Neo-adjuvant Pembrolizumab and Radiotherapy in Localised MSS Rectal Cancer (PEMREC)

A Phase II Study to Evaluate Safety and Efficacy of Neo-adjuvant Pembrolizumab and Radiotherapy in Localised MSS Rectal Cancer

This project investigates the clinical and biological impact of combining immunotherapy (pembrolizumab) with short course radiotherapy (5Gy, five times) in the neo-adjuvant treatment of localised microsatellite stable (MSS) rectal cancer.

Study Overview

• Status: Recruiting
• Conditions: Rectal Cancer; Rectum Cancer
• Intervention / Treatment: Drug: Pembrolizumab

• Study Type: Interventional
• Enrollment (Anticipated): 25
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Thibaud Kössler, MD PhD; Phone Number: +41 (0)22 372 77 68; Email: thibaud.kossler@hcuge.ch
• Study Contact Backup: Name: Sandra Bettinelli Riccardi, PhD; Phone Number: +41223722903; Email: Sandra.BettinelliRiccardi@hcuge.ch

Study Locations

• Switzerland
  • Geneva, Switzerland, 1205
    • Recruiting
    • Hôpitaux universitaires de Genève
    • Contact: Thibaud Kössler, MD PhD; Email: thibaud.kossler@hcuge.ch

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male/female participants who are at least 18 years of age on the day of signing informed consent with histologically confirmed diagnosis of rectal adenocarcinoma will be enrolled in this study.
• Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Evaluation of ECOG is to be performed within 7 days prior to the date of allocation.
• Patients with previously untreated localized T3-T4 N0 or T any or N1-2, M0 rectal adenocarcinoma.
• Tumour must be microsatellite stable (MSS).
• A multi-disciplinary tumour board should recommend neo-adjuvant short course radiotherapy and surgery.
• Have provided archival tumour tissue sample or newly obtained core or excisional biopsy of a tumour lesion not previously irradiated. Formalin-fixed paraffin embedded (FFPE) tissue blocks are preferred.
• Have adequate organ function as defined in the following table. Specimens must be collected within 10 days prior to the start of study treatment.

Exclusion Criteria:

• Has a microsatellite instable tumour (MSI-High).
• Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX 40, CD137).
• Has received for the same disease prior systemic anti-cancer therapy including investigational agents prior to starting pembrolizumab. Note: If participant received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study treatment.
• Has received prior radiotherapy for the same disease. If treated with radiotherapy for another disease, participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis.
• Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed.
• Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment. Note: Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent.
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug.
• Has a known additional malignancy that is progressing or has required active treatment within the past 3 years. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g. breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded.
• Has known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, i.e. without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study treatment.
• Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
• 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 has current pneumonitis.
• Has an active infection requiring systemic therapy.
• Has a known history of Human Immunodeficiency Virus (HIV).
• Has a known history of Hepatitis B virus (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as HCV RNA > 1.5E1 is detected) infection. Note: no testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority.
• Has a known history of active TB (Bacillus Tuberculosis).
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Experimental; Short Course Radiation Therapy (5 x 5 Gy in 1 week, SCRT) with 4 injections of Pembrolizumab starting on the first day of radiotherapy and surgery	Drug: Pembrolizumab; 5x5 Gy radiotherapy in 1 week, 4 cycles of Pembrolizumab (200 mg every three week), surgery

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tumour regression grade	To assess the tumour regression grade (TRG) after short course radiotherapy when given together with pembrolizumab, using the Mandard regression grade score	12 weeks after start

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tolerability and safety	To assess tolerability and safety of pembrolizumab given with short course radiotherapy before surgery, using the common terminology criteria for adverse events (CTCAE) Version 4.0	5 years
Overall Survival	To estimate overall survival (OS), defined as the time between the date of the study entry and the date of death due to any cause. Subjects who have not died at the time of last known follow-up will be censored.	5 years
Disease-free survival	To estimate disease-free survival (DFS), defined as the time between the date of the study entry and the date of recurrence, second primary cancer, or death without evidence of recurrence or second primary cancer.	3 years
Locoregional relapse-free survival	To estimate locoregional relapse-free survival (LRRFS), defined as the time between the date of the surgery and local or regional recurrence. LRRFS is evaluated in patients who had an R0 resection only	5 years
Distant metastasis-free survival	To estimate distant metastasis-free survival (DMFS), defined as the time between the date of the surgery and metastatic recurrence.	5 years
EORTC QLQ-C30	European Organization for Research and Treatment of Cancer [EORTC] Quality of Life Questionnaire-C30	30 months
EORTC QLQ-CR29	European Organization for Research and Treatment of Cancer [EORTC] Quality of Life Questionnaire-CR29	30 months

Collaborators and Investigators

• Sponsor: University Hospital, Geneva

Publications and helpful links

General Publications

• Corro C, Buchs NC, Tihy M, Durham-Faivre A, Bichard P, Frossard JL, Puppa G, McKee T, Roth A, Zilli T, Trembleau C, Di Marco M, Dutoit V, Dietrich PY, Ris F, Koessler T. Study protocol of a phase II study to evaluate safety and efficacy of neo-adjuvant pembrolizumab and radiotherapy in localized rectal cancer. BMC Cancer. 2022 Jul 15;22(1):772. doi: 10.1186/s12885-022-09820-w.

Study record dates

Study Major Dates

• Study Start (Actual): June 2, 2020
• Primary Completion (Anticipated): June 1, 2022
• Study Completion (Anticipated): March 1, 2028

Study Registration Dates

• First Submitted: September 24, 2019
• First Submitted That Met QC Criteria: September 26, 2019
• First Posted (Actual): September 30, 2019

Study Record Updates

• Last Update Posted (Actual): September 30, 2021
• Last Update Submitted That Met QC Criteria: September 29, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Keywords: Rectal cancer; Immunotherapy; Pembrolizumab; Short course radiotherapy; 5x5Gy; Localised rectal cancer
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Rectal Neoplasms; Antineoplastic Agents; Antineoplastic Agents, Immunological; Pembrolizumab
• Other Study ID Numbers: PEMREC

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No