Pembrolizumab for locally advanced, irresectable, non-metastatic dMMR colorectal cancers. The PUMA study.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis Stichting

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

13 Dec 2022 → ongoing

Decision date (initial)

2024-02-21

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Merck Sharp & Dohme (MSD)

External identifiers

EU CT number

2023-509707-32-00

EudraCT number

2021-005731-23

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy

To assess the efficacy of pembrolizumab in patients with locally advanced, irresectable dMMR colorectal cancers.

Secondary objectives 6

1. To assess the major pathological response (MPR, ≤10% viable tumor rest) in patients undergoing surgery
2. To assess resectability after induction pembrolizumab
3. To find biomarkers and evaluation strategies able to accurately assess complete and near-complete responses in patients undergoing surgery; CT-scans: can we use radiomics to accurately assess complete and near-complete response?; ctDNA analysis: can we use ctDNA to aid in assessing responses
4. To perform translational analyses, yet to be specified, but may include: RNA sequencing and inflammatory signatures to validate current findings and identify predictors of response; Immunogenic mutational load by DNA WES and correlation with putative markers of response; Analysis of immune cell infiltration and the differences between responders and non-responders; ctDNA analysis: can we predict early responders and in case of surgery, complete and near-complete responses
5. In case of surgery, to assess post-surgical outcome and infectious complications following neoadjuvant immunotherapy
6. To assess relapse free survival

Conditions and MedDRA coding

Locally advanced, irresectable dMMR colorectal cancers

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. Signed written informed consent
2. Patients at least 18 years of age
3. 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
4. Histologically or cytologically confirmed microsatellite instability-high (MSI-H) or MMR-deficient (dMMR) status
5. 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
6. Patients may not be eligible for standard of care first-line pembrolizumab for metastatic disease
7. 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
8. 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
9. 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;
10. 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
11. 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
12. 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
13. CT-scan must be performed within 28 days prior to registration

Exclusion criteria 17

1. Previous treatment with immune checkpoint inhibitors targeting including but not limited to CTLA-4, PD-1 or PD-L1
2. Previous treatment with chemotherapy for the disease under study
3. Prior radiotherapy for the disease under study
4. 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
5. History of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease
6. Allergies and Adverse Drug Reaction: history of allergy to study drug components; history of severe hypersensitivity reaction to any monoclonal antibody
7. Intercurrent illnesses, including but not limited to infections, unstable angina pectoris
8. 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
9. 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
10. 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
11. 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
12. Live vaccines in the 4 weeks prior to inclusion
13. History of uncontrolled medical or psychiatric illness
14. Psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule
15. Current pregnancy or breastfeeding
16. 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)
17. Allogenic tissue/solid organ transplant

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. To determine the objective response rate (ORR) according to RECIST 1.1 and iRECIST criteria in order to assess the efficacy of pembrolizumab in patients with locally advanced, irresectable dMMR colorectal cancers

Secondary endpoints 5

1. To assess the major pathological response (MPR, ≤10% viable tumor rest) in patients undergoing surgery
2. To find biomarkers and evaluation strategies able to accurately assess complete and near-complete responses in order to pursue organ-sparing treatment (omission of surgery) in this patient population; Post-treatment CT-scans: can we use radiomics to accurately assess complete and near-complete response?; ctDNA analysis: can we use ctDNA to assess complete response and is there a difference between complete and near-complete response in terms of minimal residual disease on ctDNA and relapse?
3. To perform translational analyses, yet to be determined, which may include the following: RNA sequencing and inflammatory signatures to validate current findings and identify predictors of response; Analysis of immune cell infiltration and differences between responders and non-responders; Immunogenic mutational load by tumor tissue DNA WES. Peripheral blood DNA WES as a control for somatic mutation sorting
4. Date of relapse, as determined by disease recurrence or disease-related death during follow-up after surgery. Follow-up will be performed according to local and/or national guidelines
5. Association between microbiota composition and treatment outcomes and the effect of neoadjuvant pembrolizumab on the gut microbiota composition

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis Stichting

Sponsor organisation

Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis Stichting

Address

Plesmanlaan 121

City

Amsterdam

Postcode

1066 CX

Country

Netherlands

Scientific contact point

Organisation

Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis Stichting

Contact name

Myriam Chalabi

Public contact point

Organisation

Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis Stichting

Contact name

Myriam Chalabi

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 1 file

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications