Safety and Efficacy of Tinostamustine in Pre-Treated Patients with Relapsed/Refractory (R/R) Hodgkin Lymphoma (HL): Early Results from an Additional Expansion Cohort of a Phase I Study

Background: Despite recent therapeutic advances, there remains an unmet medical need for patients with R/R HL. The alkylating deacetylase inhibitor tinostamustine is a multi-action therapy designed to improve drug access to DNA strands, induce DNA damage and counteract its repair in cancer cells. Tinostamustine was well tolerated, with signals of efficacy during both the dose-escalation and cohort expansion stages of a Phase I study in patients with R/R haematological malignancies, including HL (Zinzani et al. HemaSphere. 2019; 3(S1):102: PF300; Pinto et al. Hematological Oncology. 2019; 37(S2): 273; Ghesquières et al. Blood. 2021; 138 (S1): 2472).

Aims: Here we report further safety and efficacy data for tinostamustine derived from an additional R/R HL expansion cohort of a Phase I study (NCT02576496).

Methods: Patients with R/R HL who had received at least 2 lines of prior therapy and for whom no other therapy with proven clinical benefit was available were eligible for an expansion cohort to receive the recommended Phase II dose (RP2D) of tinostamustine. The RP2D was determined during dose-escalation and administered according to baseline platelet count: 80mg/m² (>100x10⁹/l to <200x10⁹/l platelets), and 100mg/m² (≥200x10⁹/l platelets) over 60 min on Day 1 of a 21-day cycle. The dose was subsequently revised to 100mg/m² for ≥100x10⁹/l platelets. Adverse events (AEs) were summarised by US National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE; version 4.03) grade for all treated patients. Treatment-related AEs, AEs leading to death, serious adverse events (SAEs), and AEs resulting in trial discontinuation were recorded. Efficacy variables included overall response rate (ORR; complete response [CR] + partial response [PR]) and survival outcomes evaluated from Cycle 3 until progression or toxicity.

Results: Twenty patients with R/R HL were recruited. Patients had a median age of 35.0 (range 25.0-74.0) years and were predominantly male (n/N=14/20, 70.0%). Most patients had an ECOG Performance Status of 0 (14/20, 70.0%) at screening and had received a median of 5 (range 3-9) lines of prior therapy; 10/20 (50.0%) were judged by the investigators to have refractory disease. At data cut-off of 30 June 2022, patients had received a median of 3 (range 1-12) cycles of tinostamustine. No unexpected AEs were observed following tinostamustine treatment. Treatment-emergent adverse events (TEAEs) were principally haematological (71 events in 13/20 patients; 65.0%) and included thrombocytopenia, neutropenia, anaemia and lymphopenia (41 events in 11 patients were Grade ≥3). Gastrointestinal AEs were observed in 14/20 patients (39 events), the majority of which were nausea or vomiting (all Grade 1 or 2). Serious TEAEs that were considered related to tinostamustine occurred in 8 patients (40.0%), including thrombocytopenia (n=1) and infusion-related reaction (n=1). Treatment discontinuation due to TEAEs occurred in 5/20 patients (25.0%; thrombocytopenia: n=4). No fatal TEAEs, or incidences of within-cycle QTc prolongations ≥500 ms, or increases from baseline ≥60 ms, were observed. 9/20 patients (45.0%) discontinued due to progressive disease. Mean ± SD time to disease progression was 5.2 ± 3.7 months (range 1.6-14.0 months). At data cut-off, all patients had progressed. 2/20 (10%) patients achieved a CR as best response following a median of 2 (range 1-3) cycles, 6/20 (30%) a PR (median of 4.5 [range 1-7] cycles) and 3/20 had stable disease (median of 3 [range 3-3] cycles). ORR was 40% (8/20 patients; 95% confidence interval: 19%, 64%) and median progression-free survival (PFS) was 3.8 months (95% confidence interval 2.3-7.6).

Conclusions: Initial results from two expansion cohorts of a Phase I study further demonstrate that tinostamustine administered on Day 1 of a 21-day cycle to patients with R/R HL was relatively well tolerated with no unexpected AEs. The main TEAEs were haematological (thrombocytopenia, neutropenia, anaemia and lymphopenia), with thrombocytopenia being the main TEAE leading to treatment discontinuation. An ORR of 40% and a median PFS of 3.8 months were observed, revealing signals of efficacy in this heavily pre-treated patient population. Based on these findings, tinostamustine appears to warrant further investigation. Updated data will be presented at the congress.

Funding: Mundipharma Research Limited and Purdue Pharmaceutical Products LP

Sureda:Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS/Celgene: Consultancy, Honoraria, Research Funding; MSD: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Jannsen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; GenMab: Consultancy, Honoraria; Pierre Fabre: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria. Pinto:Servier Affaires Medicales: Honoraria, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche AG: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck Sharp and Dohme: Honoraria, Membership on an entity's Board of Directors or advisory committees. Ghesquieres:Roche: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; BMS: Honoraria; Abbvie: Honoraria. Morschhauser:AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Miltenyi: Membership on an entity's Board of Directors or advisory committees; Janssen: Speakers Bureau; Genentech: Consultancy; Genmab: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Consultancy, Membership on an entity's Board of Directors or advisory committees; Allogene therapeutics: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees. Tournilhac:Abbvie: Honoraria, Other: Travel grant , Research Funding; Takeda: Honoraria, Other: Travel grant , Research Funding; Janssen: Honoraria, Other: Travel grant , Research Funding; Gilead: Honoraria, Other: Travel grant , Research Funding; Securabio: Honoraria, Other: Travel grant , Research Funding; IdeoGen: Honoraria, Other: Travel grant , Research Funding. Mutseaers:Astra Zeneca: Research Funding; Glaxo Smith Kline: Consultancy; BMS: Consultancy. De Jong:Mundipharma Research Limited: Current Employment; GSK: Ended employment in the past 24 months. Janik:Mundipharma Research Limited: Current Employment. Zinzani:Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Celltrion: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSA Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Beigene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Secura Bio: Membership on an entity's Board of Directors or advisory committees.