This phase Ib/II trial studies the best dose of carboplatin when given together with berzosertib, gemcitabine and pembrolizumab and to see how well it works in treating patients with stage IV squamous cell non-small cell lung cancer that has spared to other placed in the body (advanced). Berzosertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Chemotherapy drugs, such as carboplatin and gemcitabine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving berzosertib together with carboplatin, gemcitabine, and pembrolizumab may work better in treating patients with squamous cell non-small cell lung cancer compared to carboplatin, gemcitabine, and pembrolizumab alone.
PRIMARY OBJECTIVES: I. To determine the recommended phase 2 dose (RP2D) of carboplatin in combination with berzosertib (M6620) and gemcitabine/pembrolizumab, in patients with squamous cell non-small cell lung cancer (Sq-NSCLC). (Lead-in Phase 1B) II. To compare progression-free survival (PFS) of carboplatin/gemcitabine/pembrolizumab with and without berzosertib (M6620, VX-970) in patients with Sq-NSCLC, as measured by a hazard ratio in an intent-to-treat analysis. (Phase 2) SECONDARY OBJECTIVES: I. To compare progression-free survival (PFS) of carboplatin/gemcitabine/pembrolizumab with and without berzosertib (M6620, VX-970) in patients with Sq-NSCLC, as measured by a hazard ratio in an as-treated analysis. II. To compare PFS of carboplatin/gemcitabine/pembrolizumab with and without berzosertib (M6620, VX-970) in patients with ataxia telangiectasia mutated (ATM)-deficient Sq-NSCLC, as measured by a hazard ratio. III. To compare overall survival (OS) and overall response rate (ORR) of carboplatin/gemcitabine/pembrolizumab with and without berzosertib (M6620, VX-970), in patients with chemotherapy-naive Sq-NSCLC. IV. To determine the systemic drug exposure of berzosertib (M6620, VX-970) and gemcitabine, as correlates of efficacy and toxicity. V. To determine the safety and tolerability of berzosertib (M6620, VX-970) in combination with carboplatin/gemcitabine/pembrolizumab. VI. To observe and record anti-tumor activity. EXPLORATORY OBJECTIVES: I. To identify molecular subpopulations of patients who have increased sensitivity to the berzosertib (M6620, VX-970)/carboplatin/gemcitabine/pembrolizumab combination. II. To explore the prognostic and predictive qualities of the ATM immunohistochemistry (IHC) assay for clinical response and PFS. III. To explore inflammation-associated gene signatures and clinical response. OUTLINE: This is a phase Ib, dose de-escalation study of carboplatin followed by a phase II study. Patients are randomized to 1 of 2 arms. ARM A: Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1, gemcitabine hydrochloride IV over 30 minutes on days 1 and 8, carboplatin IV over 30 minutes on day 1, and berzosertib IV over 60 minutes on days 2 and 9. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive pembrolizumab IV over 30 minutes on day 1 and berzosertib IV over 60 minutes on days 2 and 9. Cycles repeat every 21 days for up to 9 months in the absence of disease progression or unacceptable toxicity. Patients then receive pembrolizumab alone IV over 30 minutes on day 1. Cycles repeat every 6 weeks for up to 1 more year in the absence of disease progression or unacceptable toxicity. Patients undergo magnetic resonance imaging (MRI) scans and/or computed tomography (CT) scans, and undergo blood specimen collection on study. ARM B: Patients receive pembrolizumab, gemcitabine hydrochloride, and carboplatin as in Arm A. Patients undergo MRI scans and/or CT scans, and undergo blood specimen collection on study. After completion of study treatment, patients are followed up every 3 months for 12 months.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
12
Given IV
Correlative studies
Given IV
Undergo CT
Given IV
Undergo MRI
Given IV
Keck Medicine of USC Koreatown
Los Angeles, California, United States
Los Angeles General Medical Center
Los Angeles, California, United States
USC / Norris Comprehensive Cancer Center
Los Angeles, California, United States
USC Norris Oncology/Hematology-Newport Beach
Newport Beach, California, United States
UM Sylvester Comprehensive Cancer Center at Aventura
Aventura, Florida, United States
Patients Who Experienced a DLT
Percentage of patients who experienced Dose Limiting Toxicities (DLTs) when treated with carboplatin in combination with berzosertib (M6620, VX-970), per CTCAE v5.0
Time frame: Up to completion of cycle 1
Recommended Phase 2 Dose (RP2D)
Determined by the number of patients who experienced Dose Limiting Toxicities (DLTs) when treated with carboplatin in combination with berzosertib (M6620, VX-970), per CTCAE v5.0, DLT is defined as the severe toxicity event that leads to the termination of the treatment. The RP2D is the highest dose level where \<2/6 DLTs are observed.
