A multicenter open-label phase II trial to evaluate nivolumab and ipilimumab for 2nd line therapy in elderly patients with advanced esophageal squamous cell cancer (RAMONA)

Nadja M Meindl-Beinker, Johannes Betge, Tobias Gutting, Elke Burgermeister, Sebastian Belle, Tianzuo Zhan, Nadine Schulte, Martin Maenz, Matthias P Ebert, Nicolai Haertel, Nadja M Meindl-Beinker, Johannes Betge, Tobias Gutting, Elke Burgermeister, Sebastian Belle, Tianzuo Zhan, Nadine Schulte, Martin Maenz, Matthias P Ebert, Nicolai Haertel

Abstract

Background: Advanced esophageal squamous cell cancer (ESCC) is frequently diagnosed in elderly patients. The impact of 2nd line chemotherapy is poorly defined. Recent data demonstrated effectiveness of checkpoint inhibitors in different squamous cell carcinomas. Therefore, we assess combined nivolumab/ipilimumab as 2nd line therapy in elderly ESCC patients.

Methods: RAMONA is a multicenter open-label phase II trial. The primary objective is to demonstrate a significant survival benefit of nivolumab/ipilimumab in advanced ESCC compared to historical data of standard chemotherapy. Primary endpoint is therefore overall survival (OS). Major secondary objective is the evaluation of tolerability. Time to QoL deterioration will thus be determined as key secondary endpoint. Further secondary endpoints are tumor response, PFS and safety. We aim to recruit a total of n = 75 subjects that have to be > 65 years old. Eligibility is determined by the geriatric status (G8 screening and Deficit Accumulation Frailty Index (DAFI)). A safety assessment will be performed after a 3 cycle run-in phase of nivolumab (240 mg Q2W) to justify escalation for eligible patients to combined nivolumab (240 mg Q2W) and ipilimumab (1 mg/kg Q6W), while the other patients will remain on nivolumab only. RAMONA also includes translational research sub-studies to identify predictive biomarkers, including PD-1 and PD-L1 evaluation at different time points, establishment of organoid cultures and microbiome analyses for response prediction.

Discussion: The RAMONA trial aims to implement checkpoint inhibitors for elderly patients with advanced ESCC as second line therapy. Novel biomarkers for checkpoint-inhibitor response are analyzed in extensive translational sub-studies.

Trial registration: EudraCT Number: 2017-002056-86 ; NCT03416244 , registered: 31.1.2018.

Keywords: Checkpoint inhibitors; Comprehensive geriatric assessment; Elderly; Esophageal squamous cell cancer; Geriatric oncology; Personalized medicine.

Conflict of interest statement

Ethics approval and consent to participate

The study was approved by the lead ethics committee of the study, Ethics Committee II at Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany [2017-004F-MA] providing approval for all 34 study sites. The approval was permitted in agreement with local ethics commissions of the participating study sites. Written informed consent for participation is obtained from all participants.

Consent for publication

Not applicable.

Competing interests

This investigator-initiated trial is sponsored by the non-profit AIO-Studien gGmbH and received funding from Bristol-Myers Squibb (BMS) GmbH & Co. KGaA, NY, USA under study contract.

BMS had no role in the study design, and has no role in data collection, management, data analysis and interpretation, or decision to submit results for presentation or publication.

NH participated at advisory boards organized by the BMS (presentation incl.), MPE served on advisory board meetings of BMS.

The authors report no further conflicts of interest.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Study scheme. Patients may be escalated to nivolumab/ipilimumab combination therapy after a 3 cycle nivolumab-only run-in phase and positive safety assessment. GA: geriatric assessment (G8 / DAFI). ***: treatment escalation according to safety assessment results (please see full protocol). **: Chemotherapy (+/− radiotherapy) (e.g. CROSS, FLOT or similar protocols) OR any palliative systemic chemotherapy. * Stage 4 OR stage 3 non-responder to radio-chemotherapy OR any relapse after chemo-radiation OR any relapse after surgery if patient is ineligible or intolerant to standard frontline therapy OR refuses other treatment. PD1: off study despite post-progression ipi/nivo in case of toxicity and/or clinical deterioration. PD2: off study if confirmed progression according to Recist criteria V 1.1 or non-response according to immune-related response criteria. Ipilimumab 1 mg/kg IV Q6W. Nivolumab 240 mg IV Q2W. Restaging (incl. Endoscopic biopsies +PD-L1 staining)

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