Months
Primary: Number of subjects with clinically significant changes on electrocardiograms (ECGs)
ECGs will be a primary outcome measure for the following groups: * Phase 1 Dose Exploration Part 1 monotherapy * Phase 1 Dose Expansion Part 2 monotherapy * Phase 1 combination arm with sotorasib and anti PD-1/L1 * Phase 1 monotherapy treatment naïve advanced NSCLC
Time frame: Baseline to 24 Months
Primary: Number of subjects with clinically significant changes in clinical laboratory values
Abnormal clinical laboratory values will be a primary outcome measure for the following groups: * Phase 1 Dose Exploration Part 1 monotherapy * Phase 1 Dose Expansion Part 2 monotherapy * Phase 1 combination arm with sotorasib and anti PD-1/L1 * Phase 1 monotherapy treatment naïve advanced NSCLC
Time frame: Baseline to 24 Months
Primary: Number of subjects with dose-limiting toxicities (DLTs)
DLTs will be a primary outcome measure for the following groups: * Phase 1 Dose Exploration Part 1 monotherapy * Phase 1 Dose Expansion Part 2 monotherapy * Phase 1 combination arm with sotorasib and anti PD-1/L1 * Phase 1 monotherapy treatment naïve advanced NSCLC
Time frame: 21 Days
Primary: Objective response rate (ORR) as assessed by RECIST 1.1 criteria
ORR will be a primary outcome measure in the following group: * Phase 1 monotherapy treatment naïve advanced NSCLC * Phase 2 monotherapy * Phase 2 monotherapy dose comparison
Time frame: 24 Months
Primary: Duration of response (DOR) as assessed by RECIST 1.1 criteria
DOR will be a primary outcome measure in the following group: \- Phase 1 monotherapy treatment naïve advanced NSCLC
Time frame: 24 Months
Primary: Disease control as assessed by RECIST 1.1 criteria
Disease control will be a primary outcome measure in the following group: \- Phase 1 monotherapy treatment naïve advanced NSCLC
Time frame: 24 Months
Primary: Duration of stable disease (SD) as assessed by RECIST 1.1 criteria
Duration of SD will be a primary outcome measure in the following group: \- Phase 1 monotherapy treatment naïve advanced NSCLC
Time frame: 24 Months
Primary: Time to response (TTR) as assessed by RECIST 1.1 criteria
TTR will be a primary outcome measure in the following group: \- Phase 1 monotherapy treatment naïve advanced NSCLC
Time frame: 24 Months
Secondary: Plasma concentration (Cmax) of sotorasib
Cmax will be a secondary outcome measure for the following groups: * Phase 1 Dose Exploration Part 1 monotherapy * Phase 1 Dose Expansion Part 2 monotherapy * Phase 2 monotherapy * Phase 1 combination arm with sotorasib and anti PD-1/L1 * Phase 1 monotherapy treatment naïve advanced NSCLC * Phase 2 monotherapy dose comparison
Time frame: 15 Weeks
Secondary: Plasma concentration (Cmax) of midazolam
Cmax of midazolam will be a secondary outcome measure for the subgroup of subjects who were administered midazolam in the following group: \- Phase 1 monotherapy treatment naïve advanced NSCLC
Time frame: 16 Days
Secondary: Time to achieve Cmax (Tmax) of sotorasib
Tmax will be a secondary outcome measure for the following groups: * Phase 1 Dose Exploration Part 1 monotherapy * Phase 1 Dose Expansion Part 2 monotherapy * Phase 2 monotherapy * Phase 1 combination arm with sotorasib and anti PD-1/L1 * Phase 1 monotherapy treatment naïve advanced NSCLC
Time frame: 15 Weeks
Secondary: Area under the plasma concentration-time curve (AUC) of sotorasib
AUC will be a secondary outcome measure for the following groups: * Phase 1 Dose Exploration Part 1 monotherapy * Phase 1 Dose Expansion Part 2 monotherapy * Phase 2 monotherapy * Phase 1 combination arm with sotorasib and anti PD-1/L1 * Phase 1 monotherapy treatment naïve advanced NSCLC * Phase 2 monotherapy dose comparison
Time frame: 15 Weeks
Secondary: Area under the plasma concentration-time curve (AUC) of midazolam
