Journal of Clinical Trials
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DOVIPA, a phase II study evaluating efficacy and safety of DOstarlimab® and oral VItamin D3 with folinic acid, 5FU, Irinotecan plus oxalipaltin (mFOLFIRINOX) in non pretreated metastatic PAncreatic Cancer.

Asmahane Benmaziane^1*, Dahna Coupez¹, Nassiba Heba¹, Fanny Foubert², Jean Emmanuel Mitry³, Baptiste Porte¹, Julien Taïeb⁴, Isabelle Trouilloud⁵, Angélique Vienot⁶, Tassadit Ben belkacem⁷ and Jaafar Bennouna^{1 *}Correspondence: Asmahane Benmaziane, Department of Medical Oncology, Hôpital Foch, Suresnes, France, Email:

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Introduction

Pancreatic cancer causes 466,003 deaths annually worldwide, including 132,134 in Europe in 2020. It accounts for nearly 29% of cancer deaths in Europe, with higher incidence in men (9.4/100,000) than in women (6.4/100,000). Projections indicate a significant rise in cases and deaths by 2040 [1].

In US, recent analyses highlighted a troubling trend in early-onset pancreatic cancer, with incidence growing faster in patients under 55 years’ old those in older above, and more rapidly in women than men. From 2001 to 2018, the annual percentage change progression was 2.36% and 0.62 % in women and men, respectively [2].

Pancreatic cancer is an aggressive disease with a poor prognosis, most often diagnosed at the metastatic stage, while the rate of resectable tumor at diagnosis is estimated to be around 20% [3].

The Prodige 4/Accord 11 phase 3 randomized study, conducted in 342 patients with metastatic pancreatic cancer demonstrated a statistical and strong clinical improvement of survival for patients receiving the triplet FOLFIRINOX compared to gemcitabine [4-6]. Overall, the median PFS was 6.4 months (versus 3.3 months with gemcitabine; p<0.0001) and the median OS 11.1 months (vs 6.8 months with gemcitabine; p>0,0001). FOLFIRINOX is now recognized as one of the standard treatments, alongside gemcitabine+nabPaclitaxel, for non-pre-treated metastatic pancreatic cancer patients with PS 0,1.

Pancreatic cancer is known as a chemo-resistant tumor model for several reasons including a high Multi-Drug Resistance (MDR1) expression on tumor cells and a poor vascularization with fibrosis of the Tumor Micro-Environment (TME) [7]. In addition, pancreatic cancer cells exhibit immunosuppressive oncogenes promoting immune escape associated with a cold TME, highly desmoplastic, acting as an obstacle to immune cells. The term "high unmet need" is very often associated with the currently available therapies for pancreatic cancers, sparking significant interest in new preventive and therapeutic approaches.

The results achieved with immune checkpoint inhibitors combined with chemotherapy are disappointing so far. The CISPD3 is a randomized phase 3 trial evaluating the benefit of adding sintilimab to mFOLFIRINOX in patients with metastatic pancreatic cancer. The ORR was 50.0% in the experimental arm and 23.9% in the standard arm with mFOLFIRINOX alone with a p value at 0.05. The median duration of response was numerically higher 7.85 and 4.63 months, respectively, but not statistically significant (p >.05). Unfortunately, the median OS was similar between the 2 arms, 10.9 and 10.8 months Hazard Ratio (HR) 1.09 (95% CI, 0.70-1.690). Similarly, the median PFS was 5.9 and 5.73 months HR 0.93 (95% CI, 0.62-1.41). It was pointed out that the chemotherapy doses were suboptimal with irinotecan 85 mg/m², oxaliplatin 68 mg/m² instead of 180 mg/m² and 85 mg/m², respectively [8].

One of the major challenges in therapeutic strategies for advanced pancreatic cancers is therefore to identify potential combinations that could enhance the effectiveness of immunotherapy. Pancreatic cancer resistance to immunotherapy is partly due to a low level of tumor-infiltrating immune cells and a high stromal density. New associations that modify the stroma and recruit immune cells are needed. In example, Vitamin D analogues, such as Calcipotriol (Cal), reduces fibrosis of the pancreatic stroma, thereby improving chemotherapy delivery.

