Adenocarcinoma - GEJ, Gastric Adenocarcinoma
Conditions
Keywords
dMMR, MSI-H, dostarlimab, watch-and-wait, surgery, immunotherapy
Brief summary
This phase II study evaluates dostarlimab followed by a watch-and-wait strategy in patients with localized dMMR/MSI-H gastric or gastroesophageal junction (GEJ) adenocarcinoma. The study aims to determine whether surgery can be safely avoided in patients achieving a complete response, defined by negative endoscopy and tumor-free biopsies after treatment.
Detailed description
Patients with localized, resectable gastric or gastroesophageal junction (GEJ) adenocarcinoma are currently treated with radical surgery, the only curative option, typically combined with perioperative chemotherapy. However, surgery is associated with substantial morbidity and a significant impact on quality of life. Given the high efficacy of immune checkpoint inhibitors in localized dMMR/MSI-H tumors, surgery omission may be a potential strategy for selected patients. This national, multicenter, open-label phase II study will evaluate dostarlimab in patients with localized dMMR/MSI-H gastric or GEJ adenocarcinoma. The primary objective is to determine whether a watch-and-wait approach can safely replace surgery in patients achieving a complete response after treatment, defined by negative endoscopy and tumor-free biopsies. Study aims Main cohort: To evaluate dostarlimab followed by a watch-and-wait approach in patients with localized dMMR/MSI-H gastric or GEJ adenocarcinoma. Additional unfit cohort (patients unfit for surgery): To evaluate the efficacy of dostarlimab in patients aged \>70 years with localized dMMR/MSI-H gastric or GEJ adenocarcinoma who are deemed unfit for surgical resection. Sample size Main initial cohort study (phase II): A total of 89 patients will be included (59 patients in the original protocol conducted in France and Italy, and an additional 30 patients to be enrolled exclusively in France). Additional unfit cohort: A total of 39 patients will be included (20 patients in the original protocol conducted in France and Italy, and an additional 19 patients to be enrolled exclusively in France).
Interventions
DRUGDostarlimab
Post-Inclusion: Dostarlimab 500mg IV q3wx4 cycles (Cs). Week 12 (W12) * cCR (both cohorts): Dostarlimab 1,000mg q6w×2 cycles. * Downstaging (Stage 2-3), no PD/mets: Dostarlimab 500mg q3w×4Cs. * Main cohort: SD/PD, Stage 1, positive(+), no cCR→Surgery. Post-surgery: Becker-TRG 1a/1b/2→Dostarlimab 1,000mg q6w×6Cs; Becker-TRG 3→Stop Trt. * Additional unfit cohort: SD/PD, Stage 1, biopsy(+) ± mets→Stop dostarlimab, withdraw from Trt, investigator-directed care, remain in FU. W24 * cCR at W12\&W24: Dostarlimab 1,000mg q6w×4Cs. * cCR at W12 but not W24: * Main cohort: Stop dostarlimab; surgery/adjuvant Trt per investigator. * Additional unfit cohort: Stop dostarlimab; withdraw from Trt; FU only. * Downstaging at W12 + cCR at W24: Dostarlimab 1,000mg q6w×4Cs. * Downstaging at W12 but no cCR at W24: * Main cohort: Surgery; if Becker-TRG 1a/1b/2, dostarlimab 1,000mg q6w×4Cs. * Additional unfit cohort: Stop dostarlimab, withdraw from Trt, investigator-directed care, remain in FU.
Sponsors
GERCOR - Multidisciplinary Oncology Cooperative Group
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
After inclusion all patients will receive dostarlimab at 500 mg q3w (± 2-3 days) for 4 cycles (C1-C4). An adaptive treatment strategy will be determined based on clinical assessment of the patient at weeks 12 (±1 week) and week 24 (±1 week).
