Maliakal, Pius

AbstractUnesbulin is being investigated in combination with dacarbazine (DTIC) as a potential therapeutic agent in patients with advanced leiomyosarcoma (LMS). This paper reports the pharmacokinetics (PK) of unesbulin, DTIC, and its unreactive surrogate metabolite 5‐aminoimidazole‐4‐carboxamide (AIC) in 29 patients with advanced LMS. Drug interactions between DTIC (and AIC) and unesbulin were evaluated. DTIC (1000 mg/m2) was administered to patients with LMS via 1‐h intravenous (i.v.) infusion on day 1 of every 21‐day (q21d) cycle. Unesbulin dispersible tablets were administered orally twice weekly (b.i.w.), starting on day 2 of every cycle, except for cycle 2 (C2), where unesbulin was dosed either on day 1 together with DTIC or on day 2, 1 day after DTIC administration. The PK of DTIC, AIC, and unesbulin in cycle 1 (C1) and C2 were estimated using noncompartmental analysis. DTIC and AIC were measurable immediately after the start of infusion and reached maximum plasma concentration (Cmax) immediately or shortly after end of infusion at 1.0 and 1.4 h (time to Cmax), respectively. Co‐administration of unesbulin orally at 200 mg or above with DTIC inhibited cytochrome P450 (CYP)1A2‐mediated DTIC metabolism, resulting in 66.7% reduction of AIC exposures. Such inhibition could be mitigated when unesbulin was dosed the day following DTIC infusion. Repeated unesbulin dosing demonstrated evidence of clinical CYP1A2 induction and increased AIC Cmax by 69.4% and area under concentration‐time curve to infinity by 57.9%. No meaningful difference in unesbulin PK was observed between C2 and C1. The combination therapy of 1000 mg/m2 i.v. DTIC q21d and 300 mg unesbulin b.i.w. in a staggered regimen is well‐tolerated in patients with LMS.

11507 Background: Leiomyosarcoma (LMS) is one of the most common subtypes of soft tissue sarcoma and is associated with high risk of relapse and a poor prognosis for advanced disease. In preclinical LMS models, unesbulin, a microtubule polymerization inhibitor, potentiated the activity of dacarbazine (DTIC) (Jernigan F, et al. Mol Cancer Ther. 2021;20:1846–1857). Here, we report preliminary safety and efficacy results from a Phase 1b dose escalation study evaluating the combination of unesbulin with DTIC in patients with advanced LMS (NCT03761095). Methods: In this single-arm, open-label, Phase 1b clinical trial, patients with advanced LMS received unesbulin orally at 200, 300, or 400 mg twice weekly (BIW) in combination with intravenous DTIC at 1,000 mg/m2 once every 21 days. The primary objectives were to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of unesbulin in combination with DTIC and to characterize the safety profile of the combination. The time-to-event continual reassessment model (TITE-CRM) was used for dose finding. An expansion cohort with up to 12 additional patients is currently being enrolled. Results: As of the data cutoff on January 6, 2022, 29 LMS patients have been treated. Median prior lines of therapy were 3 (range 1–6). Of 27 evaluable patients, 12 had non-uterine and 15 had uterine LMS. The MTD/RP2D of unesbulin was determined to be 300 mg BIW with DTIC 1,000 mg/m2 every 21 days using the TITE-CRM. At the RP2D, the most common treatment-related adverse events included fatigue, diarrhea, neutropenia, and thrombocytopenia. In the intent-to-treat population, the overall response rate (ORR) was 17.2% (5/29) and the disease control rate (DCR) (DCR = complete response + partial response + stable disease at 12 weeks) was 58.6%. At the 300 mg dose level, the ORR was 19% (4/21) and the DCR was 57.1%. Patients received a median of four cycles (range 1–12). The study is ongoing, with patients continuing to receive treatment. Conclusions: Unesbulin 300 mg BIW in combination with DTIC 1,000 mg/m2 every 21 days was well tolerated and demonstrated promising efficacy in a heavily pre-treated patient population with advanced LMS; these results support further investigation. Updated clinical results will be presented as the data mature. A randomized, placebo-controlled, Phase 2/3 trial is planned. Clinical trial information: NCT03761095.