Clinical trial NCT06476184: 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
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Ovarian Cancer
Keywords: chemotherapy
poor prognostic
unfavorable primary chemosensitivity
incomplete debulking surgery
KELIM
Lead sponsor: ARCAGY/ GINECO GROUP
Sponsor class: OTHER
Collaborators: name: Horizon 2020 - European Commission
First posted: 2024-06-26
Enrollment: 250
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 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

  +/- combined with daily sub-cutaneous administrations of GCSF (Granulocyte Colony-Stimulating Factor) 30 MUI days 3 to 5, \& 10 to 12, \& 17 to 19 (at investigator discretion, as per standard of care)
* Standard arm: 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.

Of note, bevacizumab addition in both arms is required in countries where it is available as per standard of care, according to country health coverage policy.
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

1. Histologically confirmed high-grade epithelial (serous, endometrioid, or carcinosarcoma with a ≥30% epithelial tumor component) ovarian, primary peritoneal, or fallopian-tube carcinoma
2. Adult patient aged ≥ 18 years old
3. Advanced stage III or IV disease
4. 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
5. ECOG performance status 0 or 1 (see appendix 2)
6. 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),
7. 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)
8. Patients who gave its written informed consent to participate to the study
9. Patients affiliated to a social insurance regime
10. 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

Exclusion Criteria:

1. 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)
2. Previous treatment with bevacizumab during initial standard neo-adjuvant chemotherapy
3. Has primary platinum-refractory disease, defined as disease that has progressed during the neo-adjuvant chemotherapy
4. 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
5. Treatment with other investigational agents in clinical trials.
6. 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.
7. Known psychiatric disorder that would interfere with trial compliance.
8. Pregnant or lactating patients or patients expecting to conceive children within the projected duration of the trial.
9. Patient deprived of liberty, under guardianship, or under curatorship.