Vitamin D appears to confer a protective effect against pancreatic cancer through involvement in various pro-apoptotic, antiangiogenic, anti-inflammatory, pro-differentiation, and immunomodulatory mechanisms. Pre-clinical data of the potential efficacy of vitamin D combined with Immune Checkpoint Inhibitor (ICI) are available. Paricalcitol, a modified compound of vitamin D could help to disorganize the pancreatic tumor’s stroma, which acts as a protective shield, encasing the tumor. The stroma is part of the extracellular matrix obstructing the tumor’s vasculature and inhibiting chemotherapy delivery to the tumor site. Specifically, the pancreatic stellate cells (those surrounding the tumor cells) are particularly activated in pancreatic cancer, driving the production of the stroma [9]. These stellar cells have high levels of vitamin D receptors, and their blockage inactivates stromal production [10-13]. It should also be noted that the Vitamin D receptors are expressed in all immune cells, and the availability of 25-hydroxyvitamin D in the microenvironment for local conversion to 1,25-dihydroxyvitamin D could also potentially influence the balance between regulatory and inflammatory T-cell responses [14,15].

A recent study showed that calcipotriol inhibits Cancer-Associated Fibroblast (CAF) proliferation and reduces secretion of the pro-tumorigenic factors PGE2, Leukemia Inhibitory Factor (LIF), and IL-6, consistent with the known antitumor effects of vitamin D analogs (VDAs) [16-18]. A pilot study of neoadjuvant paricalcitol in patients with resectable PDAC showed a 10 to 100-fold increase in T-cell migration in tumors after 28 days of treatment [19]. In addition, several studies suggest the use of VDAs to inhibit the immunosuppressive activity of stromal cells and it is hoped that this will improve the response to checkpoint inhibitors in patients with PDAC [20,21].

Thus, VDSAs in clinical trials are expected to provide significant benefits derived from reduced inflammation and desmoplasia, but also adverse effects on the immune system. It may be that selective agonists that reduce Treg cell activation, while maintaining strong inhibition of cytokine (IL-6) release, are particularly beneficial for patients with pancreatic cancer [22,23].

These results inspired the phase II study combining paricalcitol, nivolumab, nab-paclitaxel, cisplatin, and gemcitabine in 35 patients with previously untreated metastatic pancreatic ductal adenocarcinoma. Overall, ORR was 84% (26 PR and 1 CR), median PFS, 6 months and OS,18 months [12,13].

Based on these pre-clinical and preliminary clinical data, our phase 1/2 trial aims to evaluate the safety and efficacy of mFOLFIRINOX with dostarlimab plus oral vitamin D in patients with metastatic pancreatic cancer. A tumor biopsy is performed at 28 days from the beginning of the treatment to better understand the effect of vitamin D high dose in association with dostarlimab on tumor cells and tumor micro-environment.

In clinical practice, oral vitamin D supplementation is safe and well tolerated, confirmed by a meta-analysis where doses up to 10,000 IU per day in adults were prescribed [24]. The most commonly reported adverse effects were transient and minor gastrointestinal disturbances such as nausea, vomiting, and diarrhoea, not requiring discontinuation of supplementation. Another study found that high-dose vitamin D supplementation up to 10,000 IU per day was generally safe with mild and transient hypercalcemia and a higher incidence of hypercalciuria observed at higher doses. All cases of hypercalcemia were resolved upon retesting and were mild and transient in nature.

Objectives

The primary objective is to estimate the antitumor response of mFOLFIRINOX+Dostarlimab+oral HD vitamin D3 in patients in with non-pre-treated metastatic pancreatic Cancer.

The secondary objectives are:

1. To assess the safety and tolerability of mFOLFIRINOX+Dostarlimab+HD Vitamin D3 according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0
2. To evaluate the antitumor efficacy of mFOLFIRINOX+Dostarlimab+HD Vitamin D3

Outcomes

Primary endpoint: The primary endpoint of this study is the Objective Response Rate (ORR).

Secondary endpoints: The secondary endpoints of this study are:

• The Safety endpoints (Type, frequency and severity of Treatment Adverse Events (TAEs); safety laboratory findings)
• Efficacy endpoints: Median Progression Free Survival (mPFS), Median Overall Survival (mOS), median Duration of Response (mDOR), Clinical Benefit Rate according to RECIST 1.1 (CBR).

Trial design

DOVIPA is an open-label, multi-center, non-comparative, non-randomized, phase II study exploring the efficacy and safety of the combination of Dostarlimab and oral Vitamin D with folinic acid, 5FU, Irinotecan plus oxalipaltin (mFOLFIRINOX) in non-pre-treated metastatic Pancreatic cancer.

