A phase II study of tinostamustine in patients (pts) with advanced solid tumours.
Authors: Tinker Anna , Strauss James Fredric , Schneider Reva , Chugh Rashmi , Curigliano Giuseppe , Di Nicola Massimo A. , Oaknin Ana , Janik Tomas , Hilgier Kasia , Manamley Nick , Kummar Shivaani 
Published: June 2023

3021 Background: The novel multi-action alkylating deacetylase inhibitor tinostamustine improves drug access to DNA strands within cancer cells, breaks them and counteracts damage repair. Tinostamustine was well tolerated with signals of efficacy during dose escalation in pts with advanced solid tumours (Mita et al. Cancer Res 2019;79[13 Suppl]:CT023). Methods: This was an open-label Phase I/II trial of single agent tinostamustine in pts with advanced solid tumours (NCT03345485). The Phase II primary endpoint was objective response rate (ORR: complete response + partial response [PR]) and the rate of stable disease ≥4 mo duration following the recommended Phase II dose (RP2D; 80 mg/m2 over 1 h on Day 1 & 15 of each 4-wk treatment cycle). Secondary endpoints included progression-free (PFS) and overall survival (OS), and duration of response. Eligible pts were ≥18 y with life expectancy ≥3 mo, Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤2, histologically confirmed diagnosis of advanced/metastatic soft tissue sarcoma (STS), small-cell lung (SCLC), triple-negative breast (TNBC), ovarian (OvCa) or endometrial cancer, progression following ≥1 prior line of therapy, with no other standard therapy with proven clinical benefit available or recommended. Results: 36 pts were enrolled and evaluable for response; mean ± SD age 59.6 ± 11.2 y, 83.3% female, 80.6% Caucasian, all ECOG PS ≤1, median of 3 (range 1–9) lines of prior therapy. At data cut-off (30 November 2022) pts had received a median of 2 (range 1–8) cycles of tinostamustine. 19 pts (52.8%) discontinued treatment due to progressive disease. One pt with synovial sarcoma (STS cohort; n=10) and one pt with OvCa (n=12) achieved a PR. Overall, 14 pts (38.9%) had stable disease ≥4 mo (0/4 SCLC; 3/10 STS; 3/4 TNBC; 5/12 OvCa; 3/6 endometrial cancer); Clinical Benefit Rate, 44.4% (95% CI: 27.9%, 61.9%). Median PFS and OS for all treated pts were 2.2 mo (95% CI 1.8, 3.3 mo) and 5.5 mo (95% CI 4.1, 15.0 mo), respectively. All pts experienced ≥1 treatment-emergent adverse event (TEAE), with 56.7% of events considered related to tinostamustine. Serious tinostamustine-related AEs were reported in 30.6% of pts (13 haematological events); 10 (27.8%) pts discontinued treatment due to TEAEs (platelet count decreased: 5 events in 3 pts, including 2 Grade 3 and 1 Grade 4; all other events n=1). Two pts experienced fatal TEAEs; n=1 each of intra-abdominal haemorrhage (considered related to study drug), hypoxia/dyspnoea (not study drug related). Conclusions: Tinostamustine demonstrated modest signals of efficacy, with 2 pts achieving a PR, and manageable tolerability in pts with advanced solid tumours for whom no other standard therapy with proven clinical benefit was available or recommended. Further studies are needed to fully explore the benefits of tinostamustine in solid tumours. Clinical trial information: NCT03345485 .