Trial Title:
Neoadjuvant Pembrolizumab with a Watch-and-wait Strategy for Patients with DMMR/MSI-H Localized Colon Cancer: GERCOR G-109 PRODIGE 84 PREMICES Phase II Trial
NCT ID:
NCT06646445
Condition:
Colon Cancer
Conditions: Official terms:
Colonic Neoplasms
Microsatellite Instability
Pembrolizumab
Conditions: Keywords:
pembrolizumab
watch-and-wait
microsatellite instability
mismatch repair deficient
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Not yet recruiting
Study design:
Allocation:
Randomized
Intervention model:
Parallel Assignment
Intervention model description:
This is a multicenter open-label randomized phase II trial. Eligible patients will be
randomized to receive pembrolizumab with a watch-and-wait approach (experimental arm) or
standard strategy (surgical resection ±adjuvant chemotherapy; control arm) in a 1:1
ratio.
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Pembrolizumab 200mg IV q3w day 1 of 21-day cycle
Description:
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).
Arm group label:
Experimental Arm
Other name:
Keytruda
Intervention type:
Procedure
Intervention name:
Watch-and-wait approach
Description:
Watch-and-wait strategy:
- TAP-CT scan every 3 months (± 7 days) for 2 years from inclusion.
- Colonoscopy with biopsies at months 3, 6, 12, 24.
Arm group label:
Experimental Arm
Intervention type:
Procedure
Intervention name:
Surgery
Description:
Standard of care surgery performed with a maximal delay of 21 days (3 weeks) from
inclusion.
Arm group label:
Control Arm
Intervention type:
Drug
Intervention name:
Adjuvant chemotherapy
Description:
Adjuvant chemotherapy (5-fluorouracil/capecitabine ± oxaliplatin 3 months to 6 months)
will be prescribed according to the current guidelines, at the investigator's discretion.
Arm group label:
Control Arm
Summary:
The goal of this investigational study is to evaluate neoadjuvant pembrolizumab with a
watch-and-wait approach for localized dMMR/MSI-H CRC patients. The PREMICES trial is
based on the hypothesis that non-operative management is efficient for dMMR/MSI-H
localized CRC patients treated with neoadjuvant pembrolizumab.
Eligible patients will be randomized to receive pembrolizumab with a watch-and-wait
approach (experimental arm) or standard strategy (surgical resection ±adjuvant
chemotherapy; control arm) in a 1:1 ratio.
Detailed description:
dMMR/MSI-H is a key biomarker for predicting the success of immune checkpoint inhibitors
in colorectal cancer (CRC). Pembrolizumab has shown improved outcomes for patients with
metastatic CRC, becoming the new standard of care. Neoadjuvant immunotherapy has
demonstrated high rates of complete pathological responses in both metastatic and
localized CRC, with promising results in non-surgical approaches. Studies support using a
"watch-and-wait" strategy after immunotherapy, potentially avoiding surgery. These
findings are reshaping treatment strategies for dMMR/MSI-H CRC, particularly regarding
organ preservation and non-operative management.
The PREMICES study evaluates the efficacy of neoadjuvant pembrolizumab combined with a
watch-and-wait approach for treating localized dMMR/MSI-H CRC patients. It explores
non-operative management as a potential strategy for achieving complete clinical response
in dMMR/MSI-H localized CRC without surgery.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
1. Signed and dated informed consent (IC),
2. Aged ≥18 years,
3. An Eastern Cooperative Oncology Group Performance status (ECOG PS) of 0 or 1
(Appendix 24.7),
4. Newly diagnosed, histologically confirmed colonic or upper third rectal
adenocarcinoma, NB: material must be available from biopsy done during colonoscopy.
5. Radiological tumor assessment at screening performed within 21 days before inclusion
according to RECIST v1.1 (Appendix 24.8) by chest, abdomen, and pelvis (TAP-CT)
showing resectable localized disease (cT0-4 cN0-2 cM0) and no metastatic or
non-surgical disease,
6. 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.
