Clinical Trials /

Pembrolizumab, Capecitabine, and Radiation Therapy in Treating Patients With Mismatch-Repair Deficient and Epstein-Barr Virus Positive Gastric Cancer

NCT03257163

Description:

This phase II trial studies how well pembrolizumab works with capecitabine and radiation therapy in treating patients with mismatch repair deficient and Epstein-Barr virus positive gastric cancer. Monoclonal antibodies, such as pembrolizumab may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as capecitabine, 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, capecitabine and radiation therapy may work better at treating gastric cancer.

Related Conditions:
  • Gastric Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Pembrolizumab, Capecitabine, and Radiation Therapy in Treating Patients With Mismatch-Repair Deficient and Epstein-Barr Virus Positive Gastric Cancer
  • Official Title: A Phase II Study of Preoperative Pembrolizumab for Mismatch-Repair Deficient and Epstein-Barr Virus Positive Gastric Cancer Followed by Chemotherapy and Chemoradiation With Pembrolizumab

Clinical Trial IDs

  • ORG STUDY ID: 071702
  • SECONDARY ID: NCI-2017-01429
  • SECONDARY ID: 071702
  • SECONDARY ID: P30CA072720
  • NCT ID: NCT03257163

Conditions

  • Epstein-Barr Virus Positive
  • Gastric Adenocarcinoma
  • Mismatch Repair Protein Deficiency
  • 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 III Gastric Cancer AJCC v7
  • Stage IIIA Gastric Cancer AJCC v7
  • Stage IIIB Gastric Cancer AJCC v7
  • Stage IIIC Gastric Cancer AJCC v7

Interventions

DrugSynonymsArms
CapecitabineTreatment (pembrolizumab, capecitabine, radiation therapy)
PembrolizumabTreatment (pembrolizumab, capecitabine, radiation therapy)

Purpose

This phase II trial studies how well pembrolizumab works with capecitabine and radiation therapy in treating patients with mismatch repair deficient and Epstein-Barr virus positive gastric cancer. Monoclonal antibodies, such as pembrolizumab may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as capecitabine, 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, capecitabine and radiation therapy may work better at treating gastric cancer.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To assess efficacy (disease-free survival) of operable gastric cancer treated with PD-1
      blockade using pembrolizumab.

      SECONDARY OBJECTIVES:

      I. To characterize the safety and tolerability of pembrolizumab in the preoperative setting
      and postoperative setting with chemoradiation.

      II. To evaluate response rates, recurrence rates, and patterns of recurrence/metastasis.

      III. To characterize adverse events (AE) of pembrolizumab in combination with radiation
      therapy and capecitabine.

      IV. To evaluate overall survival rates.

      TERTIARY OBJECTIVES:

      I. To assess T cell responses and pathological responses in the tumor specimen. II. To
      correlate PD-L1 expression in tumor tissue and stroma with tumor tissue response.

      III. To evaluate ribonucleic acid (RNA) expression via Nanostring technology with tumor
      tissue response.

      OUTLINE:

      Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Treatment repeats
      every 21 days for up to 2 courses in the absence of disease progression or unacceptable
      toxicity. Within 2-6 weeks, patients undergo surgery. Beginning up to 56 days after surgery,
      patients receive pembrolizumab IV over 30 minutes on day 1 and capecitabine orally (PO) twice
      daily (BID) on days 1-14. Treatment repeats every 21 days for up to 5 courses in the absence
      of disease progression or unacceptable toxicity. Within 2-6 weeks of resting, patients
      continue to receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 21
      days for up to 11 courses in the absence of disease progression or unacceptable toxicity.
      Beginning course 4, patients undergo radiation therapy over 15-30 minutes on days 1-5 for up
      to 5 weeks.

      After completion of study treatment, patients are followed up every 12 weeks for 1 year,
      every 16 weeks for 2 years, every 4 months for year 2, and every 6 months for 2 years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (pembrolizumab, capecitabine, radiation therapy)ExperimentalPatients receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 2 courses in the absence of disease progression or unacceptable toxicity. Within 2-6 weeks, patients undergo surgery. Beginning up to 56 days after surgery, patients receive pembrolizumab IV over 30 minutes on day 1 and capecitabine PO BID on days 1-14. Treatment repeats every 21 days for up to 5 courses in the absence of disease progression or unacceptable toxicity. Within 2-6 weeks of resting, patients continue to receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 11 courses in the absence of disease progression or unacceptable toxicity. Beginning course 4, patients undergo radiation therapy over 15-30 minutes on days 1-5 for up to 5 weeks.
  • Capecitabine

Eligibility Criteria

        Inclusion Criteria:

          -  Written informed consent for the trial

          -  Must have operable gastric adenocarcinoma, T2-T4a, N0-N3, M0

          -  Staging evaluation within 42 days of enrollment consisting of staging laparoscopy,
             computed tomography (CT) scan of the abdomen and pelvis, and positron emission
             tomography (PET) scan will be acquired; also endoscopic ultrasound (EUS) tumor and
             nodal staging will be required

