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
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 发起方
- 入组人数
- 250
- 试验地点
- 140
- 主要终点
- Percentage of patients operated with late complete debulking surgery
研究概览
简要总结
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.
详细描述
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:
- Bevacizumab: planned administration: Yes, vs No
- BRCA mutation: planned administration: Yes, vs No/Unknown
- 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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- 未提供
研究组 & 干预措施
Standard
Continuation of the same 3-weekly carboplatin-paclitaxel, as administered during the neo-adjuvant chemotherapy
+/- combined with peg-GCSF or GCSF daily sub-cutaneous administrations, at investigator discretion, as per standard of care.
干预措施: Paclitaxel (Drug)
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
+/- combined with daily sub-cutaneous administrations of GCSF 30 MUI days 3 to 5, & 10 to 12, & 17 to 19 (at investigator discretion, as per standard of care).
干预措施: Carboplatin (Drug)
Standard
Continuation of the same 3-weekly carboplatin-paclitaxel, as administered during the neo-adjuvant chemotherapy
+/- combined with peg-GCSF or GCSF daily sub-cutaneous administrations, at investigator discretion, as per standard of care.
干预措施: Carboplatin (Drug)
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
+/- combined with daily sub-cutaneous administrations of GCSF 30 MUI days 3 to 5, & 10 to 12, & 17 to 19 (at investigator discretion, as per standard of care).
干预措施: Paclitaxel (Drug)
结局指标
主要结局
Percentage of patients operated with late complete debulking surgery
时间窗: From the date of randomization until patients operated with late complete debulking surgery, assessed up 100 days
To demonstrate the superiority in terms of efficacy of a densification of the chemotherapy with the salvage weekly dose-dense carboplatin-paclitaxel regimen compared to the continuation of the standard 3-weekly carboplatin-paclitaxel, in ovarian cancer patients found to have a poor prognostic disease (characterized by a poor chemosensitivity, with an unfavorable KELIMTM score \< 1.0, and a disease not amenable to complete interval debulking surgery) after 3 cycles of standard neo-adjuvant chemotherapy.
Overall survival (OS)
时间窗: From the date of randomization until death due to any cause, assessed up to 5 years
To demonstrate the superiority in terms of efficacy of a densification of the chemotherapy with the salvage weekly dose-dense carboplatin-paclitaxel regimen compared to the continuation of the standard 3-weekly carboplatin-paclitaxel, in ovarian cancer patients found to have a poor prognostic disease (characterized by a poor chemosensitivity, with an unfavorable KELIMTM score \< 1.0, and a disease not amenable to complete interval debulking surgery) after 3 cycles of standard neo-adjuvant chemotherapy.
次要结局
- Percentage of patients operated with late complete debulking surgery, regardless of the number of chemotherapy cycles received(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(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(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(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(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(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(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(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 (%)(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)