- In case of loss of expression of only one MMR protein by IHC or any other IHC
pattern, it is required to confirm MSI status using pentaplex PCR; Agreement of
Sponsor (GERCOR) on a dMMR/MSI status is mandatory to include the patient (the
patient's file [an anonymized mail] must be send to Sponsor before inclusion).
Approval/refusal email for inclusion of the patient will be sent by the Sponsor
within 24 hours of receipt of the Investigator email. In case of discrepancy
between IHC and PCR, the final decision about the dMMR/MSI status will be taken
by GERCOR or coordinating investigator,
7. Adequate hematological status, renal, and liver function obtained within 14 days
prior to randomization of study treatment:
1. absolute neutrophil count (ANC) ≥1.5 x 109/L; platelets ≥100 x 109/L;
hemoglobin ≥9 g/dL,
2. serum creatinine level <150 µM or clearance >50 ml/min (Modification of the
Diet in Renal Disease [MDRD] or Cockcroft and Gault),
3. 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,
8. 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,
9. A female participant is eligible to participate if she is not pregnant or
breastfeeding, and one of the following conditions applies:
1. Is a woman of non-childbearing potential as defined: i/ ≥45 years of age and
has not had menses for >1 year, ii/ amenorrhea for <2 years without a
hysterectomy and oophorectomy and have a high follicle stimulating hormone
(FSH) value in the postmenopausal range upon pre-study (screening) evaluation,
iii/ post-hysterectomy, post-bilateral oophorectomy, or post-tubal ligation
documented hysterectomy or oophorectomy must be confirmed with medical records
of the actual procedure or confirmed by an ultrasound, MRI, or CT scan,
2. Negative pregnancy blood test within 72 hours before the first dose of
pembrolizumab, AND
3. If woman of childbearing potential (WOCBP), female patient must be willing to
use a highly effective form of contraception (Appendix 24.9) from screening
throughout the study treatment and 4 months after the last dose of
pembrolizumab,
10. Male patient is eligible to participate if he agrees to the following during the
study treatment and for 4 months after the last dose of pembrolizumab:
1. Refrain from donating sperm,
2. Must use contraception/barrier as follows:
- Agree to use a male condom when having sexual intercourse with a woman of
childbearing potential (WOCBP) who is not currently pregnant.
- Agree to use a male condom when engaging in any activity that allows for
passage of ejaculate to another person,
11. Primary tumor tissue samples (archival or fresh biopsy specimen) acquired during
coloscopy together with images availability (mandatory), NB: The patient's agreement
will be specifically requested for endoscopic images in the patient information note
and IC for their use as clinical data that may be analyzed and presented in
publications. These data will be used in the same manner as other personal data. The
confidentiality of these data will be maintained,
12. Patient willing and able to comply with scheduled visits, treatment schedule,
laboratory tests, tumor biopsies, and other requirements of the study,
13. Registeration in the National Health Care System (PUMa - Protection Universelle
Maladie included).
Exclusion Criteria:
1. Tumor that is not readily resectable,
2. Bifocal colorectal adenocarcinoma,
3. 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,
4. Major surgical procedure within 4 weeks prior to the first dose of study treatment,
5. 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,
6. Metastases (stage IV disease),
7. 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,
8. 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,
9. Patient is human immunodeficiency virus (HIV)-positive with CD4+ cell count <600
cell/ml or detectable viral load,
10. Patient has active hepatitis B virus (HBV, defined as having a positive hepatitis B
surface antigen [HBsAg] test) or hepatitis C virus (HCV) prior to inclusion, NB:
Patients with past HBV infection or resolved HBV infection (defined as having a
negative HBsAg test and a positive antibody to hepatitis B core antigen antibody
test) are eligible.
NB: Patients positive for HCV antibody are eligible only if PCR testing is negative
for HCV RNA.
11. Impossibility of submitting to the medical follow-up of the study for geographical,
social, or psychiatric illness.
12. Patient under a legal protection regime (guardianship, curatorship, judicial
safeguard) or administrative decision or incapable of giving his/her consent,
Non-eligible to immunotherapy:
13. 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.