Primary outcomes:
measure: Percentage of patients operated with late complete debulking surgery
timeFrame: From the date of randomization until patients operated with late complete debulking surgery, assessed up 100 days
measure: Overall survival (OS)
timeFrame: From the date of randomization until death due to any cause, assessed up to 5 years
Secondary outcomes:
measure: Percentage of patients operated with late complete debulking surgery, regardless of the number of chemotherapy cycles received
timeFrame: 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
measure: Overall response rate according to RECIST V1.1 in the whole population
timeFrame: 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
measure: Progression-free survival in the whole population
timeFrame: 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
measure: Percentage of patients treated with a subsequent maintenance treatment with a PARP inhibitor (%) in the whole population
timeFrame: 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
measure: Progression-free survival and overall survival in these patients compared to those not treated with PARP inhibitor
timeFrame: 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
measure: 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
timeFrame: 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
measure: Adverse events graded according to the NCI Common Terminology Criteria Adverse Event Version 5.0
timeFrame: 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
measure: 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
timeFrame: 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
measure: 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 (%)
timeFrame: 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
Other outcomes:
measure: Quality of life questionnaires
timeFrame: from date of randomization through study completion, an average of 3 years
measure: Perceptions of the patient-doctor relationship in patients offered bevacizumab/debulking surgery/PARPi
timeFrame: From 4-8 weeks after a decision on bevacizumab (approx. at randomization date) through end of follow-up (2-3 years after inclusion, depending on debulking surgery)
measure: Satisfaction with decision-making process in patients offered bevacizumab/debulking surgery/PARPi
timeFrame: From 4-8 weeks after a decision on bevacizumab (approx. at randomization date) through end of follow-up (2-3 years after inclusion, depending on debulking surgery)
measure: Satisfaction with decision-making process in patients offered bevacizumab/debulking surgery/PARPi
timeFrame: From 4-8 weeks after a decision on bevacizumab (approx. at randomization date) through end of follow-up (2-3 years after inclusion, depending on debulking surgery)
measure: Emotional wellbeing following the decision-making process in patients offered bevacizumab/debulking surgery/PARPi
timeFrame: From 4-8 weeks after a decision on bevacizumab (approx. at randomization date) through end of follow-up (2-3 years after inclusion, depending on debulking surgery)
measure: Treatment beliefs in patients offered bevacizumab/PARPi
timeFrame: From 4-8 weeks after a decision on bevacizumab (approx. at randomization date) through end of follow-up (2-3 years after inclusion, depending on debulking surgery)
measure: Self-reported adherence to PARPi in patients offered PARPi
timeFrame: From 4-8 weeks after a decision on PARPi (approx. at end of chemotherapy) through end of follow-up (2-3 years after inclusion, depending on debulking surgery)
measure: Percentage of patients with BRCA (BReast CAncer) mutation (%)
timeFrame: from date of randomization through study completion, an average of 5 years
measure: Percentage of patients with BRCA wild-type HRD (Homologous Recombination Deficiency) disease (%)
timeFrame: from date of randomization until end of study, for a period of 5 years
measure: Percentage of patients with BRCA wild-type HRP (Homologous Recombination Proficient) disease (%)
timeFrame: from date of randomization through study completion, an average of 3 years
measure: Tests/assays used (names, proprietary)
timeFrame: from date of randomization until end of study, through study completion, an average of 3 years
measure: Percentage of tests/assays used (names, proprietary) (%)
timeFrame: from date of randomization until end of study, through study completion, an average of 3 years
measure: Incremental cost-utility ratio
timeFrame: from date of randomization until end of study, for a periof of 5 years
measure: Incremental cost-effectiveness ratio
timeFrame: from date of randomization until end of study, for a period of 5 years
measure: Estimate the net financial impact over 5 years
timeFrame: from date of randomization until end of study, for a period of 5 years
Locations:
city: Angers
country: France
facility: ICO Paul Papin
city: Avignon
country: France
facility: CH d'Avignon
city: Avignon
country: France
facility: Sainte-Catherine Institut du Cancer Avignon-Provence
city: Bayonne
country: France
facility: Hôpital de la Côte Basque
city: Besançon
country: France
facility: CHRU Besançon - Hôpital Jean Minjoz
city: Bordeaux
country: France
facility: Institut Bergonié
city: Brest
country: France
facility: CHU de BREST - Hôpital Cavale Blanche
city: Caen
country: France
facility: Centre François Baclesse
city: Chambray-lès-Tours
country: France
facility: Centre d'Oncologie et de Radiothérapie 37 (ROC37)
city: Cholet
country: France
facility: Centre Hospitalier de Cholet
city: Clermont-ferrand
country: France
facility: Centre Jean Perrin
city: Contamine-sur-arve
country: France
facility: Centre Hospitalier Alpes Leman
city: Créteil
country: France
facility: Centre Hospitalier Intercommunal de Créteil
city: Dijon
country: France
facility: Centre Georges François Leclerc
city: Dijon
country: France
facility: CHU de Dijon
city: Grenoble
country: France
facility: Groupe Hospitalier Mutualiste de Grenoble
city: Le Chesnay
country: France
facility: Hôpital André Mignot
city: Lille
country: France
facility: CHRU de Lille
city: Lille
country: France
facility: Centre Oscar Lambret
city: Limoges
country: France
facility: CHU de Limoges - Hôpital Dupuytren
city: Lyon
country: France
facility: Centre Léon Bérard
city: Lyon
country: France
facility: Hôpital Privé Jean Mermoz
city: Montpellier
country: France
facility: CHRU de Montpellier - Hôpital Saint-Eloi
city: Montpellier
country: France
facility: ICM Val d'Aurelle
city: Mougins
country: France
facility: Centre Azuréen de Cancérologie
city: Nantes
country: France
facility: Hôpital Privé du Confluent
city: Nice
country: France
facility: Centre Antoine Lacassagne
city: Nîmes
country: France
facility: Institut de Cancérologie du Gard - CHU de Nîmes
city: Paris
country: France
facility: Groupe Hospitalier Diaconesses - Croix Saint-Simon
city: Paris
country: France
facility: Hôpital Cochin
city: Paris
country: France
facility: Institut Curie
city: Pau
country: France
facility: Centre Hospitalier Général de Pau
city: Pierre-Bénite
country: France
facility: HCL - Centre Hospitalier Lyon Sud
city: Plérin
country: France
facility: Centre CARIO - HPCA
city: Poissy
country: France
facility: Hôpital de Poissy-Saint-Germain-en-Laye
city: Rennes
country: France
facility: Centre Eugène Marquis
city: Saint-etienne
country: France
facility: Hôpital Privé de la Loire
city: Saint-Herblain
country: France
facility: Institut de Cancérologie de l'Ouest - ICO
city: Saint-priest-en-jarez
country: France
facility: CHU Saint-Etienne - Pôle de Cancérologie
city: Strasbourg
country: France
facility: ICANS - Institut de cancérologie Strasbourg Europe
city: Suresnes
country: France
facility: Hôpital Foch
city: Thonon-les-bains
country: France
facility: Hôpitaux du Léman - site Thonon-les-Bains
city: Toulouse
country: France
facility: Oncopole Claudius Régaud - IUCT Oncopole
city: Toulouse
country: France
facility: Clinique Pasteur
city: Valence
country: France
facility: Centre Hospitalier de Valence
city: Villejuif
country: France
facility: Gustave Roussy
city: Alexandrie
country: Italy
facility: Azienda Ospedaliero-Universitaria Ss.Antonio E Biagio E C.Arrigo Alessandria
city: Bologna
country: Italy
facility: Azienda Ospedaliero-Universitaria Di Bologna IRCCS Istituto Di Ricerca E Di Cura A Carattere Scientifico
city: Florence
country: Italy
facility: Careggi University Hospital
city: Lecco
country: Italy
facility: Alessandro Manzoni Hospital
city: Milan
country: Italy
facility: Istituto Europeo Di Oncologia S.r.l.
city: Venice
country: Italy
facility: Azienda Ulss 3 Serenissima
city: Bunkyo
country: Japan
facility: The University of Tokyo Hospital
city: Fukushima
country: Japan
facility: Fukushima Medical University Hospital
city: Hidaka
country: Japan
facility: Saitama Medical University International Medical Center
city: Hirosaki
country: Japan
facility: Hirosaki University Hospital
city: Kashiwa
country: Japan
facility: The Jikei University Kashiwa Hospital
city: Kawasaki
country: Japan
facility: St. Marianna University Hospital
city: Koshigaya
country: Japan
facility: Dokkyo Medical University Saitama Medical Center
city: Kurume
country: Japan
facility: Kurume University Hospital
city: Nagoya
country: Japan
facility: Nagoya University Hospital
city: Osakasayama
country: Japan
facility: Kindai University Hospital
city: Sendai
country: Japan
facility: Tohoku University Hospital
city: Takatsuki
country: Japan
facility: Osaka Medical and Pharmaceutical University Hospital
city: Tokyo
country: Japan
facility: The Cancer Institute Hospital Of JFCR
city: Tokyo
country: Japan
facility: The Jikei University Daisan Hospital
city: Tokyo
country: Japan
facility: The Jikei University Hospital
city: Tokyo
country: Japan
facility: The Jikei University Katsushika Medical Center
Study officials:
affiliation: HCL - Centre Hospitalier Lyon Sud
name: Benoit YOU
role: PRINCIPAL_INVESTIGATOR
References: