Abstract
BackgroundCytotoxic chemotherapy combinations and targeted agents represent established treatment concepts in advanced pancreatic neuroendocrine tumors (PNETs). However, response rates, side effects and outcome data strongly vary among these therapeutic approaches. Head-to-head comparisons between chemo- and molecular therapies are missing and secondary resistances frequently occur. The RamuNET trial aims to identify the effectiveness of dual treatment with DTIC and ramucirumab in progressive advanced PNET patients.MethodsThe RamuNET study is an investigator-initiated multicenter prospective single-arm trial to evaluate the efficacy of ramucirumab in combination with dacarbazine (DTIC) over a period of at least 6 months. Patients with progressive well-differentiated and metastatic pancreatic neuroendocrine tumors are eligible. The study aims to include 45 patients over a period of 24 months with a minimum follow-up of 24 months. The primary endpoint is disease control after 6 months. Secondary endpoints include progression-free survival, biochemical response, overall survival, quality of life and toxicity. Based on the hypothesis that 80% of the patients can achieve a disease control after 6 months, the sample size calculation follows an exact binomial single-stage design. H0: p < =p0 = 60% versus H1: p > =p1 = 80%, alpha = 0.05, beta = 0.1.DiscussionThis study investigates a new therapeutic approach using the combination of cytotoxic and targeted antiangiogenic therapy in advanced PNET. If positive, this trial will be the basis for a randomized two-arm study to investigate the combination of ramucirumab and DTIC against other established therapies in PNET.Trial registrationEudraCT: 2017–001207-68. Date of registration: 2018.01.03.
Highlights
MethodsThe RamuNET study is an investigator-initiated multicenter prospective single-arm trial to evaluate the efficacy of ramucirumab in combination with dacarbazine (DTIC) over a period of at least 6 months
Cytotoxic chemotherapy combinations and targeted agents represent established treatment concepts in advanced pancreatic neuroendocrine tumors (PNETs)
Own preclinical data indicate that macrophages are expressed at high levels in human and murine pancreatic neuroendocrine tumor tissues and are predominantly polarized towards a protumoral, proangiogenic M2 phenotype, representing a promising target for therapeutic intervention
Summary
Study endpoints Primary endpoints Primary endpoint is the disease-control (DC) at 6 months as assessed by RECIST 1.1 criteria. Translational program This study concept is supported by own preclinical data indicating high amounts of VEGFR2 positive tumorinfiltrating macrophages in PNET tissues as therapeutic targets as well as literature reports from other groups and clinical trials in other tumor entities supporting the combination of anti-VEGFR2 together chemotherapy including DTIC These data indicate that systemic administration of ramucirumab may overcome therapy resistance by affecting both the tumor cell compartment and the local and systemic innate immune response, leading to a modulation of tumor-associated macrophages towards an antimetastatic phenotype. Serum and plasma will be used for central analysis of circulating, macrophage-associated cytokines and mediators of angiogenesis (e.g. IL1, IL6, VEGF, Angiopoetin-1 / -2) and correlated to clinical parameters Statistical analyses This trial is planned as a pilot study to evaluate the efficacy of combination treatment of ramucirumab and dacarbazine. Publication of the first manuscript reporting study results is planned after analysis of the primary endpoint
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