Neoadjuvant Pembrolizumab With a Watch-and-wait Strategy for dMMR/MSI-H Localized Colon Cancer: PREMICES Study.

NCT06646445 | Not Yet Recruiting Phase 2 DMC

• 1 other identifier: PREMICES G-109 PRODIGE 84
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 10

Brief Summary

The goal of this investigational, multicenter, open-label randomized, two-stage phase II study is to evaluate neoadjuvant pembrolizumab with a watch-and-wait approach in patients with localized deficient mismatch repair / high microsatellite instability (dMMR/MSI-H) colorectal cancer (CRC). The PREMICES trial is based on the hypothesis that non-operative management is effective for dMMR/MSI-H localized CRC when treated with neoadjuvant pembrolizumab. Eligible patients will be randomized in a 1:1 ratio to receive either pembrolizumab with a watch-and-wait approach (experimental arm A) or the standard strategy of surgical resection ± adjuvant chemotherapy (arm B).

Conditions

Colon Cancer

Keywords

pembrolizumab; watch-and-wait; microsatellite instability; mismatch repair deficient

Outcome Measures

Primary Outcomes (1)

• The rate of success of the experimental strategy at 6 months or after two successive colonoscopies (corresponding to timepoint at 6 months from the experimental strategy) following randomization.

  The success at 6 months is defined as an absence of death, of disease progression, or of decision to perform surgery of the primary tumor for residual cells on biopsies, or for any other reason.

  6 months

Secondary Outcomes (8)

• The rate of strategy success at 24 months

  24 months

• Incidence of Adverse Events (Safety assessment)

  Up to 4 years

• Overall surival (OS) at 6, 12 and 24 months in both study arms

  Up to 24 months

• Event-free survival (EFS) at 6, 12 and 24 months in both study arms

  Up to 24 months

• 30-day and 90-day postoperative morbidity for patients who underwent surgery in both study arms

  Up to 90 days post-surgery

Study Arms (2)

Experimental Arm A (Pembrolizumab plus watch-and-wait approach)

EXPERIMENTAL

Pembrolizumab and Watch-and-wait (TAP-CT scan, colonoscopy with biopsies)

Drug: Pembrolizumab Injection [Keytruda]; Procedure: Watch-and-wait approach

Arm B (Surgical resection ± adjuvant chemotherapy)

ACTIVE COMPARATOR

Standard of care surgery ± adjuvant chemotherapy (5-fluorouracil/capecitabine ± oxaliplatin 3 months to 6 months)

Procedure: Surgery; Drug: Adjuvant chemotherapy

Interventions

Pembrolizumab Injection [Keytruda] DRUG

Pembrolizumab 200 mg via a 30-minute IV infusion q3w on Day 1 of each 21-day cycle; 8 cycles ± 9 additional cycles (17 cycles in total).

Also known as: Keytruda

Experimental Arm A (Pembrolizumab plus watch-and-wait approach)

Watch-and-wait approach PROCEDURE

Watch-and-wait strategy: * TAP-CT scan At months 3 and 6 during 8 cycles of treatment, at months 9 and 12, and during additional 9 cycles of treatment if performed, and every 3 months thereafter for up to 2 years, * Colonoscopy with biopsies at months 3, 6, 9, 12, and 24.

Experimental Arm A (Pembrolizumab plus watch-and-wait approach)

Surgery PROCEDURE

Standard of care surgery performed with a maximal delay of 21 days (3 weeks) from randomization.

Arm B (Surgical resection ± adjuvant chemotherapy)

Adjuvant chemotherapy DRUG

Adjuvant chemotherapy (5-fluorouracil/capecitabine ± oxaliplatin 3 months to 6 months) according to the current guidelines, at the investigator's discretion.

