Utility of Adjusting Chemotherapy Dose & Dosing Schedule With the SALVage Weekly Dose-dense Regimen in Patients With Poor Prognostic OVARian Cancers Based on the Tumor Unfavorable Primary Chemosensitivity and Incomplete Debulking Surgery

Официальное название

A Pragmatic Randomized Phase III Trial to Assess the Utility of Adjusting Chemotherapy Dose & Dosing Schedule With the SALVage Weekly Dose-dense Regimen in Patients With Poor Prognostic OVARian Cancers Based on the Tumor Unfavorable Primary Chemosensitivity and Incomplete Debulking Surgery

Обзор

SALVOVAR will be a pragmatic open-label multicenter randomized phase III trial (ratio 1:1) comparing the efficacy of the salvage weekly dose-dense regimen with those of the continuation of the standard regimen.

Подробное описание

SALVOVAR is a pragmatic open-label multicenter randomized phase III trial (ratio 1:1) comparing the efficacy of the salvage weekly dose-dense regimen with those of the continuation of the same standard regimen as given during neo-adjuvant period. The randomization will be stratified on the main clinical prognostic factors assumed to impact the efficacy of the assessed arms and the overall survival:

1. Bevacizumab: planned administration: Yes, vs No 2. BRCA mutation: planned administration: Yes, vs No/Unknown 3. KELIMTM strate within unfavorable KELIM subgroup: very unfavorable \< 0.7, vs moderately unfavorable \[0.7-1.0\[

The trial will be pragmatic, as it aims at confirming the superiority of the adjusted chemotherapy compared to the continuation of the standard chemotherapy in routine clinical practice, in a population of ovarian cancer patients close to the real-life clinical activity with few selection criteria.

Вмешательства

• Препарат Carboplatin
  Patients will be randomized 1:1: * Experimental arm: Densification of the chemotherapy administration dose and dosing schedule of carboplatin-paclitaxel (carboplatin AUC 5 every 3 weeks on day 1 and paclitaxel 80 mg/m2 every week, on day 1, day 8, and day 15, with 3 week-cycles) for 3 cycles * Standard arm: Continuation of the same 3-weekly carboplatin-paclitaxel, as administered during the neo-adjuvant chemotherapy
• Препарат Paclitaxel
  Patients will be randomized 1:1: * Experimental arm: Densification of the chemotherapy administration dose and dosing schedule of carboplatin-paclitaxel (carboplatin AUC 5 every 3 weeks on day 1 and paclitaxel 80 mg/m2 every week, on day 1, day 8, and day 15, with 3 week-cycles) for 3 cycles * Standard arm: Continuation of the same 3-weekly carboplatin-paclitaxel, as administered during the neo-adjuvant chemotherapy

Первичные конечные точки

• Percentage of patients operated with late complete debulking surgery [Срок оценки: From the date of randomization until patients operated with late complete debulking surgery, assessed up 100 days]
• Overall survival (OS) [Срок оценки: From the date of randomization until death due to any cause, assessed up to 5 years]

Вторичные конечные точки (9)

