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Propranolol in Combination With Pembrolizumab and Standard Chemotherapy for the Treatment of Unresectable Locally Advanced or Metastatic Esophageal or Gastroesophageal Junction Adenocarcinoma

Primary Purpose

Clinical Stage II Esophageal Adenocarcinoma AJCC v8, Clinical Stage III Esophageal Adenocarcinoma AJCC v8, Clinical Stage III Gastroesophageal Junction Adenocarcinoma AJCC v8

Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Biopsy
Biospecimen Collection
Computed Tomography
Fluorouracil
Leucovorin
Oxaliplatin
Pembrolizumab
Propranolol Hydrochloride
Questionnaire Administration
Sponsored by
Roswell Park Cancer Institute
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Clinical Stage II Esophageal Adenocarcinoma AJCC v8

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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 Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase) (SGOT) and alanine transaminase (ALT) (serum glutamic-pyruvic transaminase) (SGPT) =< 3 X institutional ULN (=< 5 × ULN for participants with liver metastases) Participants of child-bearing potential must have a negative pregnancy test at study entry and then agree to use adequate contraceptive methods (e.g., hormonal or barrier method of birth control; abstinence) prior to study entry. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Ability to swallow and retain oral medication. Participant must understand the investigational nature of this study and sign an Independent Ethics Committee/Institutional Review Board approved written informed consent form prior to receiving any study related procedure. 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. Pregnant or nursing female participants, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive human chorionic gonadotropin (hCG) laboratory test. Other active cancers that require systemic treatment. Contraindications to the use of beta-blockers, e.g.: uncontrolled depression, unstable angina pectoris, uncontrolled heart failure ( Grade III or IV), hypotension (systolic blood pressure <100 mmHg), severe asthma or chronic obstructive pulmonary disease (COPD), uncontrolled type I or type II diabetes mellitus (HbA1C > 8.5 or fasting plasma glucose > 160 mg/dl at screening), symptomatic peripheral arterial disease or Raynaud's syndrome, untreated pheochromocytoma etc. Has received a live vaccine or live-attenuated vaccine within 30 days prior to the first dose of trial treatment and while participating in the trial. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster etc. Unwilling or unable to follow protocol requirements. Any condition which in the Investigator's opinion deems the participant an unsuitable candidate to receive study drug.

Sites / Locations

  • Roswell Park Cancer InstituteRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (mFOLFOX6, pembrolizumab, propranolol)

Arm Description

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.

Outcomes

Primary Outcome Measures

Overall response rate (ORR)
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 Outcome Measures

Incidence of toxicities and adverse events
Will be assessed as per Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0.
Progression-free survival
Will be summarized using standard Kaplan Meier methods.
Overall survival
Will be summarized using standard Kaplan Meier methods.
ORR
ORR as determined by Immune-Modified (i)RECIST.

Full Information

First Posted
December 7, 2022
Last Updated
July 28, 2023
Sponsor
Roswell Park Cancer Institute
Collaborators
United States Department of Defense
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1. Study Identification

Unique Protocol Identification Number
NCT05651594
Brief Title
Propranolol in Combination With Pembrolizumab and Standard Chemotherapy for the Treatment of Unresectable Locally Advanced or Metastatic Esophageal or Gastroesophageal Junction Adenocarcinoma
Official Title
A Phase 2 Trial of Chemotherapy, Pembrolizumab, and Propranolol in Advanced Esophageal/Gastroesophageal Junction Adenocarcinoma Patients
Study Type
Interventional

2. Study Status

Record Verification Date
July 2023
Overall Recruitment Status
Recruiting
Study Start Date
March 7, 2023 (Actual)
Primary Completion Date
March 30, 2026 (Anticipated)
Study Completion Date
March 30, 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Roswell Park Cancer Institute
Collaborators
United States Department of Defense

