Pembrolizumab, Combination Chemotherapy, and Radiation Therapy Before Surgery in Treating Adult Patients With Locally Advanced Gastroesophageal Junction or Gastric Cardia Cancer That Can Be Removed by Surgery

Phase 1b/2 Clinical Trial of Neoadjuvant Pembrolizumab Plus Concurrent Chemoradiotherapy With Weekly Carboplatin and Paclitaxel in Adult Patients With Resectable, Locally Advanced Adenocarcinoma of the Gastroesophageal Junction or Gastric Cardia

This phase Ib/II trial studies the side effects and best way to give pembrolizumab with combination chemotherapy and radiation therapy before surgery and to see how well it works in treating adult patients with gastroesophageal junction or gastric cardia cancer that has spread from where it started to nearby tissue and can be removed by surgery. Monoclonal antibodies, such as pembrolizumab, may block tumor growth in different ways by targeting certain cells. Drugs used in chemotherapy 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. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Giving pembrolizumab, combination chemotherapy, and radiation therapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed.

Study Overview

• Status: Completed
• Conditions: Gastroesophageal Junction Adenocarcinoma; Gastric Cardia Adenocarcinoma; Stage IB Gastric Cancer AJCC v7; Stage II Gastric Cancer AJCC v7; Stage IIA Gastric Cancer AJCC v7; Stage IIB Gastric Cancer AJCC v7; Stage IIIA Gastric Cancer AJCC v7; Stage IIIB Gastric Cancer AJCC v7
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Drug: Carboplatin; Drug: Paclitaxel; Biological: Pembrolizumab; Radiation: Radiation Therapy; Drug: Fluorouracil; Drug: Oxaliplatin; Procedure: Positron Emission Tomography; Procedure: Computed Tomography; Drug: Leucovorin Calcium; Procedure: Therapeutic Conventional Surgery

Detailed Description

PRIMARY OBJECTIVES:

I. To determine the safety and tolerability of pembrolizumab when combined with radiotherapy plus carboplatin and paclitaxel in locally advanced gastroesophageal junction (GEJ)/cardia adenocarcinoma. (Phase Ib) II. To evaluate the pathological complete response (pathCR) rate of pembrolizumab when combined with radiotherapy plus carboplatin and paclitaxel in locally advanced GEJ/cardia adenocarcinoma. (Phase II)

SECONDARY OBJECTIVES:

I. To determine progression-free survival (PFS), determine time to relapse (TTR), disease-free survival (DFS), R0 rate, and overall survival (OS) of pembrolizumab when combined with radiotherapy plus carboplatin and paclitaxel.

TRANSLATIONAL RESEARCH OBJECTIVES:

I. To identify tissue and/or circulating biomarkers that are associated with pathCR, DFS, and other clinical outcomes in patients with locally advanced GEJ/cardia adenocarcinoma treated with neoadjuvant pembrolizumab-based therapy.

II. To determine differences in pre-treatment vs post-treatment tissue expression of immune markers, including PDL1 and tumor infiltrating lymphocytes (CD8+, FOXP3+ Tregs, CD45RO, granzyme B), in patients treated with neoadjuvant pembrolizumab-based therapy.

III. To identify immune markers in pretreatment tissues that correlate with pathCR and long-term outcome in patients treated with neoadjuvant pembrolizumab-based therapy.

IV. To explore whether an EBV-associated tumor molecular profile89 is associated with pathCR and long-term outcome in patients treated with neoadjuvant pembrolizumab-based therapy.

V. To explore whether a microsatellite-unstable (MSI) tumor molecular profile89 is associated with pathCR and long-term outcome in patients treated with neoadjuvant pembrolizumab-based therapy.

OUTLINE:

NEOADJUVANT TREATMENT: Patients receive pembrolizumab intravenously (IV) over 30 minutes on days -7, 15, and 36 and carboplatin IV and paclitaxel IV over 1-96 hours on days 1, 8, 15, 22 and 29. Patients also undergo radiation therapy once daily (QD) 5 days per week for 4 weeks and 3 days (23 fractions).

