A mutation-specific peptide vaccine targeting <i>IDH1R132H</i> in patients with newly diagnosed malignant astrocytomas: A first-in-man multicenter phase I clinical trial of the German Neurooncology Working Group (NOA-16).

Abstract

TPS2082 Background: Mutations in the gene for isocitrate dehydrogenase type 1 frequently occur in diffuse gliomas resulting in a point mutation (IDH1R132H) in most of the cases. Preclinical studies have shown that mutation-specific T helper (Th) cell responses spontaneously occur in patients with IDH1-mutated gliomas and that a peptide vaccine encoding IDH1R132H is therapeutic in a humanized mouse tumor model. Methods: NOA-16 (ClinicalTrials.gov Identifier: NCT02454634) is a multicenter, first-in-man, phase I clinical trial, which is planned to enroll 39 patients with newly diagnosed malignant astrocytomas with IDH1R132H mutations at eight German sites. The target population is molecularly enriched for an unfavorable prognosis within the IDH1-mutated subgroup by mandating (i) absence of co-deletion of 1p/19q and (ii) loss of alpha-thalassemia/mental retardation syndrome X-linked (ATRX) expression. Patients aged ≥ 18 years with a Karnofsky performance score of ≥ 70 will receive radiotherapy only (cohort 1), combined radiochemotherapy with temozolomide (TMZ, cohort 2) or TMZ only (cohort 3) as the primary treatment based on the decision of the local investigator. Over a period of 32 weeks a total of eight vaccinations with an IDH1R132H peptide emulsified in incomplete Freund’s adjuvant produced at a central good manufacturing practice (GMP) site will be administered subcutaneously with topical imiquimod starting three months after the initiation of primary treatment. The primary end points are safety and immunogenicity as measured by IDH1R132H-specific antibody and T cell responses. Secondary outcome measures include progression-free survival (PFS) and overall response rate (ORR). Enrollment started in June 2015. The DMC reviewed the trial in December 2015 and suggested that the trial continues as planned after the first three patients had completed the first vaccinations without a regime-limiting toxicity (RLT). Eight patients have been enrolled at three sites (as of January 2016). Clinical trial information: NCT02454634.