Evaluation of Efficacy and Safety De-escalation Versus Standard Adjuvant Chemotherapy in Patients With Low Risk Localized Gastroesophageal Adenocarcinoma

Официальное название

ATTENUATION - A Multicenter Randomized Phase II Study of the Efficacy and Safety De-escalation Versus Standard Adjuvant Chemotherapy in Patients With Low Risk Localized Gastroesophageal Adenocarcinoma (PRODIGE99/FRENCH 39 Study)

Обзор

The ATTENUATION study targets patients with gastric adenocarcinoma (GA), esophageal adenocarcinoma (EAC) or gastro-esophageal junction (GEJ) who have received 4 cycles of FLOT chemotherapy before the surgery. Standard post-operative management consists of chemotherapy with 4 cycles of FLOT. However, the nature and duration of postoperative treatment are standardized and are not adapted to the specific tumor response of each patient. All patients are therefore referred to the same treatment regimen. As a result, good responders (defined in particular by wide resection of the tumor and a good response to preoperative chemotherapy on the tumor removed during surgery) may be over-treated and exposed to unnecessary adverse events. Only 50-60% of patients can start chemotherapy post-operatively, due to the potential residual adverse effects associated with surgery in particular. Thus, it would appear that preoperative chemotherapy is the most important factor in the overall efficacy of the treatment sequence. Moreover, numerous retrospective studies have reported a favorable outcome in patients with a major response to pre-operative treatment but who were unable to receive post-operative chemotherapy. The hypothesis of this study is that surveillance after surgery in patients with gastric or gastroesophageal junction tumors, with a good response to preoperative chemotherapy could provide significant clinical benefit and favorable disease progression. Participants will: * be distributed in one of the two arms * will be followed up every 3 months for 2 years, then every 6 months (clinical examination, imaging, quality-of-life questionnaire) subsequent years until 3 years after the randomization of the last patient. * followed up until their death or their progression whether local, regional or metastatic.

Вмешательства

• Другое observation alone
  Patient will not received post-operative chemotherapy. There will be only surveillance until progression.

Первичные конечные точки

• 3 year Overall Survival rate [Срок оценки: From the date of randomisation to 3 years post-randomisation follow-up visit.]
• 3 year disease-free survival rate [Срок оценки: Time from the date of randomisation to 3 year post-randomisation follow-up visit]

Вторичные конечные точки (12)

• Overall survival [Срок оценки: Time from the date of randomisation to the date of death due to any cause or to the date of last contact if patient is still alive (censored patients), assessed up to 60 months.]
• Disease-Free Survival (DFS) [Срок оценки: From the date of randomization to the date of the first documented relapse of the disease or death due to any cause, whichever occurs first, assessed up to 60 months.]
• Type of Relapses [Срок оценки: From the date of randomization to the date of the first documented relapse of the disease, assessed up to 60 months.]
• The tolerability profile [Срок оценки: From date of randomization to 3 years follow-up visit or death due to any cause, whichever came first, assessed up to 60 months]
• The health-related quality of life by QLQ-C30 [Срок оценки: At Baseline and every year after randomisation during 3 years.]
• The nutritional status by food intake changes [Срок оценки: At baseline, every 3 months visits during the first 2 years then every 6 months until 3 years post-randomisation.]
• ctDNA positivity [Срок оценки: At baseline, every 3 months visits during the first 2 years then every 6 months until 3 years post-randomisation.]
• The feasibility of using a standardized pathological report [Срок оценки: At baseline visit only]
• The health-related quality of life by QLQ-OG25 [Срок оценки: At Baseline and every year after randomisation during 3 years.]
• The nutritional status by sarcopenia [Срок оценки: At baseline, every 3 months visits during the first 2 years then every 6 months until 3 years post-randomisation.]
• The physical performance [Срок оценки: At baseline, every 3 months visits during the first 2 years then every 6 months until 3 years post-randomisation.]
• The nutritional status by systemic inflammation (CRP) [Срок оценки: At baseline, every 3 months visits during the first 2 years then every 6 months until 3 years post-randomisation.]

Критерии участия

Критерии включения

• I1. Age ≥ 18 years, I2. Histologically proven non-metastatic (M0) gastric, oesophageal or gastroesophageal junction adenocarcinoma, I3. Subjects must have completed both pre-operative chemotherapy with a fluoropyrimidine-platinum containing regimen (FLOT 4 cycles) and microscopically complete (R0) resection prior to randomization.