Patients with progressive disease receive pembrolizumab IV over 30 minutes, paclitaxel IV over 1-96 hours, and carboplatin IV on day 1. Treatment repeats every 21 days for 2-4 courses in the absence of disease progression or unacceptable toxicity.

NEOADJUVANT TREATMENT (RE-INITIATED): Patients receive pembrolizumab IV over 30 minutes on days 1 and 22 and oxaliplatin IV over 2-6 hours, leucovorin calcium IV over 15 minutes to 2 hours, and fluorouracil IV over 46-48 hours on days 1, 15, and 29. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.

Patients with progressive disease receive pembrolizumab IV over 30 minutes on days 1 and 22, oxaliplatin IV over 2-6 hours, leucovorin calcium over 15 minutes to 2 hours, and fluorouracil IV over 46-48 hours on days 1, 15, and 29. Treatment repeats every 41 days (6 weeks) for 1-3 courses in the absence of disease progression or unacceptable toxicity.

SURGERY: Within 5-8 weeks after completion of radiation therapy or 3-6 weeks after completion of chemotherapy for patients receiving chemotherapy alone, patients undergo curative-intent surgery.

ADJUVANT TREATMENT: Patients receive pembrolizumab IV over 30 minutes every 21 days. Treatment repeats every 21 days for up to 6 courses 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 1 year, every 4 months for 1 year, and then every 6 months for 1 year.

• Study Type: Interventional
• Enrollment (Actual): 31
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Phoenix, Arizona, United States, 85054
      • Mayo Clinic Hospital
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Histologically or cytologically confirmed adenocarcinoma involving the gastroesophageal junction or gastric cardia

• Central pathology review to determine evaluability of archived esophagogastroduodenoscopy (EGD)/biopsy sample

  • NOTE: If archived sample was collected > 8 weeks prior to pre-registration (reg), is not available in a timely manner, or was collected outside of Mayo Clinic and considered unevaluable, then baseline EGD with primary tumor biopsy at Mayo Clinic must be performed unless clinically contraindicated; patient is allowed to enroll regardless of whether this Mayo Clinic tissue sample is evaluable; (Only 1 EGD with primary tumor biopsy performed at Mayo Clinic =< 8 weeks prior to pre-reg is required)
  • NOTE: For both archival or newly obtained tissue, only biopsies are adequate (fine needle aspiration [FNA] is not adequate)
• Willing to provide mandatory tissue samples for research purposes
• Baseline imaging with an fludeoxyglucose (FDG)-positron emission tomography (PET) scan negative for distant metastatic disease must be obtained =< 28 days prior to registration

• Surgically resectable (T2N0, T3N0, Tany with node positivity, M0), as determined by endoscopic ultrasound (EUS) and the following minimum diagnostic work-up:

  • Whole-body PET/computed tomography (CT) (PET/CT of skull base to mid-thigh is acceptable)
  • EUS =< 21 days prior to registration
  • NOTE: Patients may have regional adenopathy including para-esophageal, gastric, gastrohepatic and celiac nodes; if celiac adenopathy is present, it must be < 2 cm
  • NOTE: If patient unable to have PET/CT then CT chest/abdomen/pelvis with contrast (preferred) or MRI chest/abdomen/pelvis with contrast

• Surgical consultation at enrolling site to confirm that patient will be able to undergo curative resection after completion of chemoradiation =< 56 days prior to registration

  • Tumor is amenable to standard resection and reconstruction

• Radiation oncology consultation at enrolling site to confirm that disease can be encompassed in a radiotherapy field =< 56 days prior to registration

  • NOTE: Radiotherapy quality assurance rapid review must be performed before the first fraction of radiation therapy (RT) is administered; if RT constraints cannot be met, the patient will be removed from the protocol prior to treatment
• Consultation with a medical oncologist at enrolling site =< 56 days prior to registration, with determination that treatment with neoadjuvant chemoradiotherapy with weekly carboplatin and paclitaxel is considered acceptable
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
• Adequate oral intake and nutritional status without current or likely need for enteral or parenteral feeding during chemoradiation or the preoperative period
• Pre-treatment pulmonary function tests (PFTs), collected =< 90 days prior to enrollment, must show forced expiratory volume in one second (FEV1) > 60% of predicted