Methodology

Participants and interventions

Study setting: This study is a French multicenter trial. Patients are recruited from the oncology departments of five teaching hospitals: Foch Hospital (Suresnes), University Hospital of Nantes (Nantes), Georges Pompidou Hospital (Paris), Saint-Antoine Hospital (Paris) and Paoli Calmettes Anti-Cancer Center (Marseille).

Eligibility criteria

This study enrolls 35 patients with non-pretreated metastatic pancreatic adenocarcinoma. Patients are eligible to be included in the study if they are between 18 and 75 years old and have histologically and cytologically confirmed, measurable metastatic pancreatic adenocarcinoma that has not previously been treated with chemotherapy. Other inclusion criteria were an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1, and a life expectancy of more than 3. The main non-inclusion criteria are patients aged over 75 years old, those with known meningeal or brain metastases, and those who have previously undergone treatment for pancreatic cancer. The required results of laboratory analyses and the other eligibility criteria are shown in Table 1.

Table 1: Inclusion and exclusion criteria.

Who will take informed consent?

Patients’ written consent will be obtained by the investigator, their oncologist, prior to any study-specific procedures. Participation is voluntary, individuals may withdraw at any stage and participation does not affect the individual’s treatment.

Additional consent provisions for collection and use of participant data and biological specimens

Biological samples (tumoral tissue and blood) will be collected as part of this trial for translational research purpose. The trial aims to better understand the mechanism of action of dostarlimab with oral HD vitamin D3 in metastatic pancreatic adenocarcinoma and analyse the tumor microenvironment in liver of patients affected by pancreatic ductal adenocarcinoma and treated with chemotherapy and immunotherapy associated with a vitamin D3.

Intervention

This study enrolls 35 patients with non-pretreated metastatic pancreatic adenocarcinoma aged 18 to 75 years with an Eastern Cooperative Oncology Group performance status ≤ 1. The inclusion period lasts for 18 months and the follow-up period is 24 months.

Patients receive the following treatment regimen (1 cycle, d1-d42):

• Intravenous (IV) dostarlimab: 500mg IV q3Weeks (cycle 1 to cycle 4), d1-d21, then 1000 mg IV q6Weeks (from cycle 5 onwards).
• Oral vitamin D3 8000 IU/d for 14 days, then 4000IU/d.
• mFOLFIRINOX d1, d15, d29 is administered as follow: oxaliplatin 85 mg/m² on day1, IV infusion over 2 h, immediately followed by folinic acid 400 mg/m² or calcium levofolinate 200 mg/m² given as a 2-h IV infusion, with the addition of irinotecan 180 mg/m² as per dose-level given as a 90-min intravenous infusion through a Y-connector immediately followed by 5-fluorouracil 2400 mg/m² over 46 h continuous infusion.

Safety run-in phase

Given that the safety profile of the mFOLFIRINOX+dostarlimab +vitamin D3 combination has not been evaluated so far, a safety run-in phase was planned. There are no specific selection criteria in this safety run-in, inclusion and non-inclusion criteria are the same as the criteria for main cohort. A total of 6 patients are required in the safety run-in phase.

The first step of the safety run-in phase is planned to enroll 3 patients treated with mFOLFIRINOX+dostarlimab+vitamin D3. An Internal Safety Committee (ISC) decide whether it is safe to include 3 more patients in the second safety cohort according to the definition of Dose Limiting Toxicity (DLT). If there was no safety issue, the second step will be performed. The second step of safety run-in phase planned to enroll 3 patients to receive the same regimen.

DLT was defined as follows:

• Grade 4 neutropenia (absolute neutrophil count <0.5 × 10⁹/l) for ≥ 7 days;
• Febrile neutropenia or neutropenia grade 3/4 concomitant with infection, any grade 3/4 diarrhea or grade ≥ 2 concomitant with grade 4 neutropenia;
• Symptomatic thrombocytopenia;
• Any grade 4 toxicity related to study treatment (except vomiting in the absence of appropriate medication) or any toxicity which necessitated a cycle delay of >15 days.

The study design schematic is presented in Figure 1:

Study procedure/Treatment

Study plan: The study plan below summarizes the study assessments per visit along the study (Table 2).

Table 2: Study schedule.

Figure 1: Study design.

Study drugs: Although the Foch Hospital acts as the coordinating agency for the trial, the responsibility for treatment of patients rests with the individual investigator.

In accordance with study’s policy, protocol treatment is to begin within 7 working days of enrolment.

