SALVOVAR trial: 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.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Arcagy Gineco

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

30 Jul 2024 → ongoing

Decision date (initial)

2024-05-07

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Horizon (Europe)

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Efficacy, Dose response

To demonstrate the superiority in terms of efficacy of a densification of the chemotherapy with the salvage weekly dose-dense carboplatin-paclitaxel regimen (experimental arm) compared to the continuation of the standard 3-weekly carboplatin-paclitaxel (control arm), 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.
The efficacy is defined with 2 co-primary endpoints:
• Percentage of patients operated with late complete debulking surgery after receiving 3 cycles of randomized chemotherapy
• Overall survival.

Secondary objectives 9

1. - To compare the efficacy of the salvage weekly dose-dense regimen (experimental arm) with those of the continuation of the standard regimen (control arm) in terms of other endpoints: • Radiological response, based on the best radiological response using RECIST criteria • Progression-free survival • Percentage of patients operated with late complete debulking surgery regardless of the number of chemotherapy cycles received
2. - To assess the impact of the adjustment to the salvage weekly dose-dense regimen on the rate of subsequent prescription of PARP inhibitors (since these drugs are indicated in patients with complete or partial response to platinum-based chemotherapy) in terms of survival.
3. - To assess the impact of adding bevacizumab to chemotherapy (experimental or control arm) on the efficacy outcomes
4. - To compare the safety profiles of the salvage weekly dose-dense chemotherapy arm (experimental arm) with those of the standard regimen (control arm) with/without bevacizumab, based on the observed adverse-events
5. - To compare the quality of life and patient-reported outcomes of the salvage chemotherapy arm (experimental arm) with those of the standard regimen (control arm)
6. - To assess, the determinants of the shared treatment decision-making process, based on physician and patient perception, regarding the prescription of bevacizumab as a chemosensitizer, the potential utility of late debulking surgery in the case of favorable response to chemotherapy, and the prescription of PARP inhibitor and/or bevacizumab as a maintenance treatment in the context of therapeutic uncertainty
7. - To assess the predictive value of tumor biomarkers involved in homologous recombination (BRCA mutation; homologous recombination deficiency based on genomic instability score), and of the heterogeneity in the assays used in real-life setting, on the efficacy outcomes (overall response rate, progression-free survival, overall survival).
8. - To assess the cost-utility and cost-effectiveness evaluations of the experimental treatment (medico-economic evaluation) in the French context: - Salvage weekly dose-dense regimen vs the standard 3-weekly regimen, as per randomization - Addition of bevacizumab to chemotherapy, as per investigator decision - Late debulking surgery after chemotherapy in the case of favorable response to chemotherapy, as per investigator decision - Maintenance treatment with bevacizumab with/without PARP inhibitor, or surveillance, as per investigator decision.
9. - To evaluate the financial sustainability of the experimental treatment for the payer (budget impact analysis) in the French context.

Conditions and MedDRA coding

Patients with poor prognostic OVARian cancers based on the tumor primary chemosensitivity and incomplete debulking surgery.

Regulatory references

Plan to share IPD

Yes

IPD plan description

In alignment with the consortium’s commitment to transparency and scientific rigor, SalvOvar will adhere strictly to the FAIR (Findable, Accessible, Interoperable, Reusable) data principles in our data-sharing practices. By following the recommendations outlined by PhRMA and EFPIA, we will ensure that participant-level data, study-level data, protocols, clinical study reports, results reports, and the publication of results will be shared in a manner that promotes scientific discovery while safeguarding participant privacy and data integrity. Through these efforts, the consortium will foster a culture of open science and collaboration, enhancing the value and reach of our research for the benefit of the wider community.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. 1. Histologically confirmed high-grade epithelial (serous, endometrioid, or carcinosarcoma with a ≥30% epithelial tumor component) ovarian, primary peritoneal, or fallopian-tube carcinoma
2. 2. Adult patient aged ≥ 18 years old
3. 3. Advanced stage III or IV disease
4. 4. Treated with 3 to 4 neo-adjuvant cycles of standard 3-weekly carboplatin-paclitaxel regimen in first-line setting, and characterized by: o Unfavorable standardized KELIMTM score < 1.0 calculated with the KELIM academic tool and available for free on internet site (https://www.biomarker-kinetics.org/CA-125-neo) (poor primary chemosensitivity) o 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) GINECO-OV130b/ENGOT-ov78– SALVOVAR – Protocol - Version 1.0 – 14/DEC/2023 (From FORM 113-04: Protocol – Application date: 30/SEP/2022) Page 8 on 108 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. 5. ECOG performance status 0 or 1 (see appendix 2)
6. 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. 7. Adequate renal and liver functions o Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 × upper limit of normal (ULN), or ≤5 × ULN in context of liver metastases o Total bilirubin ≤1.5 × ULN (patients with Gilbert’s are eligible if total bilirubin ≤3 × ULN) o Albumin ≥3 g/dL o 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. 8. Patients who gave its written informed consent to participate to the study
9. 9. Patients affiliated to a social insurance regime
10. 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 8