• Adequate organ function =< 21 days prior to registration:

  • Aspartate transaminase (AST) level =< 2.5 x upper limit of normal (ULN) and alanine transaminase (ALT) =< 3 x upper limit of normal (ULN)
  • Total bilirubin level of =< 1.5 x ULN
  • Creatinine level =< 1.2 x ULN or creatinine clearance > 60 mL/min/1.73 m^2 for patients with creatinine levels above or below the institutional normal
  • Hemoglobin (Hgb) >= 9 g/dl without transfusion or epoetin dependency (=< 7 days prior to assessment)
  • Absolute neutrophil count >= 1.5 x 10^9/L
  • Platelets >= 100 x 10^9/L
  • Albumin >= 2.5 g/dl

• Female patients of childbearing potential must be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication

  • NOTE: Patients of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year

• Female patients of childbearing potential must have a negative urine or serum pregnancy test =< 7 days prior to registration

  • NOTE: If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required

• Male patients must agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy

  • NOTE: Abstinence is acceptable if this is the established and preferred method of contraception for the subject
• Provide signed written informed consent
• Willing to return to enrolling institution for follow-up

• Willing to provide mandatory tissue and blood samples for research purposes

  • NOTE: Patients must be willing to provide at the time surgical resection; for patients who do not undergo surgery, any on-study tumor biopsy obtained for clinical purposes subsequent to the baseline biopsy must also be available for analysis

Exclusion Criteria:

• Tumor characteristics - any of the following are excluded:

  • Evidence of distant metastases
  • Tumors whose location is restricted to the tubular esophagus (i.e., without involvement of the GEJ or cardia)
  • Tumors whose proximal end are at the level of the carina or higher
  • Invasion of the tracheobronchial tree or presence of tracheoesophageal fistula
  • Palpable supraclavicular nodes, biopsy-proven involvement of supraclavicular nodes, or radiographically involved supraclavicular nodes (> 1.5 cm in greatest dimension)
  • T1N0M0, T4Nany, or in situ carcinoma
  • Tumor must not extend 5 or more cm into the stomach
• Received prior treatment or receiving current treatment for this malignancy
• Prior radiation to chest or abdomen, or to > 30% of the marrow cavity
• Inadequate caloric or fluid intake whereby there is a current or likely future need for enteral or parenteral feeding during chemoradiation or the preoperative period
• Major surgery =< 4 weeks prior to registration
• Active autoimmune disorders, including patients known to be human immunodeficiency virus (HIV) positive, or those requiring chronic steroid administration (excluding inhaled steroids)
• Uncontrolled diabetes (i.e., will interfere with the performance of the FDG PET/CT scans)
• Prior allergic reactions to drugs containing Cremophor, such as teniposide or cyclosporine, or study drugs involved in this protocol, or to a monoclonal antibody or prior hypersensitivity to platinum-containing agents

• Heart conditions - any of the following:

  • Any atrial fibrillation =< 3 months prior to registration
  • Unstable angina =< 12 months prior to registration
  • Prior symptomatic congestive heart failure
  • Documented myocardial infarction =< 6 months prior to registration (pretreatment electrocardiogram [ECG] evidence of infarct only will not exclude patients)
  • Prior significant ventricular arrhythmia requiring medication
  • Prior 2nd or 3rd degree heart block or other types of clinically significant conduction delay =< 6 months prior to registration
  • Clinically significant pericardial disease (including pericardial effusion, pericarditis) or cardiac valvular disease =< 12 months prior to registration
  • NOTE: As part of history and physical, all patients must be assessed for signs or symptoms of cardiac disease, or for prior history of cardiac disease; these conditions include but are not limited to diseases related to cardiac valves, pericardium, myocardium, atrioventricular delays or arrhythmias; it is strongly recommended that signs or symptoms of potentially clinically significant disease be evaluated with comprehensive cardiac echo
• Prior pancreatitis that was symptomatic or required medical intervention =< 6 months prior to registration (known toxicity of pembrolizumab)
• Prior enteritis that was symptomatic or required medical intervention =< 6 months prior to registration (known toxicity of pembrolizumab)
• Uncontrolled hyper/hypothyroidism or hyper/hypocorticism =< 6 months prior to registration (known toxicity of pembrolizumab)

