A Phase 2 Trial of Chemotherapy, Pembrolizumab, and Propranolol in Advanced Esophageal/Gastroesophageal Junction Adenocarcinoma Patients
Overview
- Phase
- Phase 2
- Status
- Recruiting
- Enrollment
- 40
- Locations
- 1
- Primary Endpoint
- Overall response rate (ORR)
Overview
Brief Summary
This phase II trial tests what effects the addition of propranolol to pembrolizumab and standard chemotherapy (mFOLFOX) may have on response to treatment in patients with esophageal or gastroesophageal junction cancer that cannot be removed by surgery and has spread to nearby tissue or lymph nodes (unresectable locally advanced) or has spread from where it first started (primary site) to other places in the body (metastatic). Propranolol is a drug that is classified as a beta-blocker. Beta-blockers affect the heart and circulation (blood flow through arteries and veins). Cancer patients may be under a tremendous amount of stress with elevated levels of norepinephrine (a hormone produced by the adrenal glands in response to stress). Increased adrenergic stress may dampen the immune system, which beta-blockers, like propranolol, may be able to counteract. 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. Drugs used in the standard chemotherapy regimen, mFOLFOX (leucovorin, fluorouracil and oxaliplatin) 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. Adding propranolol to pembrolizumab and standard mFOLFOX chemotherapy may increase the effectiveness of the pembrolizumab + mFOLFOX regimen.
Detailed Description
PRIMARY OBJECTIVE:
I. To determine the clinical efficacy of propranolol in combination with pembrolizumab and standard chemotherapy in frontline metastatic esophageal or gastroesophageal junction (GEJ) adenocarcinoma.
SECONDARY OBJECTIVE:
I. To evaluate the progression-free survival, overall survival, overall response rate, and safety profile of the combination of pembrolizumab and propranolol with standard chemotherapy.
EXPLORATORY OBJECTIVE:
I. To correlate baseline or changes in the levels of biomarkers (e.g., like, peripheral T-cell subsets/myeloid-derived suppressor cells [MDSC]/cytokines), perceived stress and exercise Perceived Stress Scale (PSS) with efficacy (overall response rate [ORR], progression-free survival [PFS], overall survival [OS]), and chronotropic effect of exercise.
OUTLINE:
Patients receive mFOLFOX6 (leucovorin intravenously [IV], oxaliplatin IV, and fluorouracil IV), pembrolizumab IV, and propranolol orally (PO) on study. Patients also undergo tumor biopsy during screening and computed tomography (CT) scans and collection of blood samples during screening and on study.
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Age \>= 18 years of age.
- •Participants must be newly diagnosed, treatment-naive with unresectable locally advanced or metastatic esophageal/gastroesophageal junction (GEJ) adenocarcinoma. Any prior systemic treatment for resectable disease must be six months or before. Prior PD-1/PD-L1 treatment is allowed as long as the treatment was completed more than 1 year ago.
- •Have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1
- •Available archival Formalin-Fixed Paraffin-Embedded (FFPE) from a prior biopsy collected within 1 year or, participant must be willing to have a tissue biopsy taken prior to start of study treatment.
- •Have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria present.
- •Platelet \>= 75,000/uL
- •Hemoglobin \>= 8 g/dL (without transfusion in the past 14 days)
- •Absolute Neutrophil Count (ANC) \>= 1500/uL
- •Creatinine clearance (Cockcroft Gault) \>= 30 mL/min
- •Total bilirubin: =\< 2 × upper limit of normal (ULN) OR direct bilirubin =\< ULN for participants with total bilirubin levels \> 2 × ULN
Exclusion Criteria
- •Patients with HER 2-positive cancer.
- •Patients with active, untreated central nervous system metastases or leptomeningeal disease.
- •Patients with active autoimmune disease, requiring ongoing immunosuppressive therapy or history of transplantation.
- •Patients currently treated with systemic immunosuppressive agents: If a patient is currently on steroids, they must be on a steroid dose less than or equal to an equivalent prednisone dose of 10 mg daily.
- •Has a history of (non-infectious) pneumonitis/interstitial lung disease that required treatment.
- •Has a concurrent Human Immunodeficiency Virus (HIV) infection.
- •Concurrent active Hepatitis B (defined as Hepatitis B virus surface antigen \[HBsAg\] positive and/or detectable Hepatitis B virus \[HBV\] deoxyribonucleic acid DNA) and Hepatitis C virus (defined as anti-HCV antibody \[Ab\] positive and detectable HCV ribonucleic acid \[RNA\]) infection. Note: Hepatitis B and C screening tests are not required unless known history of HBV and HCV infection.
