1934P - Pharmacokinetics of unesbulin in a phase Ib study of patients with advanced leiomyosarcoma

Background

Patients with metastatic or unresectable leiomyosarcoma (LMS) have a poor prognosis and a high risk of relapse with limited therapeutic options. In a phase 1b dose escalation study, unesbulin, an oral microtubule polymerization inhibitor, plus dacarbazine (DTIC), showed promising efficacy and tolerability in patients with advanced LMS. Here we report the results of drug-drug interactions (DDI) and the impact of food on the PK of unesbulin (NCT03761095).

Methods

This analysis evaluated the PK of unesbulin 300 mg in patients with advanced LMS. The DDI was investigated by staggering or coadministering unesbulin with DTIC. For the food effect assessment (FEA), patients received DTIC 1000 mg/m² on Day 1 and unesbulin 300 mg twice weekly starting Day 2 of every cycle (21 day/cycle schedule). Unesbulin was administered under fasted conditions on Day 2 and under fed conditions (low-fat diet) on Day 5. Blood samples for the FEA were collected at predose and up to 72 hours postdose.

Results

When DTIC was coadministered with unesbulin, the C_max, and AUC_0-24h of 5-aminoimidazole-4-carboxamide (an inactive metabolite of DTIC) were reduced by 77.4% and 61.7%, respectively. No apparent difference was observed in mean unesbulin exposure when administered with or without food, but the inter-subject variability (CV%) reduced significantly from 42% - 59% under fasted condition to 19% - 29% with a low-fat diet. Table: 1934P

^∗Reported as median (minimum-maximum); ^†Reported as mean (CV%).

Conclusions

The DDI evaluation showed that CYP1A2-mediated inhibition of DTIC metabolism can be mitigated by staggering unesbulin and DTIC doses by one day. Results showed no clinically meaningful difference in mean unesbulin exposures when administered with or without food. However, administering unesbulin with a low-fat diet is recommended as it reduces the inter-subject variability. Unesbulin is being evaluated in an ongoing randomized, placebo-controlled, phase 2/3 trial, SUNRISELMS (NCT05269355).

Clinical trial identification

NCT03761095.

Editorial acknowledgement

Medical writing assistance, supported financially by PTC Therapeutics, Inc., was provided by Ilaria Esposito, PhD (Lighthouse Medical Communications).

Legal entity responsible for the study

PTC Therapeutics.

Funding

PTC Therapeutics.

