Using Pembrolizumab before surgery for high-risk colorectal cancer

NEOPRISM-CRC : Neoadjuvant Pembrolizumab Stratified to Tumour Mutation Burden for High Risk Stage 2 or Stage 3 MMR-deficient Colorectal Cancer

This study is testing if giving the immunotherapy drug pembrolizumab before surgery can help people with high-risk colorectal cancer avoid recurrence and improve their chances of a successful surgery.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 88 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: University College, London (Academic / other)
• Drugs / interventions: pembrolizumab, chemotherapy, immunotherapy
• Locations: 6 sites (Cambridge and 5 other locations)
• Trial ID: NCT05197322 on ClinicalTrials.gov

What this trial studies

The NEOPRISM-CRC trial is a phase II clinical trial aimed at evaluating the efficacy and safety of pembrolizumab, an immunotherapy drug, in patients with high-risk Stage 2 or Stage 3 colorectal cancer that is MMR-deficient or MSI-H. The trial investigates whether administering pembrolizumab prior to surgery can delay or prevent cancer recurrence and improve the chances of complete tumor removal. It will also assess the treatment's safety, potential delays to surgery due to side effects, and its impact on patients' quality of life. Participants will undergo a trial colonoscopy for tissue sampling if they consent.

Who should consider this trial

Good fit: Ideal candidates are patients with histologically proven adenocarcinoma of the colon or rectum that is MMR-deficient or MSI-H, and who are fit for planned curative surgery.

Not a fit: Patients with colorectal cancer that does not exhibit MMR deficiency or high microsatellite instability may not benefit from this treatment.

Why it matters

Potential benefit: If successful, this treatment could significantly reduce the risk of cancer recurrence in patients with high-risk colorectal cancer.

How similar studies have performed: Previous studies have shown promising results for immunotherapy in advanced colorectal cancer, indicating potential success for this neoadjuvant approach.

Eligibility criteria

Inclusion Criteria:

1. Histologically proven adenocarcinoma of the colon or rectum which is MMR-d by IHC or MSI-H by PCR (or microsatellite testing if routine practice).
2. Patient is fit (ECOG 0-1) and eligible for planned curative surgery in keeping with NICE guidelines and considered fit/suitable for adjuvant chemotherapy as per local site investigator's discretion based on:

   1. Radiological node positive T1-4 CRC or
   2. Node negative high risk T3 defined as EITHER ≥ 5mm of extramural depth of invasion OR unequivocal EMVI on imaging (regardless of depth) or Node negative T4 disease
3. Patients with rectal cancer are eligible if it is determined that neoadjuvant chemo-radiotherapy is not required to achieve a R0 resection.
4. Patients presenting with acute colonic obstruction may enter the trial only after obstruction is relieved by a successful defunctioning stoma/stent, and when recovered to a fitness level consistent with the other eligibility criteria
5. Adequate bone marrow function:

   * White Blood Cell \>3.0 x 10\^9/L;
   * Absolute neutrophil count ≥1.5 x 10\^9/L
   * Platelets ≥100 x 10\^9/L.
   * Haemoglobin ≥90 g/L
6. Adequate renal function:

   GFR \>50 mL/min estimated using validated creatinine clearance calculation (e.g. Cockroft-Gault) NB If the calculated creatinine clearance is \< 50 mL/min, a formal 24 hour urine collection or isotope clearance must be carried out demonstrating GFR ≥ 50 mL/min as per institutional standards
7. Adequate liver function:

   Total bilirubin \< 1.5 times Upper Limit of Normal (ULN) OR direct bilirubin ≤ULN for participants with total bilirubin levels \>1.5 × ULN

   AST and ALT ≤ 2.5 × ULN
8. Adequate coagulation:

   International normalized ratio (INR) OR prothrombin time (PT) and Activated partial thromboplastin time (aPTT) ≤1.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants
9. Aged ≥18 years
10. Able and willing to provide written informed consent
11. Female patients of child bearing potential must be willing to use highly effective contraception for the duration of trial treatment and for 120 days after last dose of pembrolizumab

Exclusion Criteria:

1. Any patient for whom radiotherapy is advised by the MDT
2. Strong evidence of distant metastases or peritoneal nodules (M1)
3. 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 (e.g. CTLA-4, OX-40, CD137)
4. Prior systemic anti-cancer therapy including investigational agents within 4 weeks prior to registration.

   (NB: Participants must have recovered from all AEs due to previous therapies to ≤Grade 1 or baseline, with the exception of alopecia. Participants with ≤Grade 2 neuropathy may be eligible.) (NB: If participant received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study treatment.)
5. Has received a live vaccine or live-attenuated vaccine within 30 days prior to registration (seasonal flu vaccines that do not contain live virus are permitted). Administration of killed vaccines is allowed
6. Any investigational agents or investigational devices within 4 weeks prior to registration 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.
7. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (dosing exceeding 10mg daily of prednisolone or equivalent), or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment Note: the use of physiologic doses of corticosteroids may be approved after consultation with UCL CTC.
8. Patients with concurrent or previous malignancy that could compromise assessment of the primary or secondary endpoints of the trial
9. Has known active CNS metastases and/or carcinomatous meningitis.
10. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or to any of its excipients.
11. Has previous severe or life-threatening skin adverse reaction with other immune-stimulatory anticancer agents
12. 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).

    NB: Replacement therapy (e.g. levothyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is permitted.
13. History of (non-infectious) pneumonitis/interstitial lung disease that required steroids, or current pneumonitis/interstitial lung disease
14. Active infection requiring systemic therapy
15. Known history of Human Immunodeficiency Virus (HIV). NB: Testing for HIV for the NEOPRISM-CRC trial is not mandatory, however if this test has been done the result should be known prior to registration.
16. Known active infection for hepatitis B (hepatitis B surface antigen \[HbsAg\] reactive) or known active hepatitis C (defined as hepatitis C virus \[HCV\] RNA \[qualitative\] is detected)

    * Testing is required to determine eligibility. Hepatitis C antibody testing is allowed for initial screening purposes in sites where HCV RNA is not part of standard of care.
    * Patients who are HbsAg positive are eligible if they have received HBV antiviral therapy for at least 4 weeks and have undetectable HBV viral load prior to registration. Participants should remain on anti-viral therapy throughout trial treatment and follow local guidelines for HBV anti-viral therapy post completion of trial treatment.
    * Patients with history of HCV infection are eligible if HCV viral load is undetectable at screening and have completed anti-viral therapy at least 4 weeks prior to registration.
17. Known history of active TB (Mycobacterium tuberculosis).
18. Has had an allogenic tissue/solid organ transplant.
19. Has peritonitis (secondary to perforated tumour)
20. Has a colonic obstruction that has not been defunctioned or stented
21. 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.
22. Known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the study.
23. Female patients of child bearing potential who is pregnant or breastfeeding, or expecting to conceive within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of pembrolizumab

Where this trial is running

Cambridge and 5 other locations

• Addenbrookes Hospital — Cambridge, United Kingdom (Recruiting)
• Beatson West of Scotland Cancer Centre — Glasgow, United Kingdom (Recruiting)
• St James University Hospital (SJUH) — Leeds, United Kingdom (Completed)
• University College Hospital — London, United Kingdom (Recruiting)
• Christie Hospital NHS Trust, Wilmslow Road, — Manchester, United Kingdom (Recruiting)
• Southampton General Hospital — Southampton, United Kingdom (Completed)

Study contacts

• Principal investigator: Kai-Keen Shiu — University College London Hospitals
• Study coordinator: Reshma Bhat

Conditions Adenocarcinoma of the Colon