• Percentage of patients operated with late complete debulking surgery, regardless of the number of chemotherapy cycles received [Срок оценки: from the date of randomization until objective tumor progression based on RECIST 1.1, or death due to any cause, whichever occurs first assessed up to 3 years]
• Overall response rate according to RECIST V1.1 in the whole population [Срок оценки: from the date of randomization until objective tumor progression based on RECIST 1.1, or death due to any cause, whichever occurs first assessed up to 3 years]
• Progression-free survival in the whole population [Срок оценки: from the date of randomization until objective tumor progression based on RECIST 1.1, or death due to any cause, whichever occurs first assessed up to 3 years]
• Percentage of patients treated with a subsequent maintenance treatment with a PARP inhibitor (%) in the whole population [Срок оценки: from the date of randomization until objective tumor progression based on RECIST 1.1, or death due to any cause, whichever occurs first assessed up to 3 years]
• Progression-free survival and overall survival in these patients compared to those not treated with PARP inhibitor [Срок оценки: from the date of randomization until objective tumor progression based on RECIST 1.1, or death due to any cause, whichever occurs first assessed up to 3 years]
• To assess the impact of adding bevacizumab to chemotherapy (salvage or standard arm) on the efficacy outcomes In the population of patients treated with bevacizumab: - Overall response rate according to RECIST V1.1 [Срок оценки: from the date of randomization until objective tumor progression based on RECIST 1.1, or death due to any cause, whichever occurs first assessed up to 3 years]
• Adverse events graded according to the NCI Common Terminology Criteria Adverse Event Version 5.0 [Срок оценки: from the date of randomization until objective tumor progression based on RECIST 1.1, or death due to any cause, whichever occurs first assessed up to 3 years]
• To assess the impact of adding bevacizumab to chemotherapy on the efficacy outcomes In the population of patients treated with bevacizumab: - Progression-free survival & overall survival according to RECIST V1.1 [Срок оценки: from the date of randomization until objective tumor progression based on RECIST 1.1, or death due to any cause, whichever occurs first assessed up to 3 years]
• To assess the impact of adding bevacizumab to chemotherapy on the efficacy outcomes In the population of patients treated with bevacizumab: - Percentage of patients operated with a late complete debulking surgery (%) [Срок оценки: from the date of randomization until objective tumor progression based on RECIST 1.1, or death due to any cause, whichever occurs first assessed up to 3 years]

Критерии участия

Критерии включения

• Histologically confirmed high-grade epithelial (serous, endometrioid, or carcinosarcoma with a ≥30% epithelial tumor component) ovarian, primary peritoneal, or fallopian-tube carcinoma
• Adult patient aged ≥ 18 years old
• Advanced stage III or IV disease
• Treated with 3 to 4 neo-adjuvant cycles of standard 3-weekly carboplatin-paclitaxel regimen in first-line setting, and characterized by:

• Unfavorable standardized KELIMTM score < 1.0 calculated with the KELIMTM academic tool and available for free on internet site (https://www.biomarker-kinetics.org/CA-125-neo) (poor primary chemosensitivity)
• Not amenable to complete interval debulking surgery (incomplete interval debulking surgery attempt, or disease not operated at all because considered not amenable to complete surgery by surgeon) Of note, a pre-screening inclusion before the start of neo-adjuvant chemotherapy is encouraged as a way of prospectively assessing the CA-125 longitudinal kinetics and surgery evaluation, and subsequently selecting the patients for the randomization sequence
• ECOG performance status 0 or 1 (see appendix 2)
• Adequate organ and bone marrow function for weekly-dense chemotherapy: red blood cells (baseline Hemoglobin ≥8 g/dL without red blood cell transfusion within 3 weeks before the blood work), white blood cells (Absolute neutrophil count (ANC) ≥1500 cells/mm3) and platelets (Platelet count ≥100,000/mm3),
• Adequate renal and liver functions

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 × upper limit of normal (ULN), or ≤5 × ULN in context of liver metastases
• Total bilirubin ≤1.5 × ULN (patients with Gilbert's are eligible if total bilirubin ≤3 × ULN)
• Albumin ≥3 g/dL
• Creatinine clearance ≥40 mL/min/1.73 m2 (measured or estimated, ideally with CKD-EPI formula on https://www.kidney.org/professionals/kdoqi/gfr\_calculator)
• Patients who gave its written informed consent to participate to the study
• Patients affiliated to a social insurance regime
• Patients willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up

Non-inclusion Criteria:

• Low-grade endometrioid, clear cell, mucinous, or sarcomatous histology, or mixed tumors containing any of these histologies, or low-grade or borderline ovarian tumor. Contraindication to the drugs assessed in the SALVOVAR trial (carboplatin, paclitaxel, GCSF)
• Previous treatment with bevacizumab during initial standard neo-adjuvant chemotherapy
• Has primary platinum-refractory disease, defined as disease that has progressed during the neo-adjuvant chemotherapy
• Patients with concomitant cancer, except: adequately treated non-melanoma skin cancer, curatively treated in-situ cancer of the cervix, or other solid tumors curatively treated with no evidence of disease for ≥ 5 years
• Treatment with other investigational agents in clinical trials during the randomized chemotherapy phase for both arms.
• Clinically significant uncontrolled condition(s) which, in the opinion of the Investigator, may confound the results of the trial or interfere with the patient's safety or participation, including but not limited to:

• Unstable angina.
• Myocardial infarction within 6 months of first dose.
• Uncontrolled and/or severe concomitant diseases (uncontrolled hypertension, ≥ Grade 3 (per CTCAE v5.0) arrhythmia, heart failure, cirrhosis).
• Active infectious disease requiring IV therapy (bacteria, viruses) within 2 weeks of first dose.
• Gastric-outlet obstruction.
• Small bowel obstruction (SBO) defined as computed tomography (CT) scan showing: Dilated loops of small bowel ≤12 weeks of study entry, symptomatic ascites/effusions requiring paracentesis or thoracentesis ≤30 days of study entry.
• Known psychiatric disorder that would interfere with trial compliance.
• Pregnant or lactating patients or patients expecting to conceive children within the projected duration of the trial.
• Patient deprived of liberty, under guardianship, or under curatorship.

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 · 50 центров

• ICO Paul Papin — Angers
• CH d'Avignon — Avignon
• Sainte-Catherine Institut du Cancer Avignon-Provence — Avignon
• Hôpital de la Côte Basque — Bayonne
• CHRU Besançon - Hôpital Jean Minjoz — Besançon
• Institut Bergonié — Bordeaux
• CHU de BREST - Hôpital Cavale Blanche — Brest
• Centre François Baclesse — Caen
• … и ещё 42 центра

Япония · 16 центров

• The University of Tokyo Hospital — Bunkyō City
• Fukushima Medical University Hospital — Fukushima
• Saitama Medical University International Medical Center — Hidaka
• Hirosaki University Hospital — Hirosaki
• The Jikei University Kashiwa Hospital — Kashiwa
• St. Marianna University Hospital — Kawasaki
• Dokkyo Medical University Saitama Medical Center — Koshigaya
• Kurume University Hospital — Kurume
• … и ещё 8 центров

Италия · 6 центров

• Azienda Ospedaliero-Universitaria Ss.Antonio E Biagio E C.Arrigo Alessandria — Alessandria
• Azienda Ospedaliero-Universitaria Di Bologna IRCCS Istituto Di Ricerca E Di Cura A Caratte — Bologna
• Careggi University Hospital — Florence
• Alessandro Manzoni Hospital — Lecco
• Istituto Europeo Di Oncologia S.r.l. — Milan
• Azienda Ulss 3 Serenissima — Venice

Нидерланды · 4 центра

• Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis Stichting — Amsterdam
• Leids Universitair Medisch Centrum (LUMC) — Leiden
• Radboud University Medical Center — Nijmegen
• Erasmus Universitair Medisch Centrum Rotterdam (Erasmus MC) — Rotterdam

Публикации

• Chator C, Yanaihara N, Chabaud S, Parma GM, Dima AL, Clamp A, Ferron G, Kroep JR, Leary A, Cibula D, Fiteni F, Bruchim I, Serrier H, Carroll S, Belmont AS, Peron J, You B. SALVOVAR: a pragmatic randomized phase III trial comparing the SALVage weekly dose-dense regimen to the standard 3-weekly regimen in patients with poor prognostic OVARian cancers. Ther Adv Med Oncol. 2025 Dec 23;17:1758835925139 PMID 41466844

Идентификаторы

NCT: NCT06476184 · 2023-508260-30-01 · RECF-005636

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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