AUC of midazolam will be a secondary outcome measure for the subgroup of subjects who were administered midazolam in the following group: \- Phase 1 monotherapy treatment naïve advanced NSCLC
Time frame: 16 Days
Secondary: Clearance of midazolam from the plasma
Clearance of midazolam from the plasma will be a secondary outcome measure for the subgroup of subjects who were administered midazolam in the following group: \- Phase 1 monotherapy treatment naïve advanced NSCLC
Time frame: 16 Days
Secondary: Terminal half-life (t1/2) of midazolam
t1/2 of midazolam will be a secondary outcome measure for the subgroup of subjects who were administered midazolam in the following group: \- Phase 1 monotherapy treatment naïve advanced NSCLC
Time frame: 16 Days
Secondary: Objective response rate (ORR) as assessed by RECIST 1.1 criteria
ORR will be a secondary outcome measure for the following groups: * Phase 1 Dose Exploration Part 1 monotherapy * Phase 1 Dose Expansion Part 2 monotherapy * Phase 1 combination arm with sotorasib and anti PD-1/L1
Time frame: 24 Months
Secondary: Duration of response (DOR) as assessed by RECIST 1.1 criteria
DOR will be a secondary outcome measure for the following groups: * Phase 1 Dose Exploration Part 1 monotherapy * Phase 1 Dose Expansion Part 2 monotherapy * Phase 2 monotherapy * Phase 1 combination arm with sotorasib and anti PD-1/L1 * Phase 2 monotherapy dose comparison
Time frame: 24 Months
Secondary: Disease control as assessed by RECIST 1.1 criteria
DOR will be a secondary outcome measure for the following groups: * Phase 1 Dose Exploration Part 1 monotherapy * Phase 1 Dose Expansion Part 2 monotherapy * Phase 2 monotherapy * Phase 1 combination arm with sotorasib and anti PD-1/L1 * Phase 2 monotherapy dose comparison
Time frame: 24 Months
Secondary: Progression-free survival (PFS) as assessed by RECIST 1.1 criteria
PFS will be a secondary outcome measure for the following groups: * Phase 1 Dose Exploration Part 1 monotherapy * Phase 1 Dose Expansion Part 2 monotherapy * Phase 2 monotherapy * Phase 1 combination arm with sotorasib and anti PD-1/L1 * Phase 2 monotherapy dose comparison * Phase 1 monotherapy treatment naïve advanced NSCLC
Time frame: 24 Months
Secondary: Duration of stable disease (SD) as assessed by RECIST 1.1 criteria
Duration of SD will be a secondary outcome measure for the following groups: * Phase 1 Dose Exploration Part 1 monotherapy * Phase 1 Dose Expansion Part 2 monotherapy * Phase 1 combination arm with sotorasib and anti PD-1/L1
Time frame: 24 Months
Secondary: Depth of response (best percentage change from baseline in lesion sum diameters) as assessed by RECIST 1.1 criteria
Depth of response will be a secondary outcome measure for the following group: \- Phase 2 monotherapy dose comparison
Time frame: Baseline to 24 Months
Secondary: Time to response (TTR) as assessed by RECIST 1.1 criteria
DOR will be a secondary outcome measure for the following groups: * Phase 1 Dose Exploration Part 1 monotherapy * Phase 1 Dose Expansion Part 2 monotherapy * Phase 2 monotherapy * Phase 1 combination arm with sotorasib and anti PD-1/L1 * Phase 2 monotherapy dose comparison
Time frame: 24 Months
Secondary: Overall survival (OS)
OS will be a secondary outcome measure for the following groups: * Phase 1 Dose Exploration Part 1 monotherapy * Phase 1 Dose Expansion Part 2 monotherapy * Phase 2 monotherapy * Phase 1 combination arm with sotorasib and anti PD-1/L1 * Phase 2 monotherapy dose comparison * Phase 1 monotherapy treatment naïve advanced NSCLC
Time frame: 24 Months
Secondary: sotorasib exposure and QTc interval relationship
sotorasib exposure and QTc interval relationship will be a secondary outcome measure for the following groups: * Phase 1 Dose Exploration Part 1 monotherapy * Phase 1 Dose Expansion Part 2 monotherapy
Time frame: 24 Months
Secondary: Progression-free survival (PFS) at 6 months