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
Inclusion and
Exclusion criteria
are identical in both cohorts, except for inclusion criteria 3 and 4. Inclusion criteria The patient is eligible to be included in the study only if all the following criteria apply: 1. Is capable of giving signed and dated informed consent, 2. Has an ECOG PS of 0-1, 3. Age ≥18 years old: * A patient over 70 years of age is eligible to participate in the main initial cohort if the patient respects all the criteria and has a score G8 of ≥14. * A patient over 70 years with a score G8 \<14 should have a consultation with an onco-geriatrician to determine the best treatment or therapeutic strategy based on age and co-morbidity. After this consultation, the patient is eligible for main initial cohort if "fits for surgery" with no contraindications to repeated UGI endoscopy with biopsies (no change to the initial protocol) and can follow the study plan and procedures outlined in the study. * If a patient is over 70-year-old, has a G8 score \<14, and is unfit for surgery (as determined by onco-geriatric advice and multidisciplinary team \[MDT\] conclusion), the patient cannot be included in the phase II study (main initial cohort). This patient can be included in the unfit supplemental cohort, with the available Geriatric Core Dataset (G-CODE) test result being mandatory for inclusion (No switching between cohorts is allowed). 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), performed within 6 weeks before inclusion, according to the 7th Edition of the International Union Against Cancer; NB1: Echo-endoscopy will be performed only if the tumor is not obstructive at UGI endoscopy ± a new UGI endoscopy with 10 biopsies, photos (if not done at the first UGI endoscopy done for diagnosis). If obstructive, the tumor will be classified as cT3 or cT4 (in the situation when the tumor was obstructive and prevented EUS, it was classified T3N+, if it did not invade the adjacent organs on CT scan, because obstructing tumors represented locally advanced disease in the vast majority of cases in previous studies). In this case a new UGI endoscopy must be done with 10 biopsies, photos (if not done at the first GGI endoscopy done for diagnosis). NB2: Echo endoscopy is not mandatory/performed for patient included in additional unfit cohort. TNM stage will be determine by CT scanner. 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 as follows: \- MMR protein expression status will be evaluated by immunohistochemistry (IHC) with four antibodies (anti-hMLH1, anti-hMSH2, anti-hMSH6, anti-hPMS2) according to the local procedures. dMMR will be defined as loss of MLSH1 and PMS2, loss of MSH2 and MSH6, or loss of only one protein with presence of MSI-H. MSI analysis will be performed by polymerase chain reaction \[PCR\] using a pentaplex panel (BAT-25, BAT-26, NR-21, NR-24, and NR-27; PROMEGA). MSI-H is defined as instability in two or more of the five studied markers. For this study, samples with 2 unstable markers will also undergo MMR analysis by IHC. Agreement of Sponsor (GERCOR) on a dMMR/MSI status is mandatory to include the patient (the patient's file \[an anonymized mail\] must be sent to Sponsor). 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, 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 ≥30 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 6 weeks 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, and one of the following conditions applies: * Is a woman of non-childbearing potential as defined: i/ ≥ 45 years of age and has not had menses for \>1 year, ii/ Amenorrheic for \<2 years without a hysterectomy and oophorectomy and have a 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, magnetic resonance imaging (MRI), or CT scan. Tubal ligation must be confirmed with medical records of the actual procedure, otherwise the patient must fulfill the criteria in Inclusion criteria 15. Information must be captured appropriately within the site's source documents, * Has negative pregnancy blood test within 72 hours before the first dose of dostarlimab, AND * If woman of childbearing potential (WOCBP), female patient must be willing to use a highly effective form of contraception from screening throughout the study treatment and 4 months after the last dose of dostarlimab, 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: * Refrain from donating sperm, * Must use contraception/barrier as follows: * Agree to use a male condom when having sexual intercourse with a 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, 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), NB: The patient's agreement will be specifically requested for endoscopic images in the patient information note and informed consent 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, 16. Is willing and able to comply with scheduled visits, treatment schedule, laboratory tests, tumor biopsies, and other requirements of the study, 17. Is registered in the National Health Care System (PUMa - Protection Universelle Maladie included).