Abstract CT023: Dose escalation of tinostamustine in patients with advanced solid tumors
Authors: Mita Alain , Loeffler Markus , Bui Nam , Mehrling Thomas , Rimmel Bobbie J. , Natale Ronald B. , Kummar Shivaani 
Published: August 2019

Abstract
Despite advances in the treatment of solid tumors in recent years, unmet medical needs remain for patients with advanced disease. The alkylating deacetylase inhibiting molecule tinostamustine (EDO-S101) is a novel multi-action drug that has been shown in preclinical studies to improve drug access to the DNA strands within cancer cells, break them and counteract damage repair. Here we report findings from the dose escalation phase of an open-label Phase I/II study to investigate the safety, pharmacokinetics and efficacy of tinostamustine in patients with advanced solid tumors (NCT03345485).
In the Phase I part of the study, patients were recruited using a standard 3+3 design, with the first cohort receiving 60mg/m2 tinostamustine administered IV over 30 minutes, with six ascending cohorts to a maximum dose of 100mg/m2 administered over 30 or 60 minutes.
A total of 26 patients were screened and 22 patients enrolled into the study as the safety population. Patients had a mean ± SD age of 59.7 ± 11.1 years, 59.1% were female, 77.3% Caucasian and 22.7% Asian; all patients had received prior systemic therapy with or without radiotherapy. The (mean ± SD) tinostamustine dose was 407.3 ± 218.44 mg/m2, and the mean ± SD time on therapy was 10.4 ± 8.6 weeks. All patients experienced ≥1 treatment-emergent adverse events (TEAE), of which 22.7% were serious; 3 patients withdrew from the study due to TEAEs (CTCAE Grade 4 thrombocytopenia). The most common TEAEs related to study treatment were mild or moderate in intensity and included nausea (81.8% of patients), QTc prolongation (59.1%), thrombocytopenia (54.5%), anemia (45.5%), lymphopenia (40.9%), fatigue (36.4%), vomiting (31.8%) and leukopenia (31.8%). Importantly, despite a high percentage of patients experiencing some degree of QTc prolongation, external review determined that the majority of abnormalities were not clinically significant. Only one of the 22 patients enrolled (4.5%) experienced a QTc prolongation event that was considered to be clinically significant, this was a dose-limiting toxicity of Grade 3 QTc-prolongation in a patient receiving 100mg/m2 tinostamustine over 60 minutes. Nausea and vomiting were well managed using antiemetics. At 16 weeks’ follow-up, 4.5% of patients had a tumour response of partial response and 36.4% stable disease. Pharmacokinetic (PK) studies showed that peak serum concentrations (Cmax) of tinostamustine reached therapeutic levels. A more detailed analysis of PK data will be presented at the conference.
In patients with advanced solid tumors and limited treatment options, tinostamustine was generally well tolerated with preliminary signs of efficacy observed in this Phase I study across diverse tumor types. The Phase II portion of this study will enable a more comprehensive assessment of the efficacy of tinostamustine in larger patient cohorts within five specific tumor types.
Funding: Mundipharma-EDO GmbH.
Citation Format: Alain Mita, Markus Loeffler, Nam Bui, Thomas Mehrling, Bobbie J. Rimmel, Ronald B. Natale, Shivaani Kummar. Dose escalation of tinostamustine in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT023.