PFS at 6 months will be a secondary outcome measure for the following group: \- Phase 2 monotherapy
Time frame: 6 Months
Secondary: Progression-free survival (PFS) at 12 months
PFS at 12 months will be a secondary outcome measure for the following group: \- Phase 2 monotherapy
Time frame: 12 Months
Secondary: Overall survival (OS) at 12 months
OS at 12 months will be a secondary outcome measure for the following group: \- Phase 2 monotherapy
Time frame: 12 Months
Secondary: Number of subjects with treatment-emergent adverse events
Treatment-emergent adverse events will be a secondary outcome measure for the following group: \- Phase 2 monotherapy
Time frame: 24 Months
Secondary: Number of subjects with grade ≥3 treatment-emergent adverse events
Grade ≥3 treatment-emergent adverse events will be a secondary outcome measure for the following group: \- Phase 2 monotherapy
Time frame: 24 Months
Secondary: Impact of treatment on disease-related symptoms and health related quality of life (HRQOL) as assessed by EORTC QLQ-C30
Impact of treatment on disease-related symptoms and HRQOL will be a secondary outcome measure for the following group: \- Phase 2 monotherapy dose comparison
Time frame: 24 Months
Secondary: Impact of treatment on disease-related symptoms and HRQOL as assessed by disease-specific modules Quality-of-Life Questionnaire Lung Cancer Module (QLQ LC13)
Impact of treatment on disease-related symptoms and HRQOL will be a secondary outcome measure for the following group: \- Phase 2 monotherapy dose comparison
Time frame: 24 Months
Secondary: Impact of treatment on disease-related symptoms and HRQOL as assessed by non-small cell lung cancer symptom assessment questionnaire (NSCLC SAQ) for NSCLC
Impact of treatment on disease-related symptoms and HRQOL will be a secondary outcome measure for the following group: \- Phase 2 monotherapy dose comparison
Time frame: 24 Months
Secondary: Impact of treatment on disease-related symptoms and HRQOL as assessed by Patient Global Impression of Severity (PGIS)
Impact of treatment on disease-related symptoms and HRQOL will be a secondary outcome measure for the following group: \- Phase 2 monotherapy dose comparison
Time frame: 24 Months
Secondary: Impact of treatment on disease-related symptoms and HRQOL as assessed by Patient Global Impression of Change (PGIC) in cough, dyspnea and chest pain for NSCLC
Impact of treatment on disease-related symptoms and HRQOL will be a secondary outcome measure for the following group: \- Phase 2 monotherapy dose comparison
Time frame: 24 Months
Secondary: Treatment-related symptoms and impact on the subject as assessed by EORTC QLQ-C30
Treament related symptoms and impact on the subject will be a secondary outcome measure for the following group: \- Phase 2 monotherapy dose comparison
Time frame: 24 Months
Secondary: Treatment-related symptoms and impact on the subject as assessed by selected questions from the Patient-reported Outcome of the Common Terminology Criteria for Adverse Events (PRO-CTCAE library)
Treatment-related symptoms and impact on the subject will be a secondary outcome measure for the following group: \- Phase 2 monotherapy dose comparison
Time frame: 24 Months
Secondary: Treatment-related symptoms and impact on the subject as assessed by a single item about symptom bother, item GP5 of the Functional Assessment of Cancer Therapy - General (FACT-G)
Treatment-related symptoms and impact on the subject will be a secondary outcome measure for the following group: \- Phase 2 monotherapy dose comparison
Time frame: 24 Months
Secondary: Change from baseline in physical function as assessed by EORTC QLQ-C30
Treatment-related symptoms and impact on the subject will be a secondary outcome measure for the following group: \- Phase 2 monotherapy dose comparison
Time frame: Baseline to 24 Months