Periodic Reporting for period 1 - SALVOVAR (A EUROPEAN MULTI-DISCIPLINARY CLINICAL PROJECT MEANT TO IMPROVE THE MANAGEMENT OF PATIENTS WITH POOR PROGNOSTIC OVARIAN CANCER AFTER NEOADJUVANT CHEMOTHERAPY: RESTORING HOPE, SALVAGING LIVES)
Reporting period: 2023-05-01 to 2024-10-31
Among patients with an advanced ovarian cancer treated with neoadjuvant chemotherapy (representing 50-60% of all patients managed in first-line setting in Europe), about 35% of them belong to a poor prognostic group because they have a disease that is: 1) poorly chemosensitive, and 2) not amenable to complete interval debulking surgery). These patients have a 10-20% overall survival at 5 years. The wider prescription of maintenance treatment with PARP inhibitors (after chemotherapy) may not beneficial to them, since these drugs were mainly shown to be active in patients with highly chemosensitive disease and less bulky cancer. As a consequence, if no solution is found for these patients, the survival gap between patients with highly and poorly chemosensitive disease will necessarily increase in a near future with the progressive higher access to PARP inhibitors in Europe.
In this context, any strategy able to increase the chemosensitivity in these patients is of high interest, as it would rationally enhance the feasibility of late complete subsequent debulking surgery and the access/efficacy to PARP inhibitor maintenance treatment. A previous retrospective analysis of ICON-8 trial suggested that the densification of the chemotherapy dose and dosing schedule, with the weekly dose-dense administration of paclitaxel at 80 mg/m2, combined to weekly carboplatin AUC5 every 3 weeks, may be more effective than the standard 3-weekly regimen in patients with a poorly chemosensitive disease.
The following hypothesis will be tested in SALVOVAR trial: the unfavorable prognosis of ovarian cancer patients, belonging to the poor prognostic group during neo-adjuvant chemotherapy, could be improved by the adjustment of the chemotherapy regimen with a salvage weekly dosedense administration, which would 1) enhance the chemotherapy effects, 2) increase the access of these patients to late complete interval debulking surgery, and 3) improve the efficacy of maintenance with PARP inhibitors (shown to be active in patients with highly platin-sensitive disease) and/or bevacizumab.
Moreover, the trial is designed to provide data about the efficacy, toxicity, cost/effectiveness of the different complementary therapeutic strategies, available for prescription (such as addition of bevacizumab, maintenance treatment with PARP inhibitor and/or bevacizumab, late debulking surgery….), their impact on patients’ quality of life, the impact of country coverage policy of the actual prescriptions and patient prognosis, and the determinants of the decision-making process in the context of therapeutic uncertainty.
Primary Objective:
- To demonstrate the superiority in terms of efficacy of a densification of the chemotherapy with the salvage weekly dose-dense carboplatinpaclitaxel 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 to 4 cycles of standard neo-adjuvant chemotherapy.
Co-Primary Endpoint:
- Percentage of patients operated with late complete debulking surgery (expected increase from 5% to 20%)
- 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
The project is structured with 9 interconnected work packages (WPs), each addressing different aspects of this innovative therapeutic strategy. WP1 serves as the cornerstone, providing the essential international clinical trial framework and data upon which the other WPs build. WP2 oversees the trial's methodological and statistical design, while WP9 ensures effective project management and goal realization. WP6 focuses on collecting patient-reported outcomes and assessing quality of life, whereas WP3 investigates how treatment decisions are made between physicians and patients in contexts of therapeutic uncertainty. WP4 works to define and standardize the surgical eligibility criterion, developing an e-learning program to train surgeons (criteria of non-resectability after neo-adjuvant chemotherapy, criteria for complete late debulking surgery). WP5 investigates the heterogeneity of clinical practices for tumor homologous recombination status testing and maintenance treatment across Europe, and WP7 evaluates the economic impact of the dose-dense approach. Finally, WP8 manages communication and dissemination efforts.
In this context, any strategy able to increase the chemosensitivity in these patients is of high interest, as it would rationally enhance the feasibility of late complete subsequent debulking surgery and the access/efficacy to PARP inhibitor maintenance treatment. A previous retrospective analysis of ICON-8 trial suggested that the densification of the chemotherapy dose and dosing schedule, with the weekly dose-dense administration of paclitaxel at 80 mg/m2, combined to weekly carboplatin AUC5 every 3 weeks, may be more effective than the standard 3-weekly regimen in patients with a poorly chemosensitive disease.
The following hypothesis will be tested in SALVOVAR trial: the unfavorable prognosis of ovarian cancer patients, belonging to the poor prognostic group during neo-adjuvant chemotherapy, could be improved by the adjustment of the chemotherapy regimen with a salvage weekly dosedense administration, which would 1) enhance the chemotherapy effects, 2) increase the access of these patients to late complete interval debulking surgery, and 3) improve the efficacy of maintenance with PARP inhibitors (shown to be active in patients with highly platin-sensitive disease) and/or bevacizumab.
