NEOadjuvant PembRolizumab In Stratified Medicine - ColoRectal Cancer

Study Overview
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Brief Summary
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Colorectal cancer (CRC) is the 2nd to 3rd most common malignant disease in developed countries, with over 1 million new cases and 500,000 deaths worldwide each year. The primary treatment for early stage CRC is surgery to remove the tumour, which is possible in 80% of patients. Even after surgery up to half of patients will develop recurrence or spread of the disease (metastases) which is incurable. Survival after 5 years is approximately 14% for patients with metastatic disease. Clinical trials using immunotherapy drugs called 'immune checkpoint inhibitors' have shown excellent results in advanced colorectal cancer patients who have certain genetic characteristics called 'mismatch repair deficiency (MMR-d)' and 'high microsatellite instability (MSI-h)'. The benefits of immunotherapy as a treatment prior to surgery to remove the tumour (neoadjuvant treatment) has been observed in both melanoma and in glioblastoma with enhanced local and systemic anti-tumour responses. Pembrolizumab is an immunotherapy drug and works by helping the body's own immune system to fight the cancer cells. The NEOPRISM-CRC trial will investigate whether giving pembrolizumab before surgery is safe, and whether it improves the chances of the tumour being removed completely, and whether this delays or prevents the cancer from coming back. Pembrolizumab treatment lasts for a maximum of 9 weeks (maximum of 3 cycles of treatment, each cycle consisting of 3 weeks) and is given prior to surgery. Following surgery patients will be followed up for at least 3 years after their surgery and to a maximum of 5 years. Target recruitment is 32 patients and recruitment is expected to take place over a 24 month period. Blood, tissue, mouth swabs and stool samples will be collected from patients throughout the trial to better understand the biology of immunotherapy as a treatment for CRC prior to surgery.

Detailed Description
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The NEOPRISM-CRC study is a phase II clinical trial. The purpose of the trial is to evaluate the efficacy and safety of pembrolizumab (Study IMP) in patients with high risk Stage 2 or Stage 3 MMR-deficient colorectal cancer stratified with tumour mutation burden status. Pembrolizumab is a type of immunotherapy that has demonstrated excellent results in clinical trials for patients with advanced colorectal cancer who have certain genetic characteristics (mismatch repair deficiency (MMR-d) / high microsatellite instability (MSI-H)). There are previous studies providing evidence that checkpoint inhibitors when given before surgery have shown better local and systemic anti-tumour responses in melanoma and glioblastoma than surgery alone. The main question the researcher wants to investigate is whether pembrolizumab given prior to having surgery improves pathological complete response rate in advanced colorectal cancer patients with MSI-H or MMR-d. The trial will investigate whether the treatment is safe, and whether it improves the chances of the tumour being removed completely, and whether this delays or prevents the cancer from coming back. The trial will also investigate whether pembrolizumab causes any delay to surgery due to side effects. The trial will also measure post-surgery complications and impact of the treatment on patient's quality of life. Once patients have consented to the NEOPRISM-CRC trial, a trial colonoscopy will be performed and tissue samples taken during the procedure will be shipped to the FoundationOne Medicine testing Laboratory and analysed to determine the TMB (tumour mutation burden) status assessed by the FOUNDATIONONE®CDx (FM1) test. In addition, a PCR (Polymerase Chain reaction) test or Microsatellite testing will be done to confirm the Microsatellite Instability (MSI) status. Patients will receive one of two pre-operative regimens depending upon their TMB status/MSI status All patients will have one cycle of pembrolizumab 200 mg IV (a cycle is 21 days). Prior to cycle 2 the FM1 result should be available and patients will continue their treatment as follows: If results is TMB-high or medium (or MSI-h if FM1 test is not evaluable): A further two cycles of pembrolizumab 200 mg IV every 21 days and then will proceed to surgery 4 - 6 weeks after last dose of pembrolizumab If result is TMB-low (or if FM1 test and MSI result are not evaluable): No further cycles of pembrolizumab; will proceed to surgery 4 - 6 weeks after last dose of pembrolizumab Following surgery, patients will receive standard of care adjuvant treatment which may include post-operative chemotherapy in accordance with investigators clinical decision. Patients will continue to be followed up according to routine standard of care for a maximum of 5 years after surgery. Target recruitment is 32 patients and recruitment is expected to take place over a 24 month period.

