Watch-and-wait strategy to initiate Dostarlimab-based Immunotherapy in localized deficient mismatch repair (dMMR) and/or microsatellite instability high (MSI-H) oEso-gastric junction and gastric adenocarcinoma: A two cohort open-label GERCOR phase II study

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Gercor

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Digestive System Diseases [C06]

Trial duration

18 Dec 2023 → ongoing

Decision date (initial)

2023-10-20

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy

To evaluate clinical complete response (cCR) at 1 year defined as the rate of patients who at 1 year from the start of therapy with dostarlimab are alive, were not operated for tumor resection, are free of disease progression (locoregional or metastases), have all negative biopsies, and show endoscopy downstaging stage 3 or 4 (endoscopic grade)

Secondary objectives 13

1. To assess the number of patients who did not undergo surgery for tumor resection without distant metastases at specific time points (12 months and 24 months),
2. To assess the number of patients who did not undergo surgery for tumor resection due to distant metastases at specific time points (12 months and 24 months),
3. To assess pathological response (Tumor regression grade by Becker classification) on surgical specimen when surgery for tumor resection
4. To assess event-free survival (EFS), Time To Treatment failure (TTF), and OS for the whole population,
5. To assess DFS in case of surgery for tumor resection with and without adjuvant treatment with dostarlimab,
6. To evaluate the safety of dostarlimab by the National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] v5.0,
7. To evaluate the morbidity in case of surgery (complication or death occurring within 90 postoperative days according to the Clavien Dindo’s classification),
8. To evaluate HRQoL by the EORTC Core Quality of Life questionnaire (EORTC QLQ-C30) and EORTC oesophago-gastric (EORTC QLQ-OG25) questionnaires in patients with or without surgery.
9. To evaluate the efficacy of dostarlimab according to selected tumor biomarkers: - PD-1 and PD-L1 expression (for PD-L1, combined positive score [CPS] in addition to tumor proportion score [TPS]); ≥1% and ≥5% versus no expression), - CD3+, CD8+, and FOXP3 (high expression versus low expression) and inflammatory signature upon RNAseq.
10. To evaluate whether PD-L1, PD-1, anti-CTL4, TIM-3, LAG-3, GAL9, IDO, and TIGIT expression could be predictive of patients’ response,
11. To evaluate ctDNA presence and its predictive and prognostic value at baseline and during treatment and follow up,
12. To evaluate blood proteome at baseline and during therapy,
13. To evaluate predictive and prognostic significance of dMMR/MSI-H Lynch versus sporadic tumors (Lynch syndrome defined as germline mutations in the mismatch repair genes and sporadic cases as those without germline mutation, without MLH1 mutation in IHC, and with hMLH1 promoter hypermethylation.

Conditions and MedDRA coding

metastatic gastric cancer

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 17

1. Is capable of giving signed and dated informed consent,
2. Has an ECOG PS of 0-1,
3. Is between ≥18 and ≤75 years old,The patient over 75 years of age is eligible only if all the following conditions are met: The patient’s G8 questionnaire score is above 14 AND The patient is eligible for surgery and has no contraindications to repeated UGI endoscopy with biopsies,
4. Has histologically proven non-metastatic gastric or OGJ adenocarcinoma cT2 to T4, Nx, M0 after computed tomography thorax-abdomen-pelvis (TAP-CT) and echo-endoscopy (EUS) according to the 7th Edition of the International Union Against Cancer;
5. Has no peritoneal carcinomatosis (optional coelioscopy; recommended in case of doubt/ suspicious on CT/ imaging),
6. Has not received prior therapy (chemotherapy, radiotherapy, or immunotherapy) for localized gastric or OGJ adenocarcinoma,
7. Tumor status confirmed to be dMMR/MSI-H
8. Has hematological status: absolute neutrophil count (ANC) ≥1.5 x 109/L; platelets ≥100 x 109/L; hemoglobin ≥9 g/dL,
9. Has adequate renal function: serum creatinine level ≤150 μM and clearance ≥50 ml/min (Modification of the Diet in Renal Disease [MDRD] or Cockcroft and Gault),
10. Has adequate liver function: ≤1.5 x upper limit of normal (ULN) of direct bilirubin ≤ ULN for participants with total bilirubin levels >1.5 x ULN (inclusion possible if known Gilbert syndrome), alkaline phosphatase <5 x ULN, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) ≤2.5 x ULN,
11. Has international normalized ratio (INR), prothrombin time (PT), and activated partial thromboplastin time (aPTT) ≤1.5 x ULN, except for the patient on anticoagulant therapy who must have PT-INR-aPTT within therapeutic range is deemed appropriate by the Investigator,
12. Has radiological tumor assessment at screening performed within 28 days before inclusion according to RECIST version 1.1 by chest, abdomen, and pelvis CT, showing the absence of metastatic or non-surgical disease,
13. A female participant is eligible to participate if she is not pregnant or breastfeeding,
14. Male participants are eligible to participate if they agree to the following during the study treatment and for 4 months after the last dose of dostarlimab:
15. Provides primary tumor tissue samples (processed as formalin-fixed, paraffin-embedded [FFPE] blocks or freshly frozen) acquired during UGI endoscopy together with images (mandatory),
16. Is willing and able to comply with scheduled visits, treatment schedule, laboratory tests, tumor biopsies, and other requirements of the study,
17. s registered in a National Health Care System (PUMa - Protection Universelle Maladie included).