• Pulmonary conditions - any of the following:

  • Respiratory condition that required any oxygen supplementation =< 6 months prior to registration
  • Prior or current pneumonitis
  • Clinically significant pulmonary hypertension =< 12 months prior to registration
  • Lung infection requiring treatment =< 3 months prior to registration
  • Pulmonary embolism requiring treatment =< 6 months prior to registration
  • Pleural effusion requiring drainage =< 12 months prior to registration
• Prior fistula within thorax, including bronchoalveolar or esophageal
• Body mass index (BMI) >= 35 mg/m^2 =< 56 days prior to registration
• Pre-existing motor or sensory neurotoxicity greater than Common Terminology Criteria for Adverse Events (CTCAE) grade 1
• Acute bacterial, viral, or fungal infection requiring treatment at the time of registration
• Active infection or other serious underlying medical condition which would impair the ability of the patient to receive the planned treatment
• Uncontrolled intercurrent illness including, but not limited to, psychiatric illness/social situations, or other co-morbid systemic illnesses or severe concurrent diseases which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens
• Prior malignancy =< 5 years prior to registration (except non-melanotic skin cancer or carcinoma-in-situ of the cervix) (must be disease free for a minimum of 5 years); if there is a history of prior malignancy, patient must not be receiving other specific treatment (other than hormonal therapy) for cancer
• Dementia or altered mental status that would prohibit the understanding and giving of informed consent

• Any of the following because this study involves an agent where the genotoxic, mutagenic and teratogenic effects are unknown:

  • Pregnant or breastfeeding
  • Patient of childbearing potential who is unwilling to employ adequate contraception
• Received live vaccine =< 30 days prior to registration

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (pembrolizumab, chemotherapy, radiation, surgery); See Detailed Description

Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Carboplatin; Given IV; Other Names: Blastocarb; Carboplat; Carboplatin Hexal; Carboplatino; Carbosin; Carbosol; Carbotec; CBDCA; Displata; Ercar; JM-8; Nealorin; Novoplatinum; Paraplatin; Paraplatin AQ; Paraplatine; Platinwas; Ribocarbo; Drug: Paclitaxel; Given IV; Other Names: Taxol; Anzatax; Asotax; Bristaxol; Praxel; Taxol Konzentrat; Biological: Pembrolizumab; Given IV; Other Names: Keytruda; MK-3475; Lambrolizumab; SCH 900475; Radiation: Radiation Therapy; Undergo radiation therapy; Other Names: Cancer Radiotherapy; Irradiate; Irradiated; Radiotherapeutics; RT; Therapy, Radiation; irradiation; radiotherapy; RADIATION; Drug: Fluorouracil; Given IV; Other Names: 5-FU; 5-Fluracil; Fluracil; 5-Fluoro-2,4(1H, 3H)-pyrimidinedione; 5-Fluorouracil; AccuSite; Carac; Fluoro Uracil; Fluouracil; Flurablastin; Fluracedyl; Fluril; Fluroblastin; Ribofluor; Ro 2-9757; Ro-2-9757; Drug: Oxaliplatin; Given IV; Other Names: 1-OHP; Dacotin; Dacplat; Eloxatin; Ai Heng; Aiheng; Diaminocyclohexane Oxalatoplatinum; Eloxatine; JM-83; Oxalatoplatin; Oxalatoplatinum; RP 54780; RP-54780; SR-96669; Procedure: Positron Emission Tomography; Undergo PET scan; Other Names: Medical Imaging, Positron Emission Tomography; PET; PET Scan; Positron Emission Tomography Scan; Positron-Emission Tomography; proton magnetic resonance spectroscopic imaging; Procedure: Computed Tomography; Undergo CT scan; Other Names: CT; CAT; CAT Scan; Computerized Axial Tomography; tomography; computerized tomography; CT SCAN; Drug: Leucovorin Calcium; Given IV; Other Names: Wellcovorin; citrovorum factor; folinic acid; Adinepar; Calcifolin; Calcium (6S)-Folinate; Calcium Folinate; Calcium Leucovorin; Calfolex; Calinat; Cehafolin; Citofolin; Citrec; Cromatonbic Folinico; Dalisol; Disintox; Divical; Ecofol; Emovis; Factor, Citrovorum; Flynoken A; Folaren; Folaxin; FOLI-cell; Foliben; Folidan; Folidar; Folinac; Folinate Calcium; Folinic Acid Calcium Salt Pentahydrate; Folinoral; Folinvit; Foliplus; Folix; Imo; Lederfolat; Lederfolin; Leucosar; leucovorin; Rescufolin; Rescuvolin; Tonofolin; Procedure: Therapeutic Conventional Surgery; Undergo curative-intent surgery

