Efficacy of Pembrolizumab in Locally Advanced, Unresectable, Non-Metastatic dMMR Colorectal Cancer: A Clinical Evaluation

Trial ID: 2023-509707-32-00
Sponsor: Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis Stichting

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Diseases & Conditions

Colorectal cancer

Objectives

The primary objective of this study is to assess the **efficacy** of pembrolizumab in patients with locally advanced, irresectable, non-metastatic dMMR colorectal cancers. This is clinically relevant as it aims to determine the therapeutic potential of pembrolizumab, an immune checkpoint inhibitor, in a specific subset of colorectal cancer patients who have limited treatment options due to the advanced and irresectable nature of their disease.

Secondary objectives include:

To assess the major pathological response (MPR, ≤10% viable tumor rest) in patients undergoing surgery.
To assess resectability after induction pembrolizumab.
To find biomarkers and evaluation strategies able to accurately assess complete and near-complete responses in patients undergoing surgery, including the use of CT-scans and ctDNA analysis.
To perform translational analyses, which may include RNA sequencing, inflammatory signatures, immunogenic mutational load by DNA WES, and analysis of immune cell infiltration to validate current findings and identify predictors of response.
In case of surgery, to assess post-surgical outcome and infectious complications following neoadjuvant immunotherapy.
To assess relapse-free survival.

Participants

The clinical trial involves participants diagnosed with **locally advanced, irresectable dMMR colorectal cancers**. The study population includes both male and female subjects, aged 18 years and older, with an **ECOG performance status** of 0 or 1. Participants are required to have histologically or cytologically confirmed microsatellite instability-high (MSI-H) or MMR-deficient (dMMR) status, with no signs of distant metastases. The trial does not include a vulnerable population. The sponsor has not provided the total number of participants. Selection criteria include the absence of eligibility for standard first-line pembrolizumab treatment for metastatic disease and the requirement for a CT-scan within 28 days prior to registration. Participants must meet specific laboratory test criteria and adhere to contraceptive guidelines if applicable. The trial does not focus on any particular lifestyle considerations such as diet or physical activity.

Plans and Procedures

The clinical trial is designed to evaluate the efficacy of **pembrolizumab** in patients with locally advanced, irresectable, non-metastatic dMMR colorectal cancers. This is a phase II, randomized, double-blind, controlled trial. The trial is expected to last until March 2026, with recruitment having commenced in November 2022. Participants will be involved in the study for a maximum treatment period of 24 months, receiving pembrolizumab via intravenous infusion. The trial includes several key visits: an initial screening visit, regular follow-up visits, and an end-of-study visit. The screening visit will confirm eligibility based on criteria such as age, histological confirmation of dMMR status, and absence of distant metastases. Follow-up visits will monitor the participants' response to treatment and any adverse effects. The end-of-study visit will assess the overall treatment efficacy and gather final data.

Participants are required to meet specific inclusion criteria, including providing informed consent, agreeing to use contraception, and having a confirmed diagnosis of locally advanced, irresectable colorectal cancer. Exclusion criteria are not specified in the provided data. The primary endpoint is to determine the objective response rate according to RECIST 1.1 and iRECIST criteria. Secondary endpoints include assessing major pathological response, evaluating biomarkers for organ-sparing treatment, and analyzing the association between microbiota composition and treatment outcomes. Participants may be terminated early from the study if they experience significant adverse effects, fail to comply with study protocols, or withdraw consent. The trial aims to provide valuable insights into the potential of pembrolizumab as a treatment option for this specific patient population.

Treatment

The clinical trial involves the administration of **pembrolizumab**, marketed under the name KEYTRUDA, which is a **concentrate for solution for infusion**. This experimental medication is provided in a concentration of 25 mg/mL and is intended for intravenous infusion. The maximum daily and total dose is 200 mg, administered every three weeks. The treatment period is set for a maximum of 24 months. Pembrolizumab is a monoclonal antibody that targets the PD-1 receptor, classified under the ATC code L01FF02. The active substance is derived from a protein of other origin, and the product is not formulated for pediatric use. The pharmaceutical form is a solution for infusion, and the product is manufactured by Merck Sharp & Dohme B.V.

In this study, pembrolizumab is the sole investigational product, and no additional non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are utilized. Participant compliance with the dosing schedule is monitored through regular clinical assessments and infusion records. The trial aims to evaluate the efficacy of pembrolizumab in patients with locally advanced, irresectable, non-metastatic dMMR colorectal cancers, as outlined in the study titled "Pembrolizumab for locally advanced, irresectable, non-metastatic dMMR colorectal cancers. The PUMA study."

Efficacy

The efficacy of **pembrolizumab** in patients with locally advanced, irresectable dMMR colorectal cancers will be assessed through a series of primary and secondary endpoints. The primary endpoint is the objective response rate (ORR), which will be determined according to RECIST 1.1 and iRECIST criteria. This will provide a measure of the drug's effectiveness in reducing tumor size or achieving complete response in the target patient population.