1. 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. 2. Previous treatment with bevacizumab during initial standard neo-adjuvant chemotherapy
3. 3. Has primary platinum-refractory disease, defined as disease that has progressed during the neo-adjuvant chemotherapy
4. 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. 5. Treatment with other investigational agents in clinical trials.
6. 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. GINECO-OV130b/ENGOT-ov78– SALVOVAR – Protocol - Version 1.0 – 14/DEC/2023 (From FORM 113-04: Protocol – Application date: 30/SEP/2022) Page 9 on 108 • 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. 7. Known psychiatric disorder that would interfere with trial compliance.
8. 8. Pregnant or lactating patients or patients expecting to conceive children within the projected duration of the trial.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. - Percentage of patients operated with late complete debulking surgery after receiving 3 additional cycles of randomized chemotherapy (expected increase from 5% in the control arm to 20%)% in the experimental arm)
2. - Overall survival improvement by 49% (HR = 0.61) in the whole population translating in an improvement in median OS from 20 months (control arm) to 32.8 months (experimental arm) with a 1:1 randomization

Secondary endpoints 16

1. - Overall response rate according to RECIST V1.1 in the whole population (see appendix 4)
2. - Progression-free survival in the whole population
3. - Percentage of patients treated with a subsequent maintenance treatment with a PARP inhibitor (%) in the whole population
4. - Progression-free survival and overall survival in these patients compared to those not treated with PARP inhibitor
5. - In the population of patients treated with bevacizumab: • Overall response rate according to RECIST V1.1 • Progression-free survival & overall survival according to RECIST V1.1 • Percentage of patients operated with a late complete debulking surgery (%)
6. - Adverse events graded according to the NCI Common Terminology Criteria Adverse Event Version 5.0 (see appendix 3)
7. - Quality of life questionnaires
8. - To determine the impact of patient beliefs, preferences and experiences on the decision-making process; endpoint: shared decision-making
9. - To determine the impact of the shared decision-making process on outcomes in the short- and medium-term; endpoints: satisfaction with care, satisfaction with decision, patient-doctor relationship, emotions, treatment beliefs, treatment adherence, and quality of life.
10. - Percentage of patients with BRCA mutation (%)
11. - Percentage of patients with BRCA wild-type HRD disease (%)
12. - Percentage of patients with BRCA wild-type HRP disease (%)
13. - Tests/assays used (names, proprietary), and percentage of each of them (%)
14. - Incremental cost-utility ratio and incremental cost-effectiveness ratio
15. - Net financial impact over 5 years
16. - Percentage of patients operated with late complete debulking surgery, regardless of the number of chemotherapy cycles received

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Auxiliary 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Arcagy Gineco

Sponsor organisation

Arcagy Gineco

Address

1 Parvis Notre Dame Place Jean Paul Ii

City

Paris

Postcode

75004

Country

France

Scientific contact point

Organisation

Arcagy Gineco

Contact name

Benoit You

Public contact point

Organisation

Arcagy Gineco

Contact name

Benoit You

Locations

3 EU/EEA countries · 62 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 33 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

8 submissions — initial application plus substantial / non-substantial modifications