Disclosure

B.A. Van Tine: Financial Interests, Personal, Other, Licenses/Patent: Sigma-2 Receptor Ligands and Therapeutic uses therefor (006766): Accuronix Therapeutics: Financial Interests, Personal, Other, Licenses/Patent: Modular Platform for Targeted Therapeutic Delivery (006755): Accuronix Therapeutics: Financial Interests, Personal, Other, Licenses/Patent: Conjugates as Antitumor Compounds, Methods of synthesis and Uses Thereof (014229): Accuronix Therapeutics; Financial Interests, Personal, Other, Consulting. Also attended advisory board (travel included): Epizyme; Financial Interests, Personal, Other, Consulting: ADRx working on a cancer project and they are requesting my expertise.: ADRx; Financial Interests, Personal, Advisory Board, This was a 7 day contract about tenosynovial giant cell tumors (TGCT). They evaluating a new investigational drug to license into Ayala for the treatment of TGCT and wish to talk to a KOL about the current treatment options, to better understand if there is an unmet need for another drug on the market (in addition to pexidartinib): Ayala Pharmaceuticals; Financial Interests, Personal, Advisory Role, Consulting/Advisor (2020) exp. 7/23: Cytokinetics Inc; Financial Interests, Personal, Other, Consulting and Ad Board: Bayer; Financial Interests, Personal, Advisory Board, Attended an Advisory Board Meeting (2021) : Deciphera Pharmaceuticals; Financial Interests, Personal, Other, Extended the consulting relationship 9/2022. GIST Expert Interview Project: Deciphera Pharmaceuticals; Financial Interests, Personal, Other, Consulting: Daiichi Sankyo Inc., Advenchen, Putnam, Salarius Pharmaceuticals, Inc., Boxer Capital LLC, Acuta Capital Partners, LLC Acuta Capital Partners, LLC, Aadi; Financial Interests, Personal, Advisory Board, Attended an Advisory Board Meeting: Daiichi Sankyo Inc.; Financial Interests, Personal, Officer, Consulting: EcoR1; Financial Interests, Personal, Invited Speaker, Educational Speaker: Targeted Oncology; Financial Interests, Personal, Advisory Board, Attended Advisory Board Meeting. Travel paid to conference to present abstract (2019) Paying for travel to present abstract: Adaptimmune; Financial Interests, Personal, Speaker, Consultant, Advisor, 45 minute telephone interview about an early stage compound, tegavivant, being explored for the treatment of osteosarcoma: Iterion Therapeutics, Inc.; Financial Interests, Personal, Other, OncLive Virtual Workshop: Intellisphere LLC; Financial Interests, Personal, Other, 2023 West Oncology talk-Memphis: Total Health Conference; Financial Interests, Personal, Advisory Board, Attended a Virtual Advisory Board Meeting (: Apexigen Inc; Financial Interests, Personal, Advisory Board, Attended Ad Board: PTC Therapeutics; Financial Interests, Personal, Advisory Board: Aadi Biosciences, Boehringer Ingelheim, Regeneron Pharmaceuticals, Curis; Non-Financial Interests, Personal, Advisory Board, Ad Board (not paid): EcoR1 Capital, LLC; Non-Financial Interests, Personal, Member of Board of Directors, Non-paid: Polaris; Financial Interests, Institutional, Research Grant: GSK, Merck, Pfizer, Tracon Pharm. M.A. Ingham: Financial Interests, Personal, Stocks or ownership: Regeneron; Financial Interests, Personal, Speaker, Consultant, Advisor: Daiichi Sankyo, Xencor, Apexigen, Epizyme, Caris Life Sciences; Financial Interests, Personal, Research Funding: APIM Therapeutics Apexigen; Financial Interests, Institutional, Research Funding: Apexigen, Mirati Therapeutics, PTC Therapeutics, Intensity, Boehringer Institution, Bioatla, Merck, Astellas Pharma, AstraZeneca; Other, Personal, Full or part-time Employment: Regeneron. S. Attia: Financial Interests, Personal, Research Funding: Desmoid Tumor Research Foundation; Financial Interests, Institutional, Research Funding: AB Science, Tracon Pharma, Bayer, Novartis, Lilly, Karyopharm Therapeutics, Epizyme, Blueprint Medicines, Genmab, CBA Pharma, Merck, Philogen, Gradalis, Deciphera, Takeda, Incyte, Springworks, Adaptimmune, Advenchen Laboratories, Bavarian Nordic, BTG, PTC Therapeutics, GSK, Forma Therapeutics, Tracon Pharma, Ayala Pharmaceuticals, Trillium Therapeutics, Boehringer Ingelheim, Salarius Pharmaceuticals, Theseus Pharmaceuticals, Monopar Therapeutics, C4 Therapeutics, InhibRx, Noxopharm, Rain Therapeutics. C.F. Meyer: Financial Interests, Personal, Speaker, Consultant, Advisor: Deciphera, BioAtla, Adaptimmune; Financial Interests, Personal, Licencing Fees or royalty for IP: UpToDate. J.D. Baird: Financial Interests, Personal, Full or part-time Employment: PTC Therapeutics, Inc.; Financial Interests, Personal, Stocks or ownership: PTC Therapeutics, Inc.; Financial Interests, Personal, Licencing Fees or royalty for IP: PTC Therapeutics, Inc.. D. D'Silva, K. O'Keefe, R. Kong, P. Maliakal, L. Gao: Financial Interests, Personal, Full or part-time Employment: PTC Therapeutics, Inc.; Financial Interests, Personal, Stocks or ownership: PTC Therapeutics, Inc. G.K. Schwartz: Financial Interests, Personal, Stocks or ownership: Bionaut Labs, GenCirq, January Therapeutics; Financial Interests, Personal, Speaker, Consultant, Advisor: AADi, Agenus, Apexigen, Array BioPharma, Astex Pharmaceuticals, Bionaut Labs, Boehringer Ingelheim, Concarlo, Ellipses Pharma, Epizyme, Gencirq, Ipsen, January Therapeutics, Kirilys Therapeutics, Oncogenuity, OnCusp Therapeutics, PureTech, Sellas Life Sciences, Shanghai Pharma; Financial Interests, Institutional, Research Funding: Adaptimmune, Calithera Biosciences, Daiichi Sankyo, Fortress Biotech, Inctye, Karyopharm Therapeutics, Lilly, Oxford BioTherapeutics, SpringWorks Therapeutics, TopAlliance BioSciences Inc, Tracon Pharma; Financial Interests, Personal and Institutional, Research Funding: Astex Pharmaceuticals.