Study drug includes both investigational and non-investigational medicinal product:

• Investigational Medicinal Product (IMP) à dostarlimab and vitamin D3
• Non-Investigational Medicinal Product (Non-IMP) mFOLFIRINOX and LV5FU

Treatment plan: The treatment schedule is summarized in Table 3 and illustrated in Figure 2:

Table 3: Treatment schedule.

Toxicity management: Toxicity assessment will be done according to CTCAE 5.0. Toxicity management is provided in study protocol.

Dostarlimab: Dose reduction is not allowed. Dosing delay or discontinuation may be required based on individual safety and tolerability. If delay is greater than 28 days, dostarlimab dosing should resume only after careful consideration. Recommended modifications to manage adverse reactions are provided in protocol according to the updated investigator’s brochure of dostarlimab.

Vitamin D3: No dose modification of oral vitamin D3. If albumin-corrected serum calcium >1 UNL (Upper Normal Level), stop oral vitamin D3 supplementation until normal value. For all other grade ≥ 3 toxicities suspected to be related to vitamin D3, oral vitamin D3 must be discontinued until back to grade 1 according to CTCAE v5.0. SPC of vitamin D3 updated on 18/07/2023 will be used as reference for toxicity management and assessment. The sponsor's opinion should be consulted if there are any questions about precautions or restrictions on use.

Chemotherapy: Modified FOLFIRINOX/LV5FU will not be supplied. They will be obtained from commercially available sources and reimbursed by insurance companies. Toxicities management recommendations are provided in the study protocol.

Criteria for discontinuing or modifying treatment: The study treatment can be discontinued early at any time: At the request of the patient, whatever the reason; at the request of the investigator for any reason in keeping with the patient’s best interests; at the request of the sponsor; in case of non-confirmation of the selection criteria; and in case of unacceptable toxicity.

Strategies to improve adherence to oral treatment: Patient adherence to the oral treatment will be evaluated at each visit and at the end of the study through the patient diary.

Provisions for post-trial care: At the end of the clinical research, the patient will be followed up by their oncologist and will benefit from the usual care for their disease. The sponsor has taken out an insurance policy covering the financial consequences of its civil liability in compliance with the regulations.

Concomitants treatments/Procedures: No drug-drug interaction studies have been conducted with dostarlimab. Monoclonal antibodies such as dostarlimab are not substrates for cytochrome P450 or drug transporters. Dostarlimab is not a cytokine and is unlikely to be a cytokine modulator. Additionally, pharmacokinetic drug-drug interactions of dostarlimab with small molecule drugs is not expected. There is no evidence of drug-drug interaction mediated by non-specific clearance of lysosome degradation for antibodies.

Statistical considerations

Study population: All patients included in the study will be recorded. All withdrawals from the study will be listed and described with the reasons for withdrawal. The distribution of patients will be described in total.

There will be 3 populations defined for this study: Safety Population (SP), Intent-To-Treat population (ITT) and the Per-Protocol Population (PP).

• Safety Population (SP): all patients included in the study, who signed a free and informed consent form, met all inclusion criteria and had no non-inclusion criteria. Description of demographic and clinical data at baseline as well as safety and toxicity parameters
• Intent-To-Treat population (ITT): all patients included in the study, submitted to the treatment drug and having a case report form
• Per-protocol population (PP): all patients exposed to the study product and no major deviation from the protocol

All efficacy endpoints will be analysed on the basis of both the Intent-To-Treat population (ITT). The Per-Protocol Population (PP) will allow a sensibility assessment of the robustness of the results with respect to protocol deviations. The decision whether a protocol deviation is major or not for the exclusion of patients from the PP set will be made in a blind review meeting.

Statistical methods: Overall descriptive summaries will be provided where appropriate for each of the primary and secondary variables, as well as baseline individual characteristics.

Descriptive statistics will be calculated according to the nature of the parameter:

• Quantitative variables will be described by the number of data (observed and missing), mean, standard deviation, minimum, maximum, first and third quartiles, and median.
• Qualitative variables will be described by the number and percentage of patients for each modality. Percentages are calculated only on complete data (exclusion of missing data).

The statistical unit will be the patient. Type 1 error rate will be set at 0.05. Comparisons will be two-sided unless specified otherwise. Statistical analysis will be done with the statistical package SAS (version 9.4 or later) and R (version 4.2 or later).

