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Safety and Feasibility of PD-1 Blockade in the Treatment of Rectal Cancer

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04357587
Recruitment Status : Recruiting
First Posted : April 22, 2020
Last Update Posted : August 20, 2020
Sponsor:
Information provided by (Responsible Party):
Case Comprehensive Cancer Center

Brief Summary:
Colorectal cancer is the third most common cancer worldwide and the second leading cause of cancer mortality in the United States. The current standard of care (SOC) for locally advanced rectal cancer includes neoadjuvant chemotherapy and radiation followed by surgery. However, great variability exists in patient's response to neoadjuvant chemoradiotherapy with only about 20-25% of patients achieving a complete response while other patients achieve a partial or no treatment response. The purpose of this study is to test the investigational agent, Pembrolizumab, in combination with SOC radiation and Capecitabine (or 5-Fluorouacil) in treatment of patients with mismatch repair deficient locally advanced rectal cancer.

Condition or disease Intervention/treatment Phase
Rectal Neoplasms Drug: Pembrolizumab Radiation: External beam radiation Drug: Capecitabine Phase 1

Detailed Description:

This study investigates the safety, tolerability, and feasibility of Pembrolizumab, an immunotherapy agent, in combination with SOC radiation and Capecitabine (or 5-Fluorouacil) in treatment of patients with mismatch repair deficient locally advanced rectal cancer. Pembrolizumab is an investigational (experimental) drug that works by enhancing the functional activity of the target lymphocytes (immune cells) to facilitate tumor regression and ultimately immune rejection. Pembrolizumab in combination with radiation and Capcitabine (or 5-Fluorouacil) is experimental because it is not approved by the Food and Drug Administration (FDA) for this specific indication.

The primary objective of this study is to determine the safety, tolerability and feasibility of neoadjuvant pembrolizumab in combination with capectiabine (or 5-Fluorouracil ) in the treatment of patients with MMR-d locally advanced rectal cancer

The secondary objective of this study is to determine the treatment response in MMR-d rectal cancer patients treated with neoadjuvant chemoradiotherapy and Pembrolizumab.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 10 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Neoadjuvant Immunotherapy in Rectal Cancer: A Pilot Study Examining the Safety and Feasibility of PD-1 Blockade in the Treatment of Rectal Cancer
Actual Study Start Date : August 6, 2020
Estimated Primary Completion Date : August 1, 2021
Estimated Study Completion Date : August 1, 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Pembrolizumab
Experimental pembrolizumab and SOC external beam radiation and capecitabine
Drug: Pembrolizumab
200 mg intravenously (IV) on days 1, 22, and 43

Radiation: External beam radiation
Daily fractions of 200 cGy, 5 days a week for the first 5 weeks of the study, excluding weekends

Drug: Capecitabine
825 mg/m2 orally twice a day on days where radiation therapy is given




Primary Outcome Measures :
  1. Rate of adverse events (AEs) as defined by the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 [ Time Frame: 30 days after intervention ]
    Safety endpoint will be defined by rate of AEs as defined by the CTCAE v5.0

  2. Proportion of participants able to complete planned neoadjuvant treatment protocol [ Time Frame: 45 days after intervention ]
    Tolerability as defined by proportion of participants that are able to complete the planned neoadjuvant treatment protocol

  3. Feasibility as defined by proportion of participants with any delay in planned surgery of more than 30 days [ Time Frame: 115 days after intervention ]
    Feasibility as defined by proportion of participants with any delay in the planned surgery of more than 30 days


Secondary Outcome Measures :
  1. Treatment response as measured by AJCC tumor regression grade (TRG) [ Time Frame: at time of surgical resection, an average of 10 weeks after radiation ]

    Treatment response as measured by pathologic assessment of treatment response using the AJCC TRG following surgical resection.

    AJCC TRG grading ranges from 0-3:

    0 (complete response): no viable cancer cells

    1. (near complete response): single cells or rare small groups of cancer cells
    2. (partial response): residual cancer with evident tumor regression but more than single cells or rare small groups of cancer cells
    3. (poor or no response): extensive residual cancer with no evident tumor regression.

  2. Treatment response as measured by MRI tumor regression grade [ Time Frame: 4-6 weeks before intervention ]

    Treatment response as measured by MRI tumor regression grade.

    The MRI tumor regression grade uses the following scale:

    1. No/minimal fibrosis visible (tiny linear scar) and no tumor signal
    2. Dense fibrotic scar (low signal intensity) but no macroscopic tumor signal (indicates no or microscopic tumor)
    3. Fibrosis predominates but obvious measurable areas of tumor signal visible
    4. Tumor signal predominates with little/minimal fibrosis
    5. Tumor signal only: no fibrosis, includes progression of tumor

  3. Treatment response as measured by Carcinoembryonic antigen (CEA) blood test [ Time Frame: 4-6 weeks before intervention ]
    Treatment response as measured by CEA levels



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Must have confirmed rectal adenocarcinoma Defined as, 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 tumor board.
  • MMR-deficiency confirmed on immunohistochemistry or MSI status confirmed by PCR.
  • ECOG Performance status 0-1
  • Life expectancy of ≥ 6 months, in the opinion of and as documented by the treating physician.
  • Must have normal organ and marrow function as defined below:

    • 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
    • AST (SGOT) ≤ 2.5 x institutional upper limit of normal (ULN)
    • ALT (SGPT) ≤ 2.5 x institutional upper limit of normal (ULN)
  • 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.
  • Participants 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.
  • Participants 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 participants 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 participants 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
  • HIV-positive participants on combination antiretroviral therapy, participants 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.
  • Participants with a diagnosis of immunodeficiency, active autoimmune disease (including inflammatory bowel disease) or those receiving immunosuppressive therapy within 7 days (other than Prednisone ≤ 5mg daily) prior to the planned start of study treatment will be excluded.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04357587


Contacts
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Contact: David Liska, MD +1 216-444-9219 LISKAD@ccf.org

Locations
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United States, Ohio
Cleveland Clinic, Case Comprehensive Cancer Center Recruiting
Cleveland, Ohio, United States, 44122
Contact: David Liska, MD    216-444-9219    LISKAD@ccf.org   
Principal Investigator: David Liska, MD         
Sponsors and Collaborators
Case Comprehensive Cancer Center
Investigators
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Principal Investigator: David Liska, MD Cleveland Clinic, Case Comprehensive Cancer Center
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Responsible Party: Case Comprehensive Cancer Center
ClinicalTrials.gov Identifier: NCT04357587    
Other Study ID Numbers: CASE1220
First Posted: April 22, 2020    Key Record Dates
Last Update Posted: August 20, 2020
Last Verified: August 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Individual participant data that underlie the results reported in this article, after deidentification (text, tables, figures, and appendices).
Supporting Materials: Study Protocol
Time Frame: Beginning 9 months and ending 36 months following article publication
Access Criteria: Investigators whose proposed use of the data has been approved by an independent review committee ("learned intermediary") identified for this purpose can request the data for meta-analysis by emailing the corresponding author

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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
Additional relevant MeSH terms:
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Rectal Neoplasms
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Intestinal Diseases
Rectal Diseases
Capecitabine
Pembrolizumab
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antineoplastic Agents, Immunological