Safety and Feasibility of PD-1 Blockade in the Treatment of dMMR or MSI-H Rectal Cancer

NCT04357587 | Completed Phase 1 DMC FDA Drug

• 1 other identifier: CASE1220
• Study Type: interventional
• Target: 6
• Locations: 1 country
• Sites: 1

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.

Conditions

Rectal Neoplasms

Outcome Measures

Primary Outcomes (6)

• Rate of adverse events (AEs) as defined by the Common Terminology Criteria for Adverse Events (CTCAE) v5.0

  Safety endpoint will be defined by rate of AEs as defined by the CTCAE v5.0

  30 days after intervention

• Proportion of participants able to complete planned neoadjuvant treatment protocol

  Tolerability as defined by proportion of participants that are able to complete the planned neoadjuvant treatment protocol

  45 days after intervention

• Feasibility as defined by proportion of participants with any delay in planned surgery of more than 30 days

  Feasibility as defined by proportion of participants with any delay in the planned surgery of more than 30 days

  115 days after intervention

• Treatment response as measured by AJCC tumor regression grade (TRG)

  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.

  at time of surgical resection, an average of 10 weeks after radiation

• Treatment response as measured by MRI tumor regression grade

  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

  4-6 weeks before intervention

• Treatment response as measured by Carcinoembryonic antigen (CEA) blood test

  Treatment response as measured by CEA levels

  4-6 weeks before intervention

Study Arms (1)

Pembrolizumab

EXPERIMENTAL

Experimental pembrolizumab and SOC external beam radiation and capecitabine

Drug: Pembrolizumab; Radiation: External beam radiation; Drug: Capecitabine

Interventions

Pembrolizumab DRUG

200 mg intravenously (IV) on days 1, 22, and 43

Pembrolizumab

External beam radiation RADIATION

Daily fractions of 200 cGy, 5 days a week for the first 5 weeks of the study, excluding weekends

Pembrolizumab

Capecitabine DRUG

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

Pembrolizumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 x institutional upper limit of normal (ULN)
• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Case Comprehensive Cancer Center: lead

Study Sites (1)

Cleveland Clinic, Case Comprehensive Cancer Center

Cleveland, Ohio, 44122, United States

Location

MeSH Terms

Conditions

Rectal Neoplasms

Interventions

pembrolizumab; Capecitabine

Condition Hierarchy (Ancestors)

Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Fluorouracil; Uracil; Pyrimidinones; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides

Study Officials

• David Liska, MD

  Cleveland Clinic, Case Comprehensive Cancer Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 20, 2020
• First Posted: April 22, 2020
• Study Start: August 6, 2020
• Primary Completion: September 25, 2023
• Study Completion: September 25, 2023
• Last Updated: May 29, 2024

Record last verified: 2024-05

Data Sharing

• IPD Sharing: Will share
• Shared Documents: 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

Locations

US (1)