The main objective of this study is to determine the success rate (ORR) of the combination of Dostarlimab with mFOLFIRINOX+oral vitamin D3. The proportion of patients with an Objective Response at the end of the study will be described along with two-sided 95% exact confidence intervals, calculated using the Clopper-Pearson method. A Chi² test will be used to compare the ORR to the boundaries of efficiency (60%) and futility (30%).

Safety endpoints will be described in total, by severity and by causal assessment to the treatment.

Figure 2: Study treatment schedule design.

Efficacy assessment

All patients will undergo a Computed Tomography (CT) scan of the chest, abdomen, and pelvis at the specified time points in the study.

Patients who are unable (due to coexisting medical condition) or unwilling to have a CT-scan of the chest, abdomen and pelvis at baseline will be excluded from the study. Patients who become unable to undergo this imaging exam after selection may continue in the study for assessment of overall survival.

A patient's follow-up period will end 24 months after first intake or upon death, whichever comes first.

Assessment of response

Change in disease or response will be assessed by measuring the diameter of target and non-target lesions according to RECIST 1.1 criteria, at baseline, then after every 6 weeks (+/-2 week) starting from day 1 of cycle 1 until disease progression identified by the investigator, start of a new anti-cancer treatment, pregnancy of the patient, withdrawal of consent by the patient, or end of the study.

The response criteria below will be evaluated in reference to the Baseline Sum of Diameters (BSD).

• Complete Response (CR) will be defined as complete absence of measurable, non-measurable but assessable, and un-assessable disease with no new lesions and no disease-related symptoms. RECIST 1.1 criteria will be used.
• Partial Response (PR) will be defined as >30% reduction from baseline of uni-dimensionally measurable disease, with no new lesions.
• Progressive Disease (PD) will be defined as >20 % increase of a uni-dimensionally measurable lesion.
• Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.

The primary endpoint of this study is the Objective Response Rate (ORR), defined as the proportion of patients with an objective response at the completion of their follow-up (truncated at 24 months), among all eligible patients. An objective response will be defined as the best overall response of Complete Response (CR) or Partial Response (PR) assessed by investigators using validated criteria (i.e. RECIST 1.1).

Clinical Benefit Rate (CBR) will be measured as the proportion of patients with the Best Overall Response equal to Complete Response, Partial Response or Stable Disease, among all eligible patients.

Assessment of survival

All survival analyses will be censored at 24 months, maximum length of follow-up of the patients.

Progression Free Survival (PFS) will be measured as the duration each patient lives with the pancreatic cancer without it getting worse, starting with the first dose of treatment. The event will therefore be disease progression or death. The definition of "progression" will be based on a change in the radiological aspects or the appearance of a new lesion. If a patient is alive and progression-free at the end of the study or lost to follow-up, he will be censored from the analysis. The last response assessment that indicates absence of progression will be considered as the censoring date. The median PFS will be assessed as the time after which half of the patients are progression-free and alive.

Overall Survival (OS) will be defined as the duration from the first dose of treatment to each patient’s death. The death of a patient may be either directly related to the pancreatic cancer or due to an unrelated cause. If a patient is alive at the end of the study or lost to follow-up, he will be censored from the analysis. The last assessment that indicates life status will be considered as the censoring date. The median OS will be assessed as the time after which half of the patients are alive.

Duration of Response (DOR) will be defined as the time from onset of first response (PR or CR as defined above) to progression or death due to any reason, whichever occurs first. In case no event (progression or death) is observed at the end of study, the last response assessment that indicates absence of progression will be considered as the censoring date. Median DOR will be estimated as long as specific quantiles.

Safety assessment

This is a French phase II clinical trial where dostarlimab will be tested in a new cohort patient with metastatic pancreatic cancer, and therefore be considered as an IMP. Foch Hospital Clinical Trial Vigilance Department will be in charge of the sponsor Safety circuit of the trial.

The Safety Circuit and definitions will be carried out in compliance with the Regulation (EU) No 536/2014.

An Internal Safety Committee (ISC) was appointed by the sponsor and will comprise: The main investigator, the other oncologist experts within the study (Investigators), and the responsible of vigilance.

Role of the ISC: The major task of the internal board will to evaluate possible problems with respect to safety and efficacy continuously during the study process.

Further, once a year for the duration of the trial, the sponsor sends a safety report to the competent authorities. The ASR should be submitted, to the EV database, from the start of the clinical trial until the end of the clinical trial. The start of the annual period of the ASR is the date of the sponsor’s first authorisation to conduct the clinical trial. The data lock point is the last day of the one-year reporting period.