14. Prior (non-infectious) pneumonitis requiring systemic corticosteroid therapy or has
currently pneumonitis,
15. Any live, attenuated vaccine within 30 days prior to the first dose of study
treatment or such administration is anticipated during the study,
16. Prior allogeneic bone marrow transplantation or prior solid organ transplantation,
17. Treatment with systemic corticosteroids or other systemic immunosuppressive
medications (including but not limited to prednisone, dexamethasone,
cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis
factor agents) within 14 days (2 weeks) prior to the first dose of trial treatment
or is required to receive systemic immunosuppressive medications during the study.
Inhaled or topical steroids and adrenal replacement doses >10 mg daily prednisone
equivalents are permitted in the absence of active autoimmune disease.
18. Ongoing anti-cancer treatment for another cancer (to be discussed with the
coordinator in case of hormone therapy in patients with prostate and breast cancer),
19. Known hypersensitivity to any of the excipients of pembrolizumab, NB: L-histidine,
L-Histidine Hydrochloride monohydrate, sucrose, polysorbate-80 (E433).
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Institut Sainte Catherine
Address:
City:
Avignon
Country:
France
Contact:
Last name:
Clémence TOULLEC
Phone:
0490275760
Email:
c.toullec@isc84.org
Contact backup:
Last name:
Clémence TOULLEC
Facility:
Name:
CHU Besançon
Address:
City:
Besançon
Country:
France
Contact:
Last name:
Angélique VIENOT
Phone:
0370632403
Email:
a3vienot@chu-besancon.fr
Contact backup:
Last name:
Angélique VIENOT
Facility:
Name:
IHFB Cognacq Jay
Address:
City:
Levallois Perret
Country:
France
Contact:
Last name:
Benoist CHIBAUDEL
Phone:
0147595965
Email:
benoist.chibaudel@ihfb.org
Contact backup:
Last name:
Benoist CHIBAUDEL
Facility:
Name:
Centre Leon Berard
Address:
City:
Lyon
Country:
France
Contact:
Last name:
Aurélien DUPRE
Phone:
0478782933
Email:
aurelien.dupre@lyon.unicancer.fr
Facility:
Name:
Groupe Hospitalier Diaconesses Croix Saint Simon
Address:
City:
Paris
Country:
France
Contact:
Last name:
Olivier DUBREUIL
Phone:
0144742839
Email:
odubreuil@hopital-dcss.org
Contact backup:
Last name:
Olivier DUBREUIL
Facility:
Name:
Hôpital Saint Antoine
Address:
City:
Paris
Country:
France
Contact:
Last name:
Romain COHEN
Phone:
0149282336
Email:
romain.cohen@aphp.fr
Contact backup:
Last name:
Romain Cohen
Facility:
Name:
Institut Mutualiste Montsouris
Address:
City:
Paris
Country:
France
Contact:
Last name:
Raphael COLLE
Phone:
0156616241
Email:
raphael.colle@imm.fr
Contact backup:
Last name:
Raphaël COLLE
Facility:
Name:
CHU Bordeaux Haut Lévêque
Address:
City:
Pessac
Country:
France
Contact:
Last name:
Eric TERREBONNE
Phone:
0557656439
Email:
eric.terrebonne@chu-bordeaux.fr
Contact backup:
Last name:
Eric TERREBONNE
Facility:
Name:
CHU Poitiers
Address:
City:
Poitiers
Country:
France
Contact:
Last name:
David TOUGERON
Phone:
0549444886
Email:
david.tougeron@chu-poitiers.fr
Facility:
Name:
CHU Toulouse
Address:
City:
Toulouse
Country:
France
Contact:
Last name:
Rosine GUIMBAUD
Phone:
0561322142
Email:
guimbaud.r@chu-toulouse.fr
Contact backup:
Last name:
Rosine GUIMBAUD
Start date:
December 2024
Completion date:
October 2029
Lead sponsor:
Agency:
GERCOR - Multidisciplinary Oncology Cooperative Group
Agency class:
Other
Collaborator:
Agency:
Fondation ARCAD
Agency class:
Other
Source:
GERCOR - Multidisciplinary Oncology Cooperative Group
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06646445