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

Conditions
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Adenocarcinoma of the Colon

Intervention / Treatment
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* Drug: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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). 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: Radiological node positive T1-4 CRC or high risk T3 defined as EITHER ≥ 5mm of extramural depth of invasion OR unequivocal EMVI on imaging (regardless of depth) or T4 disease Patients with rectal cancer are eligible if it is determined that neoadjuvant chemo-radiotherapy is not required to achieve a R0 resection. 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 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 Note Anaemia (Hb <100 g/L) is not an exclusion, but should be corrected by transfusion prior to surgery and chemotherapy. 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 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 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 Aged ≥18 years Able and willing to provide written informed consent Willing to use highly effective contraception for the duration of trial treatment and for 120 days after last dose of pembrolizumab Exclusion Criteria: Any patient for whom radiotherapy is advised by the MDT Strong evidence of distant metastases or peritoneal nodules (M1) 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) 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.) 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 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. 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. Patients with concurrent or previous malignancy that could compromise assessment of the primary or secondary endpoints of the trial Has known active CNS metastases and/or carcinomatous meningitis. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or to any of its excipients. Has previous severe or life-threatening skin adverse reaction with other immune-stimulatory anticancer agents 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. History of (non-infectious) pneumonitis/interstitial lung disease that required steroids, or current pneumonitis/interstitial lung disease Active infection requiring systemic therapy 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. Known history of or is positive for hepatitis B (hepatitis B surface antigen [HBsAg] reactive) or known active hepatitis C (defined as hepatitis C virus [HCV] RNA [qualitative] is detected) Note: Without known history, testing is required to determine eligibility. Hepatitis C antibody testing is allowed for screening purposes in sites where HCV RNA is not part of standard of care. Known history of active TB (Mycobacterium tuberculosis). Has had an allogenic tissue/solid organ transplant. Has peritonitis (secondary to perforated tumour) Has a colonic obstruction that has not been defunctioned or stented 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. Known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the study. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of pembrolizumab

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Open label, 2 arm phase II trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Tumour Mutation Burden high or medium (or MSI-High)<br>Patients will one cycle of pembrolizumab 200 mg IV (a cycle is 21 days). Prior to cycle 2 the result of the FOUNDATIONONE®CDx test should be available and patients will continue their treatment as follows: TMB-high (defined as ≥20 mutations per Mb) or medium (defined as 6-19 mutations per Mb); FOUNDATIONONE®CDx (or MSI-H if FM1 test is not evaluable): A further two cycles of pembrolizumab 200 mg IV every 21 days Planned surgery to remove the CRC 4 - 6 weeks after last dose of pembrolizumab | Drug: Pembrolizumab<br>* Dose: 200mg by IV infusion on Day 1 of each treatment cycle<br>|
| Other: Tumour Mutation Burden low or unevaluable<br>Patients will one cycle of pembrolizumab 200 mg IV (a cycle is 21 days). Prior to cycle 2 the result of the FOUNDATIONONE®CDx test should be available and patients will continue their treatment as follows: TMB-low (defined as ≤5 mutations per Mb); FOUNDATIONONE®CDx (or if FM1 test and PCR are not evaluable): • Planned surgery to remove the CRC 4 - 6 weeks after last dose of pembrolizumab | Drug: Pembrolizumab<br>* Dose: 200mg by IV infusion on Day 1 of each treatment cycle<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathological complete response rate (pCR) | A pCR will be defined as having no residual cancer cells in the resected specimen at surgery. Patients who do not achieve pCR or who do not proceed to resectional surgery for any reason will be counted as non-responders. | Pathological complete response rate (pCR) assessed at 3 months following surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | Overall survival (OS) is defined as the time from start of treatment to time of death from any cause. | From registration to death from any cause, assessed up to a maximum of 5 years from surgery date | 
| Relapse-free survival | Relapse-free Survival (RFS) is defined as time from start of treatment to time of any signs or symptoms of the cancer or time of death from any cause. | From registration to any signs or symptoms of the cancer or death assessed up to a maximum of 5 years from surgery date | 
| Frequency and severity of adverse events | Adverse events recorded continuously in relation to each treatment cycle graded using CTCAE criteria | From informed consent to 3 months after surgery | 
| Rate of R0 resection and completed surgery | The incidence of resection types (R0, R1 and R2) will be presented in tables using frequencies, as well as the rate of surgery completed. | Assessed from surgery to 28-35 days following surgery | 
| Frequency and severity of post-operative surgical complications | The incidence of surgical complications will be described in tables by complication type/grade using frequencies using the Clavien-Dindo grading system. | Assessed from surgery up to last follow up visit (maximum of 5 years from date of surgery) | 
| Health-related Quality of Life (QoL) and functional outcome | The European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) will be used. The EORTC QLQ-C30 comprises 30 items (i.e. single questions), 24 of which are aggregated into nine multi-item scales, that is, five functioning scales (physical, role, cognitive, emotional and social), three symptom scales (fatigue, pain and nausea/vomiting) and one global health status scale. The remaining six single-item (dyspnoea, appetite loss, sleep disturbance, constipation, diarrhoea and the financial impact) scales assess symptoms. All of the scales and single-item measures range in score from 0 to 100. Higher score for the functioning scales and global health status denote a better level of functioning (i.e. a better state of the patient), while higher scores on the symptom and single-item scales indicate a higher level of symptoms (i.e. a worse state of the patient). | From informed consent to 28-35 days following surgery | 
| Health-related Quality of Life (QoL) and functional outcome | The EuroQol- 5 Dimension (EQ-5D) will be used. Each dimension in the EQ-5D has five response levels: no problems (Level 1); slight; moderate; severe; and extreme problems (Level 5). Lower score indicates better health, whereas higher score indicate more severe or frequent problems. | From informed consent to 28-35 days following surgery |