MSI/dMMR tumors in perioperative setting

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Centre Leon Berard

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

26 Nov 2021 → ongoing

Decision date (initial)

2024-11-05

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

MSD

External identifiers

EU CT number

2024-518127-30-00

EudraCT number

2020-004957-62

ClinicalTrials.gov

NCT04795661

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Therapy, Safety

To evaluate the efficacy of pembrolizumab MK-3475 in patients with untreated localized non-metastatic MSI/dMMR carcinomas or EBV+ gastric cancer, independently of their anatomical origin.

Secondary objectives 12

1. The safety of the perioperative treatment according to NCI CTC-AE v5,
2. The post-operative morbidity according to modified Clavien Dindo scoring
3. The R0 resection rate,
4. The major pathological response (≤ 10% residual viable tumor) rate
5. The recurrence-free survival (RFS),
6. The overall response rate (ORR) at 4, 10,16 and 21 weeks after the pembrolizumab MK-3475 initiation, evaluated by CT-scan and/or endoscopy and/or 18FDG PET-scan (i.e. at weeks 5-6, 11-12, 17-18 and 22-24),
7. The rate of second cancers in the Lynch syndrom spectrum,
8. The overall survival (OS),
9. The progression-free survival (PFS) after recurrence,
10. The quality of life (QoL),
11. The prognostic value of lung immune prognostic index (LIPI),
12. For patients without surgery : Progression free survival (PFS),

Conditions and MedDRA coding

MSI/dMMR tumors or EBV+ gastric cancer

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. I1. Age ≥ 18 years on the day of signing informed consent.
2. I2. Histologically proven localized non-metastatic tumor included in one of the following cohorts: - Colorectal or rectal Cancer (cT3/T4 N0 M0 ou cT N+ M0) OR - Oesogastric (gastric, gastro-oesophageal or oesophageal) cancer (cT2 to cT4, N, M0) OR - Other tumor types (cT2 to cT4, N, M0) : small bowel adenocarcinoma (duodenum, jejunum, ileum)
3. I3. MSI/dMMR established by immunohistochemistry (IHC) [MMR protein expression] and polymerase chain reaction (PCR) (or NextGeneration Sequencing (NGS)) [both techniques are required] and validated by coordinator's team. MMR and/or MSI tumors will be assessed using IHC with four antibodies (anti-MLH1, anti-MSH2, anti-MSH6 and anti-PMS2) and PCR (pentaplex panel is recommended: BAT-25, BAT-26, NR-21, NR-24, and NR-27) prior to screening. Loss of MLH1 and PMS2 / or MSH2 and MSH6 / or MSH6 alone / or PMS2 alone protein staining by IHC indicates dMMR, and tumor with ≥ 2 unstable markers analyzed on PCR proves MSI/dMMR. NGS will be accepted instead of PCR analysis.
4. I4. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 to 1 within 7 days prior to the inclusion.
5. I5. Adequate bone-marrow, hepatic, and renal functions, within 10 days prior to the start of study treatment with: - Hemoglobin ≥ 9 g/dl or ≥ 5.6 mmol/l, neutrophils ≥ 1.0 x 109, platelets ≥ 100 x 109, - Creatinine ≤ 1.5 x ULN or calculated creatinine clearance ≥ 30 ml/min/1.73m² using either MDRD or CKD-EPI formula, - AST and ALT ≤ 3 x ULN, total bilirubin ≤ 1.5 ULN (or direct bilirubin ≤ ULN for participants with total bilirubin levels >1.5 × ULN), - INR or 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.
6. I6. Covered by a medical/health insurance.
7. I7. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures.
8. I8. Patients of childbearing potential accepting to use effective contraceptive measures or abstain from heterosexual activity, for the course of the study through 4 months after the last dose of pembrolizumab MK-3475 adjuvant treatment or 6 months after adjuvant chemotherapy or being surgically sterile. Refer to Appendix 1 for approved methods of contraception.
9. I9. Signed and dated IRB/IE approved informed consent form.

Exclusion criteria 19

1. E1. MSS/pMMR tumors.
2. E10. Active infections.
3. E12. Live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed
4. E13. Known history of active TB (Bacillus Tuberculosis).
5. E14. Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study.
6. E15. Pregnant or breastfeeding woman or patient expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 4 months after the last dose of study treatment.
7. E16. Patient requiring tutorship or curatorship.
8. E17. Ongoing anti-cancer treatment for another cancer (to be discussed with the coordinator in case of hormone therapy).
9. E18. Prior history of other malignancies (except for HNPCC or Lynch syndrome-related cancers) unless the subjects has been free of the disease for at least 2 years
10. E19. Patient hospitalized at the moment of inclusion and treatment initiation (palliative care unit, retirement home … are considered as hospitals).
11. E2. Metastatic disease (stage IV).
12. E20. Recent hemorrhage (in the month before inclusion).
13. E3. HIV positive with CD4 count under 400 cells/mm3 .
14. E4. Concurrent active Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] positive and/or detectable HBV DNA) or Hepatitis C virus (defined as anti-HCV Ab positive and detectable HCV RNA) infection).
15. E5. Active systemic autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg. thyroxine, insulin) is not considered a form of systemic treatment and is allowed.
16. E6. Interstitial lung disease.
17. E7. Prior (non-infectious) pneumonitis requiring systemic corticosteroid therapy or current pneumonitis.
18. E8. History of severe hypersensitivity to another monoclonal antibody.
19. E9. Receiving immunosuppressive therapy or having received corticosteroids (in dosing exceeding 10 mg daily of prednisone equivalent) within the last 2 months before inclusion.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary endpoint will be the rate of complete pathological response (pCR) after surgery according to local pathological evaluation. A complete pathological response will be defined as 0% viable tumor cells in tumor or nodal site (ypT0N0).

Secondary endpoints 12

1. Safety profile
2. Rate of surgical complications
3. Percentage of patients with R0 resection
4. Percentage of patients with major pathological response
5. RFS
6. Percentage of patients with objective response 4, 10, 16 and 21 weeks
7. Percentage of patients with second cancer in the Lynch syndrome spectrum
8. OS
9. PFS
10. QoL
11. Association between LIPI score and the response to treatment
12. In the subgroup of patients without surgery: Progression free survival (PFS),

Investigational products

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

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Centre Leon Berard

Sponsor organisation

Centre Leon Berard

Address

28 Rue Laennec

City

Lyon

Postcode

69008

Country

France

Scientific contact point

Organisation

Centre Leon Berard

Contact name

Dr Clélia COUTZAC

Public contact point

Organisation

Centre Leon Berard

Contact name

Clinical project manager

Locations

1 EU/EEA country · 18 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 8 files

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

Application history

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