Time frame: Up to completion of cycle 1
12-month Progression-free Survival (PFS) - Total Population
Percentage of patients with Progression-free survival (PFS) will be estimated within disease cohorts by the product-limit (Kaplan-Meier) estimator, along with 95% confidence regions, from start of treatment to time of progression or death, whichever occurs first. Per RECIST v1.1 Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression).
Time frame: At 12 months
24-month Progression-free Survival (PFS) - Total Population
Percentage of patients with Progression-free survival (PFS) will be estimated within disease cohorts by the product-limit (Kaplan-Meier) estimator, along with 95% confidence regions, from start of treatment to time of progression or death, whichever occurs first. Per RECIST v1.1 Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression).
Time frame: At 24 months
Progression-free Survival (PFS) - Total Population
Median PFS will be estimated within disease cohorts by the product-limit (Kaplan-Meier) estimator, along with 95% confidence regions. Measured from start of treatment to time of progression or death, whichever occurs first. Per RECIST v1.1 Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression).
Time frame: Up to 30 months
12-month Progression-free Survival (PFS) - By Dose Level
Percentage of patients with Progression-free survival (PFS) will be estimated within disease cohorts by the product-limit (Kaplan-Meier) estimator, along with 95% confidence regions, from start of treatment to time of progression or death, whichever occurs first. Per RECIST v1.1 Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression).
Time frame: At 12 months
24-month Progression-free Survival (PFS) - Dose Level 1
Percentage of patients with Progression-free survival (PFS) will be estimated within disease cohorts by the product-limit (Kaplan-Meier) estimator, along with 95% confidence regions, from start of treatment to time of progression or death, whichever occurs first. Per RECIST v1.1 Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression).
Time frame: At 24 months
Progression-free Survival (PFS) - By Dose Level
Median PFS will be estimated within disease cohorts by the product-limit (Kaplan-Meier) estimator, along with 95% confidence regions. Measured from start of treatment to time of progression or death, whichever occurs first. Per RECIST v1.1 Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression).
Time frame: Up to 30 months
Best Overall Response - Total Population
Percentage of patients with Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progressive Disease (PD) per RECIST v1.1. CR: Disappearance of all target lesions. Any pathological lymph nodes (target or nontarget) with reduction in short axis to \<10 mm; PR: ≥30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters or SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters. PD: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression).
Time frame: Up to 12 months post treatment
Best Overall Response - By Dose Level
Percentage of patients with Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progressive Disease (PD) per RECIST v1.1, CR: Disappearance of all target lesions. Any pathological lymph nodes (target or nontarget) with reduction in short axis to \<10 mm; PR: ≥30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters or SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters. PD: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression).
Time frame: Up to 12 months post treatment
12-month Overall Survival (OS) - Total Population
Percentage of patients alive from start of treatment.
Time frame: At 12 months
24-month Overall Survival (OS) - Total Population
Percentage of patients alive from start of treatment.
Time frame: At 24 months
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.
UM Sylvester Comprehensive Cancer Center at Coral Gables
Coral Gables, Florida, United States
UM Sylvester Comprehensive Cancer Center at Deerfield Beach
Deerfield Beach, Florida, United States
University of Miami Miller School of Medicine-Sylvester Cancer Center
Miami, Florida, United States
University of Kansas Clinical Research Center
Fairway, Kansas, United States
HaysMed
Hays, Kansas, United States
...and 24 more locations
Overall Survival (OS) - Total Population
Median number of months that patients remain alive from start of treatment.
Time frame: Up to 30 months post treatment
12-month Overall Survival (OS) - By Dose Level
Percentage of patients alive from start of treatment.
Time frame: At 12 months
24-month Overall Survival (OS) - By Dose Level
Percentage of patients alive from start of treatment.
Time frame: At 24 months
Overall Survival (OS) - By Dose Level
Median number of months that patients remain alive from start of treatment.
Time frame: Up to 30 months post treatment
Worst Grade of Adverse Events
Number of patients with adverse events per Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, determined to be at least possibly related to treatment.
Time frame: Up to 12 months post treatment
PFS in Ataxia Telangiectasia Mutated (ATM)-Deficient Sq-NSCLC
Progression Free Survival in ataxia telangiectasia mutated (ATM)-deficient Sq-NSCLC. Median PFS estimated within disease cohorts by the product-limit (Kaplan-Meier) estimator, along with 95% confidence regions. Measured from start of treatment to time of progression or death, whichever occurs first. Per RECIST v1.1 Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression).
Time frame: Up to 30 months