Moreover, the trial is designed to provide data about the efficacy, toxicity, cost/effectiveness of the different complementary therapeutic strategies, available for prescription (such as addition of bevacizumab, maintenance treatment with PARP inhibitor and/or bevacizumab, late debulking surgery….), their impact on patients’ quality of life, the impact of country coverage policy of the actual prescriptions and patient prognosis, and the determinants of the decision-making process in the context of therapeutic uncertainty.
Primary Objective:
- To demonstrate the superiority in terms of efficacy of a densification of the chemotherapy with the salvage weekly dose-dense carboplatinpaclitaxel 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 to 4 cycles of standard neo-adjuvant chemotherapy.
Co-Primary Endpoint:
- Percentage of patients operated with late complete debulking surgery (expected increase from 5% to 20%)
- 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
The project is structured with 9 interconnected work packages (WPs), each addressing different aspects of this innovative therapeutic strategy. WP1 serves as the cornerstone, providing the essential international clinical trial framework and data upon which the other WPs build. WP2 oversees the trial's methodological and statistical design, while WP9 ensures effective project management and goal realization. WP6 focuses on collecting patient-reported outcomes and assessing quality of life, whereas WP3 investigates how treatment decisions are made between physicians and patients in contexts of therapeutic uncertainty. WP4 works to define and standardize the surgical eligibility criterion, developing an e-learning program to train surgeons (criteria of non-resectability after neo-adjuvant chemotherapy, criteria for complete late debulking surgery). WP5 investigates the heterogeneity of clinical practices for tumor homologous recombination status testing and maintenance treatment across Europe, and WP7 evaluates the economic impact of the dose-dense approach. Finally, WP8 manages communication and dissemination efforts.
Significant progress has been achieved over the first 18 months.
The clinical trial's endpoints, stratification factors, and sample size were defined, with the statistical analysis plan completed. Interim analyses were discussed and incorporated into the protocol design. Translation and adaptation of Quality of Life questionnaires (WP6) for use in all participating centers. Meanwhile, in WP3 surveys to analyse the determinants of treatment decision-making were developed and translated into the relevant languages, to be integrated to the trial protocol. A semi-structured interview guide for shared decision-making was also prepared and is being incoporated by a protocol amendment.
WP4 brought together an expert group to reach a consensus on defining the criterion “not amenable to cytoreductive surgery” and launched an e-learning program to standardize its application. WP5 conducted an online survey across centers in France, Denmark, the Netherlands, and Israel to capture data on HDR testing indications, methodologies, and reimbursement policies. WP7 prepared and submitted the ancillary protocol SALVOVAR-ECO, focusing on the economic evaluation of the dose-dense strategy, to French authorities in October 2024.
Communication and dissemination activities also advanced during this period. The SALVOVAR logo was created, and a project website launched in July 2023. A video was produced to help patients better understand the trial’s objectives and address their questions before inclusion. Efforts to raise awareness included presentations at major conferences like ESMO, GCIG and ESGO 2023. Additionally, a pop-up message was integrated into the KELIM online calculator to inform users about the SALVOVAR trial and link to its website
The clinical trial's endpoints, stratification factors, and sample size were defined, with the statistical analysis plan completed. Interim analyses were discussed and incorporated into the protocol design. Translation and adaptation of Quality of Life questionnaires (WP6) for use in all participating centers. Meanwhile, in WP3 surveys to analyse the determinants of treatment decision-making were developed and translated into the relevant languages, to be integrated to the trial protocol. A semi-structured interview guide for shared decision-making was also prepared and is being incoporated by a protocol amendment.
WP4 brought together an expert group to reach a consensus on defining the criterion “not amenable to cytoreductive surgery” and launched an e-learning program to standardize its application. WP5 conducted an online survey across centers in France, Denmark, the Netherlands, and Israel to capture data on HDR testing indications, methodologies, and reimbursement policies. WP7 prepared and submitted the ancillary protocol SALVOVAR-ECO, focusing on the economic evaluation of the dose-dense strategy, to French authorities in October 2024.
Communication and dissemination activities also advanced during this period. The SALVOVAR logo was created, and a project website launched in July 2023. A video was produced to help patients better understand the trial’s objectives and address their questions before inclusion. Efforts to raise awareness included presentations at major conferences like ESMO, GCIG and ESGO 2023. Additionally, a pop-up message was integrated into the KELIM online calculator to inform users about the SALVOVAR trial and link to its website
In operational terms, the study initiation package was submitted to the Clinical Trial Information System (CTIS), receiving authorization on May 7, 2024. The first trial site in France was activated in June 2024, followed by the opening of 60 additional French sites and 14 sites in Japan by October 2024. Six patients out of the targeted 250 were randomized during this period. Preparations for opening trial sites in Italy, Czech Republic, Israel, the Netherlands, and the UK were initiated. The project team also developed the electronic Case Report Form (e-CRF) and finalized the data monitoring plan.