Assessment of Ramucirumab plus paclitaxel as switch maintenance versus continuation of first-line chemotherapy in patients with advanced HER-2 negative gastric or gastroesophageal junction cancers: the ARMANI phase III trial

Abstract

Background: Platinum/fluoropyrimidine regimens are the backbone of first-line chemotherapy for advanced gastric cancer (AGC). However response rates to first line chemotherapy range from 30 to 50% and disease progression occurs after 4-6 cycles. The optimal duration of first-line therapy is still unknown and its continuation until disease progression represents the standard. However this strategy is often associated with cumulative toxicity and rapid development of drug resistance. Moreover, only about 40% of AGC pts. are eligible for second-line treatment.

Methods: This is a randomized, open-label, multicenter phase III trial. It aims at assessing whether switch maintenance to ramucirumab plus paclitaxel will extend the progression-free survival (PFS) of subjects with HER-2 negative AGC who have not progressed after 3 months of a first-line with a platinum/fluoropyrimidine regimen (either FOLFOX4, mFOLFOX6 or XELOX). The primary endpoint is to compare Progression-Free Survival (PFS) of patients in ARM A (switch maintenance to ramucirumab and placlitaxel) versus ARM B (continuation of the same first-line therapy with oxaliplatin/fluoropyrimidine). Secondary endpoints are: overall survival, time-to-treatment failure, overall response rate, duration of response, percentage of patients that will receive a second line therapy according to arm treatment, safety, quality of life. Exploratory studies including Next-Generation Sequencing (NGS) in archival tumor tissues are planned in order to identify potential biomarkers of primary resistance and prognosis.

Discussion: The ARMANI study estimates if patients treated with early swich with ramucirumab plus paclitaxel received benefit when compared to those treated with continuation of first line therapy. The hypothesis is that the early administration of an active, non-cross resistant second-line regimen such as ramucirumab plus paclitaxel may prolong the time in which patients are progression-free, and consequently have a better quality of life. Moreover, this strategy may rescue all those subjects that become ineligible for second-line therapy due to the rapid deterioration of health status after the first disease progression.

Trial registration: ARMANI is registered at ClinicalTrials.gov ( NCT02934464 , October 17, 2016) and EudraCT(2016-001783-12, April 202,016).

Keywords: Clinical trial; First line; Maintenance; Metastatic gastric cancer; Ramucirumab.

Conflict of interest statement

Ethics approval and consent to participate

The study was registered on April 202,016 at EudraCT database (2016–001783-12) and on October 172,016 at The trial was approved by the Ethics Committee of the Fondazione IRCCS Istituto Nazionale Tumori di Milano and by local Committees of participating centers. All study participants will provide their written informed consent after careful explanation by their treating investigators.

This study will be conducted in full conformance with the ICH E6 guideline for Good Clinical Practice and the principles of the Declaration of Helsinki. The study will comply with the requirements of the ICH E2A guideline.

All study participants will provide their written informed consent after careful explanation by their treating investigators. Sponsor’s sample Informed Consent Form will be provided to each site. Each Site can modify the template provided, but the Sponsor will review and approve any proposed deviations from the sample Informed Consent Forms or any alternate consent forms proposed by the site (collectively, the “Consent Forms”) before IRB/EC submission. Regarding specific Informed Consent(s) on exploratory biomarkers, the investigator or authorized designee will explain to each patient the objectives of the exploratory research. Patients will be told that they are free to refuse to participate and may withdraw their specimens at any time and for any reason. All relevant changes to study procedures or new information will be communicated to all relevant parties (investigators, IRBs, trial participants, trial registries, journals, regulators) and patients will be re-consented to the most current version of the Consent Forms (or to a significant new information/findings addendum in accordance with applicable laws and IRB/EC policy).

The Sponsor maintains confidentiality standards by coding each patient enrolled in the study through assignment of a unique patient identification number. This means that patient names are not included in any of the study data sets. Patient medical information obtained by this study is confidential and may only be disclosed to third parties as permitted by the Informed Consent Form (or separate authorization for use and disclosure of personal health information) signed by the patient, unless permitted or required by law. Data generated by this study must be available for inspection upon request by representatives of the national and local health authorities, Sponsor’s monitors, representatives, and collaborators, and the IRB/EC for each study site, as appropriate.

Consent for publication

Not applicable.

Competing interests

MDB: advisor role/speaker bureau for Eli Lilly, Servier; FP: advisory role/ speaker bureau for Amgen Inc., Roche, Sanofi, Eli Lilly and Bayer Healthcare; SL: advisory role/speaker burearu for Amgen Inc., Bayer Helthcare, Merk and Eli Lilly, research funding from Amgen Inc. and Merk Serono; ST: advisor role for Eli Lilly, LR: advisory role/ speaker bureau for AstraZeneca,Abbvie, Lilly, Bayer, Sirtex Medical, Italfarmaco, Sanofi, ArQule, Baxter, Ipsen, Exelixis, Amgen, Incyte, Celgene. For the other authors there no competing interests for this study.

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Figures

Fig. 1

Study design