Secondary endpoints include the assessment of major pathological response (MPR), defined as ≤10% viable tumor rest in patients undergoing surgery. Additionally, the study will explore biomarkers and evaluation strategies to accurately assess complete and near-complete responses, potentially allowing for organ-sparing treatment. This includes the use of post-treatment CT-scans and radiomics, as well as circulating tumor DNA (ctDNA) analysis to differentiate between complete and near-complete responses in terms of minimal residual disease and relapse.

Translational analyses may be conducted, including RNA sequencing and inflammatory signatures to validate current findings and identify predictors of response. The study will also analyze immune cell infiltration and differences between responders and non-responders, as well as the immunogenic mutational load using tumor tissue DNA whole exome sequencing (WES). Peripheral blood DNA WES will serve as a control for somatic mutation sorting. Furthermore, the study will monitor the date of relapse, determined by disease recurrence or disease-related death during follow-up after surgery, in accordance with local and national guidelines. The association between microbiota composition and treatment outcomes, as well as the effect of neoadjuvant pembrolizumab on gut microbiota composition, will also be evaluated.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Signed written informed consent
Patients at least 18 years of age
Locally advanced, irresectable adenocarcinoma of the colon or rectum, not amenable to surgery, or for which induction therapy is required to reconsider surgery, or where free margins can only be obtained by major extension of the surgical procedure, as defined by one of the following: Invasion of the duodenum, stomach, spleen or pancreatic head, for which major extension of the surgical procedure would be required to obtain free margins, and/or for which the chances of positive resection margins are high; Invasion or encasement of major blood vessels (superior mesenteric vessels, iliac vessels, portal vein); Invasion or encasement of the ureter
Histologically or cytologically confirmed microsatellite instability-high (MSI-H) or MMR-deficient (dMMR) status
No signs of distant metastases on CT-scan and physical examination; patients may not be eligible for first-line treatment with pembrolizumab according to SoC
Patients may not be eligible for standard of care first-line pembrolizumab for metastatic disease
Patients may not be potentially eligible for the NICHE study: patients with primarily resectable disease, for which relatively minor extension of the procedure is required to achieve free margins, such as but not limited to a small bowel segment, abdominal wall
ECOG performance status of 0 or 1. Evaluation of ECOG is to be performed within 7 days prior to the first dose of study intervention
Screening laboratory tests must meet the criteria as defined in Table 1 and should be obtained within 10 days prior to the start of study intervention: Absolute neutrophil count (ANC) ≥1500/μL; Platelets ≥100 000/μL; Hemoglobin ≥9.0 g/dL or ≥5.6 mmol/L, Creatinine OR Measured or calculated creatinine clearance (GFR can also be used in place of creatinine or CrCl) ≤1.5 × ULN OR ≥30 mL/min for participant with creatinine levels >1.5 × institutional ULN; Total bilirubin ≤1.5 ×ULN OR direct bilirubin ≤ULN for participants with total bilirubin levels >1.5 × ULN; AST (SGOT) and ALT (SGPT) ≤2.5 × ULN; International normalized ratio (INR) OR prothrombin time (PT) ≤1.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants; 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;
A male participant must agree to use a contraception as detailed in Appendix 2 of this protocol during the treatment period and for at least 200 days (90 days plus the time required for pembrolizumab to undergo five half-lives) after the last dose of study treatment and refrain from donating sperm during this period
Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to registration (see appendix 2). If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
A female participant is eligible to participate if she is not pregnant (see appendix 2), not breastfeeding, and at least one of the following conditions applies: Not a woman of childbearing potential (WOCBP) as defined in appendix 2 OR a WOCBP who agrees to follow the contraceptive guidance in appendix 2 during the treatment period and for at least 120 days (30 days plus the time required for pembrolizumab to undergo five half lives) after the last dose of study treatment
CT-scan must be performed within 28 days prior to registration

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Exclusion Criteria

Previous treatment with immune checkpoint inhibitors targeting including but not limited to CTLA-4, PD-1 or PD-L1
Previous treatment with chemotherapy for the disease under study
Prior radiotherapy for the disease under study
Prior radiotherapy for other indications than the disease under study within 2 weeks of start of study intervention. Participants must have recovered from al radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis
History of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease
Allergies and Adverse Drug Reaction: history of allergy to study drug components; history of severe hypersensitivity reaction to any monoclonal antibody
Intercurrent illnesses, including but not limited to infections, unstable angina pectoris
Known history of Human Immunodeficiency Virus (HIV) infection and no known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection
Underlying medical conditions that, in the investigator’s opinion, will make the administration of the study drug hazardous or obscure the interpretation of toxicity determination of adverse events
Active autoimmune disease requiring systemic treatment in the past 2 years; or other medical conditions requiring systemic steroid or immunosuppressive medications, Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed
Diagnosis of immunodeficiency or conditions requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease
Live vaccines in the 4 weeks prior to inclusion
History of uncontrolled medical or psychiatric illness
Psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule
Current pregnancy or breastfeeding
Active malignancies other than disease under study within 3 years prior to inclusion, except for malignancies with a negligible recurrence rate (e.g. <10% in 5 years)
Allogenic tissue/solid organ transplant