The report shall include a list of all suspected serious adverse reactions and analysis of the safety information of the persons suitable for the investigation.

Data management

Patients will be identified in the study by an inclusion number. Each patient's clinical data will be collected prospectively by the investigator or a qualified person designated by the investigator. Information will be recorded in an eCRF, Clinfile.

Quality control: The team of the Delegation of Clinical Research and Innovation (DCRI) of Foch Hospital will be in charge of the quality control of the study. A Clinical Research Associate (CRA) of Foch hospital will be in charge of the study follow-up, of the check of informed consent forms, of the quality control of collected data.

The modalities of coordination of the study: The steering committee, chaired by the project coordinator and scientific director will include principal investigators of participating centers, study methodologist, Safety manager and DRCI Foch Study project manager. This committee meet every 6 months to ensure DOVIPA progresses. It will monitor and review the overall strategy and progress of the project; propose mitigation plan for any detected hurdle, and coordinate the valorization and communication.

An Internal Safety Committee (ISC) was appointed by the sponsor to evaluate the safety during the safety-run phase of study.

An operational meeting between the coordinator and the project manager will be held to list the project's bottlenecks and progress and meet at least every month.

Regulatory considerations: This study (NCT06757244) will be performed in accordance with:

• The Ethical principles stated in the Declaration of Helsinki (60th WMA General Assembly, Seoul, October 2013);
• The European regulation (Directive 2001/20/CE) and the French Public Health Code (articles L1121-2 and following);
• The European Regulation No 536/2014 of the European Parliament and of the Council of 16 April 2014 relating to clinical trials on medicinal products for human use and repealing Directive 2001/20/CE;
• The regulation related to the protection of persons regarding the treatment of their personal data, and to the data transfer (EU2016/679 of European Parliament and of Council of 27th April 2016)

The study will be conducted in accordance with International Guidelines on Good Clinical Practices (GCP) and Standard Operating Procedures (SOP) for clinical investigation and documentation in force at the DCRI of Foch Hospital.

Discussion

The DOVIPA study seeks to assess the efficacy and safety of the combination of mFOLFIRINOX, dostarlimab, and vitamin D3 in patients with previously untreated metastatic pancreatic adenocarcinoma. The anticipated outcomes will provide insights into the positioning of this therapeutic combination relative to standard treatments and may also help identify predictive biomarkers of response.

Impact of vitamin D3 and checkpoint inhibitors

The inclusion of vitamin D3 and checkpoint inhibitors in the DOVIPA protocol is based on emerging data suggesting their synergistic potential in metastatic pancreatic cancer. 

Vitamin D3, through its anti-fibrotic and immunomodulatory properties, may reduce stromal density, thereby facilitating chemotherapy penetration and promoting immune cell infiltration. 

Dostarlimab, a PD-1 inhibitor, aims to counteract tumor-induced immunosuppression by reactivating cytotoxic T cells. This dual approach could potentially enhance the immune response against pancreatic tumor cells, a notoriously immunosuppressive environment.

Clinical implications and future perspectives

If positive, the results of the DOVIPA study could support the repositioning of vitamin D3 and dostarlimab as therapeutic modulators to improve the efficacy of the mFOLFIRINOX regimen in metastatic pancreatic cancer. 

A phase III randomized study may be warranted to validate these findings in a larger and more stratified cohort, focusing on the identification of biomarkers predictive of response and resistance.

Trial Status

Tis trial has just started.

The updated protocol is at Version n° 3.0-date 29/07/2024

The first patient was enrolled in February 2024

Recruitment by the investigating centers is planned to continue until August 2026.

Funding

This study is supported by GSK (drug and funding), which is not involved in the study or the analysis or interpretation of the data.

Availability of Data and Materials

Data collected during the trial may be processed electronically, in accordance with the requirements of CNIL (compliance with reference methodology MR001). The investigators will share the entirety of the final trial dataset.

Declarations

Ethics approval and consent to participate

All patients participating in the study are given oral and written information about this trial and sign the informed consent form.

This clinical study was submitted to and approved by CPP Sud-Ouest et Outremer IV, Limoges, Ethics Committee on July 30, 2024.

Consent for Publication

Not applicable no identifying images or other personal or clinical details of participants are presented here or will be presented in reports of the trial results. Informed consent materials are attached as supplementary materials.

Competing Interests

There are no financial or competing interests to be declared for the investigators.

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