Clinical Trials /

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

NCT02730546

Description:

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.

Related Conditions:
  • Adenocarcinoma of the Gastroesophageal Junction
  • Gastric Cardia Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: 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
  • Official Title: 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

Clinical Trial IDs

  • ORG STUDY ID: MC1541
  • SECONDARY ID: NCI-2016-00508
  • SECONDARY ID: MC1541
  • SECONDARY ID: P30CA015083
  • NCT ID: NCT02730546

Conditions

  • Gastric Cardia Adenocarcinoma
  • Gastroesophageal Junction 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

Interventions

DrugSynonymsArms
CarboplatinBlastocarb, Carboplat, Carboplatin Hexal, Carboplatino, Carbosin, Carbosol, Carbotec, CBDCA, Displata, Ercar, JM-8, Nealorin, Novoplatinum, Paraplatin, Paraplatin AQ, Paraplatine, Platinwas, RibocarboTreatment (pembrolizumab, chemotherapy, radiation, surgery)
Fluorouracil5-Fluoro-2,4(1H, 3H)-pyrimidinedione, 5-Fluorouracil, 5-Fluracil, 5-FU, AccuSite, Carac, Fluoro Uracil, Fluouracil, Flurablastin, Fluracedyl, Fluracil, Fluril, Fluroblastin, Ribofluor, Ro 2-9757, Ro-2-9757Treatment (pembrolizumab, chemotherapy, radiation, surgery)
Leucovorin CalciumAdinepar, Calcifolin, Calcium (6S)-Folinate, Calcium Folinate, Calcium Leucovorin, Calfolex, Calinat, Cehafolin, Citofolin, Citrec, citrovorum factor, Cromatonbic Folinico, Dalisol, Disintox, Divical, Ecofol, Emovis, Factor, Citrovorum, Flynoken A, Folaren, Folaxin, FOLI-cell, Foliben, Folidan, Folidar, Folinac, Folinate Calcium, folinic acid, Folinic Acid Calcium Salt Pentahydrate, Folinoral, Folinvit, Foliplus, Folix, Imo, Lederfolat, Lederfolin, Leucosar, leucovorin, Rescufolin, Rescuvolin, Tonofolin, WellcovorinTreatment (pembrolizumab, chemotherapy, radiation, surgery)
Oxaliplatin1-OHP, Ai Heng, Aiheng, Dacotin, Dacplat, Diaminocyclohexane Oxalatoplatinum, Eloxatin, Eloxatine, JM-83, Oxalatoplatin, Oxalatoplatinum, RP 54780, RP-54780, SR-96669Treatment (pembrolizumab, chemotherapy, radiation, surgery)
PaclitaxelAnzatax, Asotax, Bristaxol, Praxel, Taxol, Taxol KonzentratTreatment (pembrolizumab, chemotherapy, radiation, surgery)
PembrolizumabKeytruda, Lambrolizumab, MK-3475, SCH 900475Treatment (pembrolizumab, chemotherapy, radiation, surgery)

Purpose

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.

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 determine the safety and tolerability of pembrolizumab when
      combined with oxaliplatin, leucovorin calcium, and fluorouracil (mFOLFOX6) (without
      radiation) in locally advanced GEJ/cardia adenocarcinoma. (Phase Ib) (re-initiated) III. 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) IV. To determine the 1-year progression-free survival (PFS) rate of pembrolizumab
      when combined with mFOLFOX6 (without radiation) in locally advanced GEJ/cardia
      adenocarcinoma. (Phase II) (only if Phase Ib is re-initiated)

      SECONDARY OBJECTIVES:

      I. To determine progression-free survival (PFS), determine time to relapse (TTR),
      disease-free survival (DFS), complete resection with no tumor within 1 mm of the resection
      margins (R0) rate, and overall survival (OS) of pembrolizumab when combined with radiotherapy
      plus carboplatin and paclitaxel.

      II. To determine the progression-free survival (PFS), pathCR rate, time to relapse (TTR),
      disease-free survival (DFS), R0 rate, and overall survival (OS) of pembrolizumab when
      combined with oxaliplatin, leucovorin, and fluorouracil (FOLFOX) chemotherapy. (only if Phase
      Ib is re-initiated)

      TERTIARY 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 programmed death ligand (PDL)1 and tumor infiltrating lymphocytes (cluster
      of differentiation [CD]8+, forkhead box P3 [FOXP3]+ regulatory t cells [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 Epstein-Barr virus (EBV)-associated tumor molecular profile 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 profile 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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (pembrolizumab, chemotherapy, radiation, surgery)ExperimentalSee Detailed Description
  • Carboplatin
  • Fluorouracil
  • Leucovorin Calcium
  • Oxaliplatin
  • Paclitaxel
  • Pembrolizumab

Eligibility Criteria

        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
      
Maximum Eligible Age:70 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Pathological complete response (PathCR) rate
Time Frame:Up to 3 years
Safety Issue:
Description:Defined as number of patients with pathologic complete responses divided by total evaluable patients.

Secondary Outcome Measures

Measure:Complete resection with no tumor within 1 mm of the resection margins (R0) rate
Time Frame:Up to 3 years
Safety Issue:
Description:Defined as the number of patients who achieve R0 resection divided by total number of evaluable patients.
Measure:Disease-free survival (DFS)
Time Frame: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
Safety Issue:
Description:The distribution of DFS will be estimated using the method of Kaplan-Meier. Two-year DFS rate and confidence interval will be estimated based on Kaplan-Meier curve.
Measure:Incidence of dose-limiting toxicities assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.0
Time Frame:Up to 3 years
Safety Issue:
Description: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.
Measure:Incidence of surgical complications
Time Frame:Up to 3 years
Safety Issue:
Description:Incidence of surgical complications will be assessed.
Measure:Overall survival (OS)
Time Frame:Time from the date of study registration to the date of death due to all causes, assessed up to 3 years
Safety Issue:
Description: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.
Measure:Pathological complete response (PathCR rate) (if Phase Ib is re-initiated)
Time Frame:Up to 3 years
Safety Issue:
Description:Defined as number of patients with pathologic complete responses divided by total evaluable patients (only done as secondary endpoint for phase 1b re-initiated treatment regimen).
Measure:Progression-free survival (PFS)
Time Frame: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
Safety Issue:
Description: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. (PFS will be examined as a secondary endpoint only for the original phase 1b treatment regimen).
Measure:Time to relapse (TTR)
Time Frame: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
Safety Issue:
Description:The distribution of TTR will be estimated using the method of Kaplan-Meier. Two-year relapse-free rate and confidence interval will be estimated based on Kaplan-Meier curve.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Mayo Clinic

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