This phase I trial seeks to find out the best dose, possible benefits and/or side effects of entinostat in combination with atezolizumab, carboplatin and etoposide for the treatment of previously untreated aggressive lung cancer that has spread (extensive-stage small cell lung cancer). Entinostat and etoposide may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as atezolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Carboplatin is a chemotherapy drug that attaches to deoxyribonucleic acid (DNA) and may kill tumor cells. Giving entinostat in combination with atezolizumab, carboplatin and etoposide may work better than atezolizumab, carboplatin and etoposide alone.
PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose (MTD) of entinostat in combination with carboplatin, etoposide, and atezolizumab. II. To determine safety and tolerability of adding entinostat to carboplatin / etoposide / atezolizumab for extensive-stage small cell lung cancer (ES-SCLC). III. To determine the feasibility of administering entinostat concomitantly with atezolizumab, carboplatin, and etoposide as determined by the proportion of patients who receive 3 or more cycles of the combination. SECONDARY OBJECTIVES: I. To observe and record anti-tumor activity. II. To determine the proportion of patients who are alive and without disease progression at 9 months (9 month progression free survival \[PFS\]) after starting entinostat, carboplatin, etoposide, and atezolizumab. EXPLORATORY OBJECTIVES: I. To estimate the clinical activity of entinostat plus carboplatin/etoposide/atezolizumab as determined by response rate (RR), progression free survival (PFS), and overall survival (OS). II. To explore the prevalence of cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) binding protein (CREBBP)/ histone acetyltransferase p300 (EP300) mutations in newly diagnosed ES-SCLC population. III. To explore the relationship between CREBBP/EP300 mutations and clinical outcomes. IV. To explore immune biomarkers that may predict response to atezolizumab and entinostat and changes in these biomarkers over the course of study treatment. V. To explore entinostat exposure-response relationships with toxicity and clinical outcomes (PFS and OS). VI. To evaluate baseline atezolizumab clearance as an early biomarker for OS and to assess the relationship between atezolizumab time-varying clearance, cachexia and clinical outcomes (PFS and OS). OUTLINE: This is a dose-escalation study of entinostat. INDUCTION THERAPY: Patients receive carboplatin intravenously (IV) over 30-60 minutes on day 1, etoposide IV over 60 minutes on days 1-3, atezolizumab IV over 30-60 minutes on day 1, and entinostat orally (PO) on days 1, 8, and 15. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. MAINTENANCE THERAPY: Patients receive atezolizumab IV over 30 minutes on day 1 and entinostat PO on days 1, 8, and 15. Treatment repeats every 21 days for up to 13 cycles in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days, every 3 months for 2 years, then every 6 months for 3 years.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
3
Memorial Sloan Kettering Cancer Center
New York, New York, United States
University of Pittsburgh Cancer Institute (UPCI)
Pittsburgh, Pennsylvania, United States
Huntsman Cancer Institute/University of Utah
Salt Lake City, Utah, United States
University of Virginia Cancer Center
Charlottesville, Virginia, United States
University of Wisconsin Carbone Cancer Center
Madison, Wisconsin, United States
Number of Participants With Dose Limiting Toxicities
The Bayesian optimal interval (BOIN) design will be used to find the MTD based on safety as determined by dose limiting toxicities.
Time frame: Up to 21 days
Number of Participants Experiencing Grade 3 and 4 Adverse Events
Defined by Common Terminology Criteria for Adverse Events version 5.0. Will be summarized by frequency and magnitude.
Time frame: Up to 30 days
Number of Participants Who Received 3 or More Cycles of the Combination of Entinostat, Atezolizumab, Carboplatin, and Etoposide
The proportion of participants who received 3 or more cycles of the combination, will be calculated with a 90% confidence interval.
Time frame: Up to cycle 4 (1 cycle = 21 days)
Progression Free Survival (PFS) Rate
Defined as the proportion of patients alive and without disease progression. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. Will be estimated with a 90% confidence interval. The Kaplan Meier estimator will be used to estimate survival curves.
Time frame: Up to 2 months
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