          -  Mismatch repair deficiency as identified by immunohistochemistry or other
             institutional standard, or Epstein-Barr virus positivity as determined by in situ
             hybridization or other institutional standard

          -  Be willing to provide tissue from a newly obtained core or excisional biopsy of a
             tumor lesion; newly-obtained is defined as a specimen obtained up to 10 weeks (70
             days) prior to initiation of treatment on day 1; subjects for whom newly-obtained
             samples cannot be provided (e.g. inaccessible or subject safety concern) may submit an
             archived specimen (if available from prior biopsy) only upon agreement from the
             sponsor

          -  Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG)
             performance scale

          -  Absolute neutrophil count (ANC) >= 1,500 /mcL

          -  Platelets >= 100,000 / mcL

          -  Hemoglobin >= 7 g/dL or >= 5.6 mmol/L with transfusion or erythropoietin (EPO)
             dependency

          -  Serum creatinine =< 1.5 X upper limit of normal (ULN) OR measured or calculated
             creatinine clearance (glomerular filtration rate [GFR] can also be used in place of
             creatinine or creatinine clearance [CrCl]) >= 60 mL/min for subject with creatinine
             levels > 1.5 X institutional ULN

          -  Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for subjects with total
             bilirubin levels > 1.5 ULN

          -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and
             alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X
             ULN

          -  Albumin >= 2.5 mg/dL

          -  International normalized ratio (INR) or prothrombin time (PT) =< 1.5 X ULN unless
             subject is receiving anticoagulant therapy as long as PT or partial thromboplastin
             time (PTT) is within therapeutic range of intended use of anticoagulants

          -  Activated partial thromboplastin time (aPTT) =< 1.5 X ULN unless subject is receiving
             anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use
             of anticoagulants

          -  Female subject of childbearing potential should have a negative urine or serum
             pregnancy within 7 days of enrollment; if the urine test is positive or cannot be
             confirmed as negative, a serum pregnancy test will be required

          -  Female subjects of childbearing potential must be willing to use an adequate method of
             contraception for the course of the study through 120 days after the last dose of
             study medication; Note: abstinence is acceptable if this is the usual lifestyle and
             preferred contraception for the subject

          -  Male subjects of childbearing potential 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 usual
             lifestyle and preferred contraception for the subject

        Exclusion Criteria:

          -  Presence of metastatic disease is not allowed; subjects must be evaluated with imaging
             consisting of CT scan and PET scan prior to enrollment for protocol therapy to exclude
             metastatic disease

          -  Prior chemotherapy, adjuvant therapy, or radiotherapy for gastric cancer

          -  Prior radiotherapy that overlaps with planned radiotherapy portal

          -  Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
             other form of immunosuppressive therapy within 7 days prior to the first dose of trial
             treatment

          -  Has a known history of active TB (Bacillus tuberculosis)

          -  Hypersensitivity to pembrolizumab or any of its excipients

          -  Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study
             day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events
             due to agents administered more than 4 weeks earlier

          -  Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy
             within 2 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at
             baseline) from adverse events due to a previously administered agent

               -  Note: subjects with =< grade 2 neuropathy are an exception to this criterion and
                  may qualify for the study

               -  Note: if subject received major surgery, they must have recovered adequately from
                  the toxicity and/or complications from the intervention prior to starting therapy

          -  Has a known additional malignancy that is progressing or requires active treatment;
             exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the
             skin that has undergone potentially curative therapy or in situ cervical cancer

          -  Has active autoimmune disease that has required systemic treatment in the past 2 years
             (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive
             drugs); replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid
             replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
             form of systemic treatment

          -  Has a history of (non-infectious) pneumonitis that required steroids or current
             pneumonitis

          -  Evidence of interstitial lung disease

          -  Has an active infection requiring systemic therapy

          -  Has a history or current evidence of any condition, therapy, or laboratory abnormality
             that might confound the results of the trial, interfere with the subject?s
             participation for the full duration of the trial, or is not in the best interest of
             the subject to participate, in the opinion of the treating investigator

          -  Has known psychiatric or substance abuse disorders that would interfere with
             cooperation with the requirements of the trial

          -  Is pregnant or breastfeeding, or expecting to conceive or father children within the
             projected duration of the trial, starting with the pre-screening or screening visit
             through 120 days after the last dose of trial treatment

          -  Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent

          -  Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)

          -  Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or
             hepatitis C (e.g., hepatitis C virus (HCV) RNA [qualitative] is detected)

          -  Has received a live vaccine within 30 days of planned start of study therapy; Note:
             seasonal influenza vaccines for injection are generally inactivated flu vaccines and
             are allowed; however intranasal influenza vaccines (e.g., Flu-Mist) are live
             attenuated vaccines, and are not allowed
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Recurrence-free survival (RFS) rate
Time Frame:3 years
Safety Issue:
Description:At the time of analysis (after 18 months of accrual and 18 additional months of follow-up), will compute a Kaplan-Meier survival curve and will compare the observed survival rate at three years to the historical level of 0.45.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Rutgers, The State University of New Jersey

Last Updated

October 9, 2017