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Pembrolizumab with Chemotherapy and Radiation Therapy before Surgery for the Treatment of Stage II-IV Rectal Cancer

Trial Status: Active

This phase I trial investigates the side effects of pembrolizumab in combination with chemotherapy and radiation therapy before surgery, and to see how well they work in treating patients with stage II-IV rectal cancer. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the tumor, and may interfere with the ability of tumor cells to grow and spread. Chemotherapy drugs, such as capecitabine and fluorouracil, 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 to kill tumor cells and shrink tumors. Giving pembrolizumab with chemotherapy and radiation therapy before surgery may make the tumor smaller and may prevent cancer from returning.

Inclusion Criteria

  • Subjects must have confirmed rectal adenocarcinoma defined as, magnetic resonance imaging (MRI) based clinical stage II (T3-4, N0), stage III (T1-4, N+), or oligometastatic locally advanced stage IV that are candidates for curative surgery
  • Tumor location at and/or below the peritoneal reflection on MRI
  • Review and discussion at multidisciplinary tumor board with consensus recommendation for neoadjuvant chemoradiation followed by curative-intent surgery. Documented in EPIC health record system (EPIC) tumor board
  • MMR-deficiency confirmed on immunohistochemistry or microsatellite instability (MSI) status confirmed by polymerase chain reaction (PCR)
  • Eastern Cooperative Oncology Group (ECOG) performance status 0-1
  • Life expectancy of >= 6 months, in the opinion of and as documented by the treating physician
  • Hemoglobin >= 8.0 g/dL
  • Leukocytes >= 3,000/k/uL
  • Absolute neutrophil count >= 1,500/k/uL
  • Platelet count >= 100,000/k/uL
  • Total bilirubin >= 1.3 mg/dL
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) =< 2.5 x institutional upper limit of normal (ULN)
  • Alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2.5 x institutional upper limit of normal (ULN)
  • Subjects must have the ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria

  • Prior treatment for rectal cancer or prior radiation for other diagnoses to the expected rectal cancer treatment fields
  • Subjects receiving any other investigational agents
  • Unresectable primary tumor or unresectable metastatic disease as determined by imaging
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to pembrolizumab or other agents used in this study
  • Subjects with uncontrolled intercurrent illness including, but not limited to: * Ongoing or active infection * Known history of pneumonitis * Symptomatic congestive heart failure * Unstable angina pectoris * Cardiac arrhythmia * Psychiatric illness/social situations that would limit compliance with study requirements
  • Pregnant or lactating females
  • Female patients who: * Are postmenopausal for at least 1 year before the screening visit, OR * Are surgically sterile, OR * Agree to practice true abstinence from heterosexual contact or agree to use effective contraception without interruption during the study therapy and 90 days after the last dose
  • Male patients who: are surgically sterile, OR agree to practice true abstinence from heterosexual contact or agree to use effective contraception without interruption during the study therapy and 90 days after the last dose
  • Human immunodeficiency virus (HIV)-positive subjects on combination antiretroviral therapy, patients with active hepatitis B or C, active tuberculosis, or administration of live vaccine within 30 days of planned start of study therapy will be excluded
  • Patients with a diagnosis of immunodeficiency, active autoimmune disease (including inflammatory bowel disease) or those receiving immunosuppressive therapy within 7 days (other than prednisone =< 5 mg daily) prior to the planned start of study treatment will be excluded


Case Comprehensive Cancer Center
Status: ACTIVE
Contact: David Liska
Phone: 216-444-9219


I. Determine the safety, tolerability and feasibility of neoadjuvant pembrolizumab in combination with capecitabine (or fluorouracil [5-Fluorouracil]) in the treatment of patients with mismatch repair deficient (MMR-d) locally advanced rectal cancer.


I. Determine the treatment response in MMR-d rectal cancer patients treated with neoadjuvant chemoradiotherapy and pembrolizumab.


I. Tumor specimens will be assessed for the expression of PD-L1, PD-1, CTLA-4, IFN-gamma, granzyme B, Foxp3, CD3, and CD8 within the tumor and at the invasive fronts and correlated with treatment response.

II. 30 mL whole blood collection used for future research studies, will be collected on weeks 0, 3, 7, 12, and 14-18 and stored in The Cleveland Clinic Lerner Research Institute.


Patients receive pembrolizumab intravenously (IV) on days 1, 22, and 43, undergo external beam radiation therapy 5 days a week for 5 weeks, and capecitabine orally (PO) twice daily (BID) or fluorouracil IV for 5 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days.

Trial Phase Phase I

Trial Type Treatment

Lead Organization
Case Comprehensive Cancer Center

Principal Investigator
David Liska

  • Primary ID CASE1220
  • Secondary IDs NCI-2020-06505
  • ID NCT04357587