PF300 DOSE ESCALATION OF TINOSTAMUSTINE IN PATIENTS WITH RELAPSED/REFRACTORY (R/R) LYMPHOID MALIGNANCIES

Background: Despite advances in the treatment of lymphoma in recent years, unmet medical needs remain, particularly for patients with R/R disease and rarer subtypes of non‐Hodgkin lymphoma (NHL). The alkylating deacetylase inhibitor tinostamustine (EDO‐S101) is a novel multi‐action therapy that is designed to improve drug access to DNA strands, and at the same time induce DNA damage and counteract its repair in cancer cells. Aims: Here we report findings from the dose‐escalation stage of a Phase I first‐in‐human study to evaluate the safety and pharmacokinetics, and to determine the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D), of tinostamustine in patients with R/R lymphoid malignancies (NCT02576496). Methods: Patients were recruited using a standard 3+3 design, with the first cohort receiving 20 mg/m 2 tinostamustine administered iv over 60 minutes, with six ascending cohorts, to a maximum dose of 120 mg/m 2 . Dose‐limiting toxicities (DLT) were defined as: any Grade (G) 3 or 4 non‐haematological toxicity (excluding alopecia and easily correctable electrolyte abnormalities); nausea, vomiting or diarrhoea ≥10 days despite aggressive symptomatic treatment; G4 neutropenia or thrombocytopenia for ≥7 days; any G2 or more toxicity for >3 weeks; any toxicity resulting in a delay of the next dose administration (Cycle 2 Day 1 ≥14). Results: A total of 27 patients with lymphoid malignancies were enrolled into the study, 10 of these patients were diagnosed with R/R Hodgkin lymphoma (HL) and 17 with NHL, including peripheral T‐cell lymphoma and diffuse large B‐cell lymphoma. The MTD of tinostamustine was determined to be 100 mg/m 2 ; shorter infusion times were evaluated in three cohorts of patients, but the recommended infusion time was confirmed as 60 minutes. Safety findings for each dose cohort for HL and NHL patients were mainly haematological toxicities: G3/4 thrombocytopenia, neutropenia and leucopenia, with incidence increasing with increasing dose. One patient experienced a G3 allergic reaction. Signals of efficacy were observed among the 27 patients with lymphoma (overall response rate [ORR] 41% [11 patients]; clinical benefit rate [CBR] 67% [18 patients]). The best response, as determined by the Investigator, was complete response (CR; 3/27 patients [11%]), which was observed in one patient with HL and two with NHL; partial response (PR; 8/27 patients [30%]) and stable disease (SD; 7/27 patients [26%]) were also observed. Nine of the 27 patients (33%) had disease progression. Summary/Conclusion: Administration of tinostamustine on Day 1 of a 21‐day cycle was well tolerated with signals of efficacy in patients with both HL and NHL, including rare forms of NHL such as peripheral T‐cell lymphoma. The RP2D for tinostamustine in lymphoid malignancies, depending on patient platelet count at treatment initiation, was determined as 80 mg/m 2 for those with >100 x 10 9 /l platelets, and 100 mg/m 2 for those with ≥200 x 10 9 /l platelets. This will be applied in the second phase of this study, where patients will be recruited into one of five different cohorts.