Exclusion criteria 19

1. Has received prior concomitant unplanned antitumor therapy (e.g., chemotherapy, molecular targeted therapy, immunotherapy),
2. Has received treatment with any investigational medicinal product within 28 days prior to study entry,
3. Has a treatment anticoagulant or hemostasis disorder contraindicating - biopsies during endoscopy,
4. Has had major surgical procedure within 28 days (4 weeks) prior to the first dose of study treatment,
5. Has other serious and uncontrolled non-malignant disease (including active infection) or is considered a poor medical risk due to a serious, uncontrolled medical disorder, nonmalignant systemic disease or active infection requiring systemic therapy. Specific examples include, but are not limited to, active, non-infectious pneumonitis; uncontrolled ventricular arrhythmia; recent (within 90 days) myocardial infarction; uncontrolled major seizure disorder; unstable spinal cord compression; superior vena cava syndrome; or any psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study,
6. Has other concomitant or previous malignancy other than the disease under study, except as noted below: i/ adequately treated in-situ carcinoma of the uterine cervix, ii/ basal or squamous cell carcinoma of the skin, iii/ cancer from which the patients was in complete remission for ≥3 years,
7. Has metastases (M stage disease) whatever the location,
8. Is pregnant or breastfeeding,
9. Has human immunodeficiency virus (HIV),
10. 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,
11. Patient under a legal protection regime (guardianship, curatorship, judicial safeguard) or administrative decision or incapable of giving his/her consent,
12. Impossibility of submitting to the medical follow-up of the study for geographical, social, or psychiatric illness.
13. Has pyloric tumor,
14. Has 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,
15. Has a history of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis on screening chest imaging,
16. Has received any live, attenuated vaccine within 14 days prior to the firs dose of study treatment or such administration is anticipated during the study,
17. Has received prior therapy with any immune-checkpoint inhibitors, including antibodies or drugs targeting CD137, CTLA-4, PD-1, or PD-L1 or other checkpoint pathways,
18. Has had prior allogeneic bone marrow transplantation or prior solid organ transplantation,
19. Has received 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 2 weeks prior to the first dose of adjuvant 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The rate of patients who achieve cCR at 1 year from the start of treatment with dostarlimab.

Secondary endpoints 12

1. The number of patients who did not undergo surgery for tumor resection without distant metastases at specific time points (12 months and 24 months),
2. The number of patients who did not undergo surgery for tumor resection with distant metastases at specific time points (12 and 24 months),
3. Pathological response (Tumor regression grade by Becker classification) on surgical specimen, when surgery performed for tumor resection,
4. EFS, TTF, and OS for the whole population
5. DFS in case of surgery for tumor resection with and without adjuvant treatment with dostarlimab,
6. The safety of dostarlimab by the NCI CTCAE v 5.0,
7. Morbidity in case of surgery (complication or death occurring within 90 postoperative days according to the Clavien Dindo’s classification),
8. HRQoL by the EORTC QLQ-C30 and EORTC QLQ-OG25 questionnaires in patients with or without surgery.
9. The efficacy of dostarlimab according to selected tumor biomarkers: - PD-1 and PD-L1 expression, - CD3+, CD8+, and FOXP3, and inflammatory signature upon RNAseq
10. Association of PD-L1, PD-1, anti-CTL4, TIM-3, LAG-3, GAL9, IDO, and TIGIT expression to patients’ response,
11. The prognostic value of ctDNA presence, at baseline and during follow up,
12. Prognostic value of dMMR/MSI-H Lynch versus sporadic tumors (Lynch syndrome defined as germline mutations in the mismatch repair genes and sporadic cases as those without germline mutation, without MLH1 mutation in IHC, and with hMLH1 promoter hypermethylation.

Investigational products

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

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Gercor

Sponsor organisation

Gercor

Address

151 Rue Du Faubourg Saint Antoine

City

Paris

Postcode

75011

Country

France

Scientific contact point

Organisation

Gercor

Contact name

Regulatory Affairs

Public contact point

Organisation

Gercor

Contact name

Regulatory Affairs

Third parties 1

Locations

2 EU/EEA countries · 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 55 files

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

Application history

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