Note for surgery: total or distal gastrectomy with D2 lymphadenectomy according to ESMO guidelines should have been completed for gastric and junctional Siewert type III cancers. Ivor Lewis oesophagectomy with two field lymphadenectomy should have been performed for junctional Siewert type I cancers and lower oesophageal adenocarcinomas. For Siewert type II cancers either total gastrectomy with D2-lymphadenectomy or oesophagectomy with two field lymphadenectomy should have been completed. Open, minimal invasive or hybrid surgical approaches are acceptable as long as the requirements above are fulfilled. In frail patients with Siewert I or II, transhiatal oesophagectomy with lymphadenectomy in the lower mediastinum without transthoracic access is acceptable. Regardless of the type of surgery a minimum of 16 (gastric cancer) or 7 lymph nodes (in case of oesophageal carcinoma) should have been resected and examined (ref TNM 8 eme edition)

I4. Low risk of disease recurrence, defined by the following criteria:

• Absence of lymph node involvement (ypN0), assessed on a min. of 16 or 7 lymph nodes according to the localization and,
• Either ypT0-2 (all TRG grade) or ypT3 (with TRG 1a-b according to Becker classification or TRG1-2 according to Mandard's classification), I5. ECOG Performance Status 0-1, I6. Patients fit to receive post-operative chemotherapy, I7. Interval between the date of surgery and the date of randomization no longer than 10 weeks, I8. Adequate organs function defined as : Absolute neutrophil count (ANC) ≥ 1.5 x 109/L; Platelets ≥ 100 x 109/L; Haemoglobin ≥ 9 g/dL (without transfusion within 7 days); Serum creatinine AND Calculated creatinine clearance as per MDRD or CKD-EPI formula ≤ 1.5 upper limit of normal (ULN) AND ≥ 40 mL/min /1.73m²; Serum total bilirubin ≤ 1.5 ULN OR Direct bilirubin ≤ ULN for patients with total bilirubin levels > 1.5 ULN (except for patients with Gilbert disease for whom a total serum bilirubin ≤ 3ULN is acceptable); AST and ALT ≤ 3 ULN; International Normalized Ratio (INR) and activated Partial Thromboplastin Time (aPTT)≤ 1.5 ULN .

I9. No contraindication to study assessments, I10. Signed and dated informed consent for prior to any study-specific procedure, I11. Women of childbearing potential accepting to use highly effective contraceptive measures or abstain from heterosexual activity, for the course of the study and at least an- 9 months after the end of the treatment with oxaliplatin - 6 months after the end of the treatment with fluorouracil - 2 months after the end of the treatment with docetaxel and men must use contraception during treatment and at least - 6 months after the end of the treatment with oxaliplatin, - 3 months after the end of the treatment with fluorouracil - 4 months after the end of the treatment with docetaxel.

I12. Patient must be covered by a medical insurance or equivalent.

Критерии исключения

• E1. Oesophageal squamous cell carcinomas, E2. Tumour with Deficient MisMatch Repair (MMR) and/or Microsatellite Instability status, E3. Dihydro Pyrimidine Dehydrogenase (DPD) deficiency, NB: if not previously done, the following blood chemistry level must be perform at screening, : blood uracil level - uracilemia dosing result is mandatory prior the inclusion E4. Persistent toxicities related to prior treatment of grade>1, E5. QTcF longer than 450 msec for men and longer than 470 msec for women, E6. Hypokalemia OR Hypomagnesemia OR Hypocalcemia Grade>1

E7. Contraindication to postoperative treatment (FLOT):

• Known history of hypersensitivity to fluorouracil, oxaliplatin, docetaxel or calcium folinate to any of their excipients, according to the SmPCs of these products OR
• Peripheral sensory neuropathy with functional impairment prior to first treatment according the SmPC of oxaliplatin OR
• Clinically significant active heart disease or myocardial infarction within 6 months OR
• Recent or concomitant treatment with brivudine or recent treatment with live vaccines (minimal wash out period before randomisation: 4 weeks) E8. Any concurrent chemotherapy, Investigational product for cancer treatment. E9. Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study E10. Suspicion of serious infection, E11. Pregnant or breastfeeding woman, E12. Patient under tutorship or curatorship of deprived of liberty.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Франция · 3 центра

• Centre Léon Bérard — Lyon
• Institut Paoli-Calmettes — Marseille
• AP-HP - Hôpital Saint-Antoine — Paris

Идентификаторы

NCT: NCT06933966 · ET23-350 · 2023-509227-41-00

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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