CYT-0851 shows promising anti-tumour activity across different tumour types

CYT-0851 is the first DNA-damage repair therapeutic with demonstrated clinical activity in both haematologic malignancies and solid tumours, as results from a phase 1-2 trial showed.

Homologous recombination is an essential, high-fidelity mechanism to repair DNA double-strand breaks. Overexpression of the cytidine deaminase family of DNA damaging enzymes in subsets of cancers leads to increased DNA damage and subsequent dependence on homologous recombination-mediated DNA repair. Inhibition of homologous recombination in cancer cells leads to accumulation of unrepaired DNA double-strand breaks and tumour cell death. RAD51 is a key enzyme involved in homologous recombination. CYT-0851 is an oral, first-in-class, small-molecule inhibitor of RAD51-mediated DNA repair. Previously, CYT-0851 showed anticancer activity in preclinical models of solid and haematological cancer [1,2].

Dr Ryan Lynch (Fred Hutchinson Cancer Research Center, WA, USA) presented the first results of a phase 1-2 trial (NCT03997968) of CYT-0851 in patients with advanced solid and haematologic cancers [3]. Primary objectives included safety, maximum tolerated dose, recommended phase 2 dose, and anti-tumour activity. Secondary and exploratory objectives included pharmacokinetics, pharmacodynamics, and predictive biomarkers of response.

At data cut-off, 39 patients were enrolled of whom 35 were treated with CYT-0851. Diagnoses were sarcoma (n=12), non-Hodgkin lymphoma (n=8), breast cancer (n=5), pancreatic cancer (n=4), ovarian cancer (n=3), head and neck cancer (n=1), small cell lung cancer (n=1), and mucoepidermoid carcinoma (n=1). Dosing ranged from 15–45 mg twice daily to 90–3,000 mg once daily.

No patients experienced dose-limiting toxicity. A total of 13 patients (37%) experienced a CYT-0851-related adverse event with only 1 patient experiencing a grade ≥3 adverse event (fatigue). No clinically significant myelosuppression or treatment-related discontinuation was observed. Preliminary pharmacokinetic analyses showed dose-proportional systemic exposure with a half-life of ~3 days, supporting the transition from twice-daily to once-daily dosing.

A total of 21 patients were response-evaluable; 3 partial responses were observed (2 patients with non-Hodgkin lymphoma, 1 patient with soft-tissue sarcoma), and 10 patients had stable disease. Dose escalation continues to establish the recommended phase 2 dose, with planned expansion in 7 disease-specific cohorts in haematological and solid cancers.

1. Day M, et al. Cancer Res. 2019;79(suppl):C14.
2. Day M, et al. Blood 2019;134(suppl 1):2080.
3. Lynch RC, et al. First-in-human phase I/II study of CYT-0851, a first-in-class inhibitor of RAD51-mediated homologous recombination in patients with advanced solid and hematologic cancers. Abstract 3006, ASCO 2021 Virtual Meeting, 4-8 June.

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Posted on 12 August, 202118 August, 2021