A Phase 1 Study of Entinostat in Combination With Atezolizumab / Carboplatin / Etoposide in Previously Untreated Extensive-Stage Small Cell Lung Cancer

National Cancer Institute (NCI)5 sites in 1 country3 target enrollmentApril 27, 2021

ConditionsExtensive Stage Lung Small Cell Carcinoma Malignant Solid Neoplasm Metastatic Malignant Neoplasm in the Brain

InterventionsAtezolizumab Carboplatin Entinostat Etoposide

Overview

Phase: Phase 1
Intervention: Atezolizumab
Conditions: Extensive Stage Lung Small Cell Carcinoma
Sponsor: National Cancer Institute (NCI)
Enrollment: 3
Locations: 5
Primary Endpoint: Number of Participants Experiencing Grade 3 and 4 Adverse Events
Status: Completed
Last Updated: 7 months ago

Overview Investigators Eligibility Criteria Arms & Interventions Outcomes Sites Similar Trials

Overview

Brief Summary

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.

Detailed Description

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.

Registry

clinicaltrials.gov

Start Date

April 27, 2021

End Date

July 11, 2023

Last Updated

7 months ago

Study Type

Interventional

Study Design

Single Group

Sex

All

Investigators

Sponsor

National Cancer Institute (NCI)

Responsible Party

Sponsor

Eligibility Criteria

Inclusion Criteria

•Patients must have histologically or cytologically confirmed extensive stage SCLC (ES-SCLC) or other solid tumors for which carboplatin and etoposide are considered appropriate therapy
•No prior systemic therapy for extensive-stage, metastatic disease. Patients with prior limited stage disease who were treated with chemotherapy and concurrent radiation will be permitted to enroll as long as their previous treatment was 12 months or more prior to study enrollment
•Patients with treated brain metastases are eligible if they have stable symptoms and no ongoing requirement for corticosteroids as therapy for brain metastases
•Patients with untreated or progressive brain metastases (active brain metastases) are eligible if the treating physician determines that immediate CNS specific treatment is not required and is unlikely to be required during the first cycle of therapy. There must be no ongoing requirement for corticosteroids as therapy for brain metastases
•Previous radiation, including whole brain radiation, is allowed \>= 7 days of study registration. Stereotactic radiation therapy within 7 days is permitted
•Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.
•At least one measurable lesion should be extra-cranial and outside of any portal of irradiation
•Archival tissue must be available, or patients must be willing to undergo a new biopsy to provide pre-treatment tumor sample (no intervening chemotherapy treatment, tissue must be from current extensive-stage/metastatic diagnosis)
•Eastern Cooperative Oncology Group (ECOG) performance status =\< 2 (Karnofsky \>= 60%)
•Absolute neutrophil count \>= 1,500/mcL

Exclusion Criteria

•Patients with evidence of leptomeningeal metastases (either by imaging or central nervous system \[CNS\] fluid findings)
•Patients who are receiving any other investigational agents
•History of allergic reactions attributed to compounds of similar chemical or biologic composition to entinostat or other agents used in study
•Patients with uncontrolled intercurrent illness
•Patients with psychiatric illness/social situations that would limit compliance with study requirements
•Pregnant women are excluded from this study because entinostat is HDACi agent with the potential for teratogenic or abortifacient effects and because of known teratogenic and abortifacient effects of cisplatin and etoposide. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with entinostat, and known risks with cisplatin and etoposide, breastfeeding should be discontinued if the mother is treated with entinostat. These potential risks may also apply to other agents used in this study
•Patients with a history of autoimmune disease (notable exceptions include hypothyroidism on thyroid replacement medication, type I diabetes, psoriasis or other cutaneous disease controlled with topical agents and without flare in 12 months requiring other treatment, celiac disease controlled with diet alone)
•Patients with a history of pulmonary fibrosis (history of radiation pneumonitis/fibrosis in the treatment field is permitted if stable and not requiring supplemental oxygen or corticosteroid use)
•Patients with prior history of allogeneic bone marrow or solid organ transplant
•Ongoing use of systemic corticosteroids or immunosuppressive agents within 14 days (inhaled corticosteroids, \< 7 day course of prednisone for asthma/chronic obstructive pulmonary disease \[COPD\] exacerbation, or chronic low-dose supplemental steroids for adrenal insufficiency permitted)

Arms & Interventions

Treatment (carboplatin, etoposide, atezolizumab, entinostat)

INDUCTION THERAPY: Patients receive carboplatin 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 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.

Intervention: Atezolizumab