Results from the Cohort-Expansion Stage of a Phase I Trial of Tinostamustine Monotherapy in Advanced Hodgkin Lymphoma (HL), Non-Hodgkin Lymphoma (NHL) and Multiple Myeloma (MM) (NCT02576496)
Authors: Sureda Balari Anna Maria , Ghesquieres Herve , Morschhauser Franck , Mutsaers Pim , Ocio Enrique M , Janik Tomas , Manamley Nick , Hilgier Kasia , Zinzani Pier Luigi 
Published: December 2023

Background
Tinostamustine, a novel alkylating deacetylase inhibitor, improves drug access to cancer cell DNA strands, breaks them and counteracts damage repair. Tinostamustine was well tolerated, with signals of efficacy, during the dose-escalation stage of a Phase I study in patients with relapsed/refractory (R/R) haematological malignancies (Zinzani et al. HemaSphere 2019;3(S1):102:PF300) and for patients with HL in the cohort-expansion stage (Ghesquières et al. Blood 2021;138(S1):2472; Sureda et al. Blood 2022;140(S1):3696).
Aims
We report safety and efficacy findings from patients with advanced haematological malignancies including HL, cutaneous T-cell lymphoma (CTCL), peripheral T-cell lymphoma (PTCL), T-cell prolymphocytic leukaemia (T-PLL) and MM treated with tinostamustine in the expansion cohorts of a Phase I study.
Methods
Patients with advanced haematological malignancies, for whom no standard treatment with proven clinical benefit was available or recommended, were recruited to receive the recommended Phase II dose of tinostamustine. Patients with HL must have received ≥2 lines of prior therapy, CTCL 1-4 prior standard systemic therapies, PTCL &gt;1 prior line of combination therapy, T-PLL ≥1 prior line of therapy and MM ≥1 prior systemic therapy. Adverse events (AEs) were assessed for severity using US National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE; version 4.03, June 2010; for QTc prolongations CTCAE version 5.0 was used). Treatment-related AEs, fatal AEs, serious adverse events (SAEs), and AEs resulting in trial discontinuation were recorded. Primary efficacy objectives were to estimate the overall response rate (ORR; complete response [CR] + partial response [PR]) and clinical benefit rate (CBR; CR + PR + stable disease ≥4 cycles [SD]) for each cohort and to evaluate the safety of tinostamustine. Secondary efficacy variables included progression-free survival (PFS) and overall survival (OS); all outcomes were evaluated from Cycle 3 until progression or toxicity.
Results
48 patients with advanced haematological malignancies were enrolled to the study and received treatment with tinostamustine (HL, n=20; CTCL, n=13; PTCL, n=8; T-PLL, n=1; MM, n=6; Table). Patients with HL, CTCL, PTCL and T-PLL received 50 mg/m 2 (1 patient), 80 mg/m 2 (7 patients) and 100 mg/m 2 (34 patients) over 60 minutes on Day 1 of a 21-day cycle; patients with MM: 60 mg/m 2 over 60 minutes on Day 1 and Day 15 of a 28-day cycle. Patients received a median of 3.5 (range 1-12) cycles of tinostamustine. No unexpected AEs were observed. Treatment-emergent AEs (TEAEs) occurred in 46/48 (95.8%) patients (500 events), with 28 patients experiencing 90 events ≥Grade 3. Gastrointestinal AEs were observed in 33/48 patients, the majority of which were nausea or vomiting. Haematological AEs, including thrombocytopenia, anaemia and neutropenia, occurred in 27/48 patients. Serious TEAEs considered related to tinostamustine occurred in 11 patients with HL or CTCL ( Table) and included thrombocytopenia (n=3) and infusion-related reaction (n=1); one patient with CTCL experienced a fatal TEAE of decreased appetite. Overall, 22/48 (45.8%) patients discontinued due to progressive disease and 13/48 (21.6%) discontinued due to AEs. In the 46 patients included in the efficacy analysis, ORR was 30.4% (95% confidence interval [CI]: 17.7%, 45.8%) and CBR 52.2% (95% CI: 36.9%, 67.1%). 4 patients achieved a CR (2 patients with HL, 2 CTCL), 10 a PR (5 HL, 4 CTCL, 1 PTCL) and 14 SD (4 HL, 4 CTCL, 3 PTCL, 3 MM). Median PFS was 4.3 months (95% CI: 2.7, 6.6 months; HL, 3.8 [2.2, 9.4] months; CTCL, 7.3 [3.2, not estimable (NE)] months; PTCL, 2.6 [1.4, NE] months; T-PLL, 0.5 [NE, NE] months; MM, 2.4 [1.4, NE] months;). Median OS was 10.3 (95% CI: 2.2, NE) months for PTCL, 5.6 (95% CI: NE, NE) months for T-PLL and not estimable for HL, CTCL and MM.
Conclusions
Results from expansion cohorts further demonstrate that tinostamustine has manageable tolerability in patients with advanced haematological malignancies with no unexpected AEs. The principal TEAEs were haematological and gastrointestinal. An ORR of 30.4% and a median progression-free survival of 4.3 months were observed, revealing signals of efficacy in this heavily pre-treated patient population for whom no other standard therapy with proven clinical benefit was available or recommended.
Funding: Mundipharma Research Limited and Purdue Pharma, LP