Arm B (Surgical resection ± adjuvant chemotherapy)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Signed and dated informed consent (IC),
• Aged ≥18 years,
• An Eastern Cooperative Oncology Group Performance status (ECOG PS) of 0 or 1,
• Newly diagnosed, histologically confirmed colonic or upper third rectal adenocarcinoma, NB: material must be available from biopsy done during colonoscopy.
• dMMR and/or MSI-high (MSI-H) tumor status as follows:
• loss of expression of ≥1 MMR protein (MLH1, MSH2, MSH6, or PMS2) or a dimeric couple (MLH1 and PMS2 or MSH2 and MSH6) on immunohistochemistry (IHC; using hMLH1, hMSH2, hMSH6, hPMS2 antibodies),
• And/or ≥ 3 instable markers by the pentaplex by polymerase chain reaction (PCR) (BAT-25, BAT-26, NR-21, NR-24, and NR-27),
• NB:
• In case of two instable markers by PCR, it is required to present confirmation of the dMMR status by IHC or comparison of PCR test with matched normal tissue.
• Adequate hematological status, renal, and liver function obtained within 14 days prior to randomization of study treatment:
• absolute neutrophil count (ANC) ≥1.5 x 10\^9/L; platelets ≥100 x 10\^9/L; hemoglobin ≥9 g/dL,
• serum creatinine level \<150 µM or clearance \>50 ml/min (Modification of the Diet in Renal Disease \[MDRD\] or Cockcroft and Gault),
• serum bilirubin ≤1.5 × upper limit of normal (ULN), alkaline phosphatase \<5 x ULN, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) ≤ 2.5 x ULN,
• International normalized ratio (INR), prothrombin time (PT), and activated partial thromboplastin time (aPTT) ≤1.5 × ULN, except for the patient on anticoagulant therapy who must have PT-INR-aPTT within therapeutic range is deemed appropriate by the Investigator,
• Has no contraindications to administration of oxaliplatin, capecitabine, or 5-fluorouracil, according to their respective summaries of product characteristics (SmPCs),

You may not qualify if:

• Tumor that is not readily resectable,
• Bifocal colorectal adenocarcinoma,
• Locally advanced middle or low rectal cancer (\<10 cm from the anal verge on MRI, sagittal slide) staged as cT3/T4 and/or N+ and/or with predictive circumferential margin \>2 mm on pretreatment MRI, NB: for rectal cancers, the margin of the tumor relative to the anal margin should be indicated on the endoscopy report,
• Major surgical procedure within 4 weeks prior to the first dose of study treatment,
• Pre-existing hemostatic disorder or medical condition requiring chronic anticoagulation that cannot be interrupted for the purpose of study specified tumor resection or endoscopic biopsies,
• Metastases (stage IV disease),
• Has history of uncontrolled or symptomatic cardiac disease,
• Prior treatment with an anti-PD(L)1, anti-LAG-3, or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways, including prior therapy with anti-tumor vaccines or other immuno-stimulatory antitumor agents,
• Prior malignancy active within the previous 3 years apart from: i/ locally curable cancers that have been apparently cured (e.g., squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast); ii/ Lynch syndrome-related non-CRC in complete remission for \> 1 year,
• Patient is human immunodeficiency virus (HIV)-positive with CD4+ cell count \<600 cell/ml or detectable viral load,
• Impossibility of submitting to the medical follow-up of the study for geographical, social, or psychiatric illness.
• Patient under a legal protection regime (guardianship, curatorship, judicial safeguard) or administrative decision or incapable of giving his/her consent,
• Non-eligible to immunotherapy:
• Any history of autoimmune disease including, but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis, NB: History of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone may be eligible.
• NB: Controlled Type 1 diabetes mellitus on a stable insulin regimen may be eligible.

Sponsors & Collaborators

• GERCOR - Multidisciplinary Oncology Cooperative Group: lead
• Fondation ARCAD: collaborator

Study Sites (10)

Institut Sainte Catherine

Avignon, France

Location

CHU Besançon

Besançon, France

Location

IHFB Cognacq Jay

Levallois-Perret, France

Location

Centre Leon Berard

Lyon, France

Location

Groupe Hospitalier Diaconesses Croix Saint Simon

Paris, France

Location

Hôpital Saint Antoine

Paris, France

Location

Institut Mutualiste Montsouris

Paris, France

Location

CHU Bordeaux Haut Lévêque

Pessac, France

Location

CHU Poitiers

Poitiers, France

Location

CHU Toulouse

Toulouse, France

Location

MeSH Terms

Conditions

Colonic Neoplasms; Microsatellite Instability; Turcot syndrome

Interventions

pembrolizumab; Surgical Procedures, Operative; Chemotherapy, Adjuvant

Condition Hierarchy (Ancestors)

Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Genomic Instability; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Combined Modality Therapy; Therapeutics; Drug Therapy

Central Study Contacts

Romain Romain, Dr

CONTACT

+33 (1) 49 28 23 45; romain.cohen@aphp.fr

Marie-Line GARCIA LARNICOL, Dr

CONTACT

+33 (1) 40 29 85 04; marie-line.garcia-larnicol@gercor.com.fr

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Pembrolizumab plus a watch-and-wait approach (experimental arm) Standard strategy (surgical resection ±adjuvant chemotherapy (control arm) 1:1 ratio

Study Record Dates

• First Submitted: October 15, 2024
• First Posted: October 17, 2024
• Study Start: September 1, 2025
• Primary Completion (Estimated): December 1, 2027
• Study Completion (Estimated): December 1, 2029
• Last Updated: June 13, 2025

Record last verified: 2025-06

Data Sharing

• IPD Sharing: Will not share

Locations

FR (10)