- •Participants that are already on beta-adrenergic (B-AR) blockers for various indications.
- •Has received prior radiotherapy within 2 weeks of start of study intervention. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (=\<2 weeks of radiotherapy) to non-central nervous system (CNS) disease.
- •Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
Arms & Interventions
Treatment (mFOLFOX6, pembrolizumab, propranolol)
Patients receive mFOLFOX6 (leucovorin IV, oxaliplatin IV, and fluorouracil IV), pembrolizumab IV, and propranolol PO on study. Patients also undergo tumor biopsy during screening and CT scans and collection of blood samples during screening and on study.
Intervention: Questionnaire Administration (Other)
Treatment (mFOLFOX6, pembrolizumab, propranolol)
Patients receive mFOLFOX6 (leucovorin IV, oxaliplatin IV, and fluorouracil IV), pembrolizumab IV, and propranolol PO on study. Patients also undergo tumor biopsy during screening and CT scans and collection of blood samples during screening and on study.
Intervention: Biopsy (Procedure)
Treatment (mFOLFOX6, pembrolizumab, propranolol)
Patients receive mFOLFOX6 (leucovorin IV, oxaliplatin IV, and fluorouracil IV), pembrolizumab IV, and propranolol PO on study. Patients also undergo tumor biopsy during screening and CT scans and collection of blood samples during screening and on study.
Intervention: Biospecimen Collection (Procedure)
Treatment (mFOLFOX6, pembrolizumab, propranolol)
Patients receive mFOLFOX6 (leucovorin IV, oxaliplatin IV, and fluorouracil IV), pembrolizumab IV, and propranolol PO on study. Patients also undergo tumor biopsy during screening and CT scans and collection of blood samples during screening and on study.
Intervention: Computed Tomography (Procedure)
Treatment (mFOLFOX6, pembrolizumab, propranolol)
Patients receive mFOLFOX6 (leucovorin IV, oxaliplatin IV, and fluorouracil IV), pembrolizumab IV, and propranolol PO on study. Patients also undergo tumor biopsy during screening and CT scans and collection of blood samples during screening and on study.
Intervention: Fluorouracil (Drug)
Treatment (mFOLFOX6, pembrolizumab, propranolol)
Patients receive mFOLFOX6 (leucovorin IV, oxaliplatin IV, and fluorouracil IV), pembrolizumab IV, and propranolol PO on study. Patients also undergo tumor biopsy during screening and CT scans and collection of blood samples during screening and on study.
Intervention: Leucovorin (Drug)
Treatment (mFOLFOX6, pembrolizumab, propranolol)
Patients receive mFOLFOX6 (leucovorin IV, oxaliplatin IV, and fluorouracil IV), pembrolizumab IV, and propranolol PO on study. Patients also undergo tumor biopsy during screening and CT scans and collection of blood samples during screening and on study.
Intervention: Oxaliplatin (Drug)
Treatment (mFOLFOX6, pembrolizumab, propranolol)
Patients receive mFOLFOX6 (leucovorin IV, oxaliplatin IV, and fluorouracil IV), pembrolizumab IV, and propranolol PO on study. Patients also undergo tumor biopsy during screening and CT scans and collection of blood samples during screening and on study.
Intervention: Pembrolizumab (Biological)
Treatment (mFOLFOX6, pembrolizumab, propranolol)
Patients receive mFOLFOX6 (leucovorin IV, oxaliplatin IV, and fluorouracil IV), pembrolizumab IV, and propranolol PO on study. Patients also undergo tumor biopsy during screening and CT scans and collection of blood samples during screening and on study.
Intervention: Propranolol Hydrochloride (Drug)
Outcomes
Primary Outcomes
Overall response rate (ORR)
Time Frame: Within 6 months of initiating combination therapy
Efficacy of pembrolizumab in combination with propranolol with standard chemotherapy measured by ORR by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, which is treated as a dichotomous variable and will be summarized using frequencies and relative frequencies.
Secondary Outcomes
- Progression-free survival(Initiation of the study treatment regimen to disease progression or death from any cause, assessed up to 2 years)
- Incidence of toxicities and adverse events(Up to 30 days after the last intervention)
- Overall survival(Treatment initiation until death from any cause, assessed up to 2 years)
- ORR(Within 6 months of initiating combination therapy)