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
Yes
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Clinical Stage II Esophageal Adenocarcinoma AJCC v8, Clinical Stage III Esophageal Adenocarcinoma AJCC v8, Clinical Stage III Gastroesophageal Junction Adenocarcinoma AJCC v8, Clinical Stage IV Esophageal Adenocarcinoma AJCC v8, Clinical Stage IV Gastroesophageal Junction Adenocarcinoma AJCC v8, Locally Advanced Esophageal Adenocarcinoma, Locally Advanced Gastroesophageal Junction Adenocarcinoma, Metastatic Esophageal Adenocarcinoma, Metastatic Gastroesophageal Junction Adenocarcinoma, Unresectable Esophageal Adenocarcinoma, Unresectable Gastroesophageal Junction Adenocarcinoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
40 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Treatment (mFOLFOX6, pembrolizumab, propranolol)
Arm Type
Experimental
Arm Description
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 Type
Procedure
Intervention Name(s)
Biopsy
Other Intervention Name(s)
BIOPSY_TYPE, Bx
Intervention Description
Undergo tissue collection
Intervention Type
Procedure
Intervention Name(s)
Biospecimen Collection
Other Intervention Name(s)
Biological Sample Collection, Biospecimen Collected, Specimen Collection
Intervention Description
Undergo collection of blood samples
Intervention Type
Procedure
Intervention Name(s)
Computed Tomography
Other Intervention Name(s)
CAT, CAT Scan, Computed Axial Tomography, Computerized Axial Tomography, Computerized Tomography, CT, CT Scan, tomography
Intervention Description
Undergo CT scans
Intervention Type
Drug
Intervention Name(s)
Fluorouracil
Other Intervention Name(s)
5 Fluorouracil, 5 Fluorouracilum, 5 FU, 5-Fluoro-2,4(1H, 3H)-pyrimidinedione, 5-Fluorouracil, 5-Fluracil, 5-Fu, 5FU, AccuSite, Carac, Fluoro Uracil, Fluouracil, Flurablastin, Fluracedyl, Fluracil, Fluril, Fluroblastin, Ribofluor, Ro 2-9757, Ro-2-9757
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Leucovorin
Other Intervention Name(s)
Folinic acid
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Oxaliplatin
Other Intervention Name(s)
1-OHP, Ai Heng, Aiheng, Dacotin, Dacplat, Diaminocyclohexane Oxalatoplatinum, Eloxatin, Eloxatine, JM-83, Oxalatoplatin, Oxalatoplatinum, RP 54780, RP-54780, SR-96669
Intervention Description
Given IV
Intervention Type
Biological
Intervention Name(s)
Pembrolizumab
Other Intervention Name(s)
Keytruda, Lambrolizumab, MK-3475, SCH 900475
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Propranolol Hydrochloride
Other Intervention Name(s)
Inderal, Innopran XL
Intervention Description
Given PO
Intervention Type
Other
Intervention Name(s)
Questionnaire Administration
Intervention Description
Perceived Stress Scale
Primary Outcome Measure Information:
Title
Overall response rate (ORR)
Description
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.
Time Frame
Within 6 months of initiating combination therapy
Secondary Outcome Measure Information:
Title
Incidence of toxicities and adverse events
Description
Will be assessed as per Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0.
Time Frame
Up to 30 days after the last intervention
Title
Progression-free survival
Description
Will be summarized using standard Kaplan Meier methods.
Time Frame
Initiation of the study treatment regimen to disease progression or death from any cause, assessed up to 2 years
Title
Overall survival
Description
Will be summarized using standard Kaplan Meier methods.
Time Frame
Treatment initiation until death from any cause, assessed up to 2 years
Title
ORR
Description
ORR as determined by Immune-Modified (i)RECIST.
Time Frame
Within 6 months of initiating combination therapy

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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 Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase) (SGOT) and alanine transaminase (ALT) (serum glutamic-pyruvic transaminase) (SGPT) =< 3 X institutional ULN (=< 5 × ULN for participants with liver metastases) Participants of child-bearing potential must have a negative pregnancy test at study entry and then agree to use adequate contraceptive methods (e.g., hormonal or barrier method of birth control; abstinence) prior to study entry. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Ability to swallow and retain oral medication. Participant must understand the investigational nature of this study and sign an Independent Ethics Committee/Institutional Review Board approved written informed consent form prior to receiving any study related procedure. 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. Pregnant or nursing female participants, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive human chorionic gonadotropin (hCG) laboratory test. Other active cancers that require systemic treatment. Contraindications to the use of beta-blockers, e.g.: uncontrolled depression, unstable angina pectoris, uncontrolled heart failure ( Grade III or IV), hypotension (systolic blood pressure <100 mmHg), severe asthma or chronic obstructive pulmonary disease (COPD), uncontrolled type I or type II diabetes mellitus (HbA1C > 8.5 or fasting plasma glucose > 160 mg/dl at screening), symptomatic peripheral arterial disease or Raynaud's syndrome, untreated pheochromocytoma etc. Has received a live vaccine or live-attenuated vaccine within 30 days prior to the first dose of trial treatment and while participating in the trial. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster etc. Unwilling or unable to follow protocol requirements. Any condition which in the Investigator's opinion deems the participant an unsuitable candidate to receive study drug.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Sarbajit Mukherjee
Organizational Affiliation
Roswell Park Cancer Institute
Official's Role
Principal Investigator
Facility Information:
Facility Name
Roswell Park Cancer Institute
City
Buffalo
State/Province
New York
ZIP/Postal Code
14263
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Sarbajit Mukherjee
Phone
716-845-7405
Email
Sarbajit.Mukherjee@RoswellPark.org
First Name & Middle Initial & Last Name & Degree
Sarbajit Mukherjee

12. IPD Sharing Statement

Learn more about this trial

Propranolol in Combination With Pembrolizumab and Standard Chemotherapy for the Treatment of Unresectable Locally Advanced or Metastatic Esophageal or Gastroesophageal Junction Adenocarcinoma

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