4264 - A Phase I study of tinostamustine in patients (pts) with advanced solid tumours

Background

The novel multi-action alkylating deacetylase inhibitor tinostamustine (EDO-S101) has been shown in preclinical studies to improve drug access to DNA strands within cancer cells, break them, and counteract damage repair. Preclinical activity has been seen in models of solid tumours including sarcoma, small cell lung cancer, breast cancer, and ovarian cancer.

Methods

Patients (pts) with advanced solid tumours were recruited to an open-label phase I/II study to investigate the safety, pharmacokinetics and efficacy of tinostamustine (NCT03345485) using a standard 3 + 3 design. Six ascending cohorts received 60–100 mg/m² tinostamustine IV over 30 or 60 minutes.

Results

The safety population contained 22 pts who had received a median of 5 lines of prior systemic therapy ± radiotherapy (mean ± SD age 59.7 ± 11.1 years, 40.9% male, 77.3% Caucasian, 22.7% Asian). Pts received a (mean ± SD) cumulative tinostamustine dose of 407.3 ± 218.44mg/m² and spent 10.4 ± 8.6 weeks on therapy. All pts experienced ≥1 treatment-emergent adverse event (TEAE), the majority of which were mild or moderate in nature (nausea, 18/22 pts; QTc prolongation, 13/22 pts; thrombocytopenia, 12/22 pts; anaemia, 10/22 pts; lymphopenia, 9/22 pts; fatigue, 8/22 pts; vomiting and leukopenia, both 7/22 pts). Nausea and vomiting were well managed with antiemetics. Five pts experienced ≥1 serious TEAE, 3 of whom withdrew from the study. Only one pt experienced a clinically significant dose-limiting toxicity of Grade 3 QTc-prolongation following 100mg/m² tinostamustine IV over 60 minutes. The RP2D is 80 mg/m² IV over 60 minutes, which resulted in mean ± SD C_max 1540 ± 852ng/ml and AUC_0–t 1700 ± 913ng*h/ml on Days 15–16. Overall, 1/22 pts (diagnosis: endometrial cancer) achieved a partial response and 8/22 pts stable disease (SD); 4/8 pts who received the RP2D achieved SD.

Conclusions

Tinostamustine was generally well tolerated in patients with advanced solid tumours and limited treatment options. The phase II portion of this study will further investigate the efficacy of the RP2D of 80 mg/m² tinostamustine IV over 60 minutes in SCLC, triple-negative breast cancer, soft tissue sarcoma, ovarian cancer, and endometrial cancer. Funding: Mundipharma EDO GmbH.

Clinical trial identification

NCT03345485.

Editorial acknowledgement

Editorial support (in the form of writing assistance, collating author comments, grammatical editing and referencing) was provided by Sarah Birch, PhD, at Makara Health Communications Ltd., UK and was funded by Mundibiopharma Ltd.

Legal entity responsible for the study

Mundipharma EDO GmbH.

Funding

Mundipharma EDO GmbH.

Disclosure

M. Loeffler: Full / Part-time employment: Mundipharma EDO. D. Remmy: Full / Part-time employment: Mundipharma EDO. T. Mehrling: Leadership role, Full / Part-time employment: Mundipharma EDO. S. Kummar: Advisory / Consultancy: Mundipharma EDO. All other authors have declared no conflicts of interest.