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clinical complete response (cCR) | At 1 year from the start of treatment with dostarlimab. | Main initial cohort: 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). Additional unfit cohort: To evaluate cCR at 1 year defined as the rate of patients who at 1 year from the start of therapy with dostarlimab are alive, are free of disease progression (locoregional or metastases), have all negative biopsies, and show endoscopy downstaging stage 3 or 4 (endoscopic grade). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The number of patients who did not undergo surgery for tumor resection without distant metastases | up to 5 years | The number of patients who did not undergo surgery for tumor resection without distant metastases at 12 and 24 months, |
| The number of patients who did not undergo surgery for tumor resection with distant metastases | up to 5 years | The number of patients who did not undergo surgery for tumor resection with distant metastases at 12 and 24 months, |
| Progression-free survival (PFS) in additional cohort | up to 5 years | Progression-free survival is defined as time from first dose of treatment to first progression of disease local or distant recurrence, or death due to any cause. Alive patients without event will be censored at the last follow-up. |
| Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs) following dostarlimab treatment | up to 5 years; from the date of dostarlimab initiation to the date of death | Patients will be assessed for AEs and SAEs throughout the study using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. Measured in both cohorts. |
| Health-related quality of life (HRQoL) by the EORTC Core Quality of Life questionnaire (EORTC QLQ-C30) | up to 5 years | HRQoL assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30). The EORTC QLQ-C30 generates scores transformed to a 0 to 100 scale. For the Global Health Status/Quality of Life scale and functional scales, higher scores indicate better HRQoL and functioning. For symptom scales/items, higher scores indicate greater symptom burden and worse quality of life. Measured in both cohorts. |
| Health-related quality of life (HRQoL) by the EORTC oesophago-gastric (EORTC QLQ-OG25) questionnaire | up to 5 years | HRQoL assessed using the European Organisation for Research and Treatment of Cancer Oesophago-Gastric Cancer Questionnaire (EORTC QLQ-OG25). The EORTC QLQ-OG25 consists of symptom scales and single-item measures that are transformed to scores ranging from 0 to 100. Higher scores indicate greater symptom burden, more problems, and worse health-related quality of life. Measured in both cohorts. |
| Number of days spent in the hospital (DIH) | up to 5 years | Number of days spent in the hospital (DIH) measured in additional unfit cohort. |
| Morbidity in case of surgery | up to 5 years | Morbidity in case of surgery (complication or death occurring within 90 postoperative days according to the Clavien Dindo's classification) measured in main cohort only. |
| Disease-free survival (DFS) | up to 5 years | Disease-free survival is defined only for patient with surgery (partial or complete gastrectomy or oesogastrectomy) as the time between the date of surgery and the date either of recurrence or death from any cause. |
| Pathological complete response (pCR) | up to 5 years | Pathological complete response is defined as 100% fibrosis or fibro-inflammation or necrosis or granulomatous reaction within an entire gross lesion without microscopic evidence of carcinoma, and no positive lymph nodes, after examination of the complete macroscopic surgical specimen equivalent to a Becker TRG Grade 1a (complete regression). |
| Loco/loco-regional and distant recurrence | up to 5 years | Loco/loco-regional recurrence is defined as cancer recurrence within the regional resection area or local anastomotic site. Distant recurrence is defined as peritoneal recurrence, liver metastasis or metastasis at other extra-abdominal sites as well as nodal metastasis beyond the regional nodes |
| Event-free survival (EFS) | up to 5 years | Event-free survival is defined as time from first dose of treatment to surgery for tumoral resection, first progression of disease local or distant recurrence, or death due to any cause. Alive patients without event will be censored at the last follow-up. |
| Overall survival (OS) | up to 5 years | Overall survival is defined as the time between the date of the first dose of study treatment and the death date. Measured in both cohorts. |
| Time to treatment failure (TTF) | up to 5 years | Time to treatment failure is defined as the interval between initiating therapy (first dose of dostarlimab) and the earliest of clinical progression, depending on whether the patient had surgery for tumoral resection or not, or death. Measured in both cohorts. |
Countries
France, Italy
Contacts
CONTACTMarie-Line GARCIA LARNICOL, MD
PRINCIPAL_INVESTIGATORThierry Andre, MD
Saint-Antoine Hospital
Outcome results
None listed