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pathological Complete Response (PathCR) Rate	Defined as number of patients with pathologic complete responses (pCR) divided by total evaluable patients. pCR is defined as no recognized cancer and margins free of tumor as found by the pathologist following resection of the esophageal specimen and accompanying lymph nodes.	Up to 3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete Resection With no Tumor Within 1 mm of the Resection Margins (R0) Rate	Defined as the number of patients who achieve R0 resection divided by total number of evaluable patients.	Up to 3 years
Disease-free Survival (DFS)	The median DFS and confidence interval will be estimated using the method of Kaplan-Meier.	Time from the date of study registration to the date of death due to all causes or recurrence, whichever occurs first, among patients who achieved an R0 resection, assessed up to 3 years
Time to Relapse (TTR)	The median TTR and confidence interval will be estimated using the method of Kaplan-Meier.	Time from the date of study registration to the date of 1st documented relapse/recurrence among patients who achieve R- resection, assessed up to 3 years
Overall Survival (OS)	The distribution of OS will be estimated using the method of Kaplan-Meier. Two-year OS rate and confidence interval will be estimated based on Kaplan-Meier curve.	Time from the date of study registration to the date of death due to all causes, assessed up to 3 years
Progression-free Survival (PFS)	The distribution of PFS will be estimated using the method of Kaplan-Meier. Two-year PFS rate and confidence interval will be estimated based on Kaplan-Meier curve.	Time from the date of study registration to the date of death due to all causes, recurrences if R0 resections are achieved, progression disease before undergoing surgery, or R1/R2 resection at surgery, whichever comes first, assessed up to 3 years
Incidence of Dose-limiting Toxicities (DLTs) Assessed by Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0	The maximum grade for each type of adverse events that are possibly, probably or definitely related to study treatments will be recorded for each patient. The frequency tables will be reviewed to determine the patterns.	Up to 3 years

Collaborators and Investigators

• Sponsor: Mayo Clinic
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Harry H. Yoon, M.D., Mayo Clinic

Study record dates

Study Major Dates

• Study Start (Actual): June 24, 2016
• Primary Completion (Actual): July 1, 2021
• Study Completion (Actual): October 31, 2023

Study Registration Dates

• First Submitted: April 1, 2016
• First Submitted That Met QC Criteria: April 1, 2016
• First Posted (Estimated): April 6, 2016

Study Record Updates

• Last Update Posted (Actual): April 18, 2024
• Last Update Submitted That Met QC Criteria: April 16, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Stomach Diseases; Stomach Neoplasms; Adenocarcinoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Protective Agents; Antineoplastic Agents, Phytogenic; Antineoplastic Agents, Immunological; Micronutrients; Vitamins; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents; Immune Checkpoint Inhibitors; Antidotes; Vitamin B Complex; Hematinics; Carboplatin; Paclitaxel; Fluorouracil; Oxaliplatin; Pembrolizumab; Leucovorin; Calcium; Levoleucovorin; Albumin-Bound Paclitaxel; Folic Acid; Calcium, Dietary
• Other Study ID Numbers: MC1541 (Mayo Clinic); NCI-2016-00508 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); 15-005311 (Other Identifier: Mayo Clinic Institutional Review Board)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No