Abstract CT182: OXC-101 shows favorable safety profile in first in human phase 1 trial in patients with advanced solid cancer
Authors: Yachnin Jeffrey , Ny Lars , Sandvall Teresa , Sanjiv Kumar , Scobie Martin , Platzack Björn , Barancewski Pawel , Breuer Olof , Gorgoulis Vassilis , Pateras Ioannis S. , Klockare Maria , Smith Austin , Berglund Ulrika Warpman , Helleday Thomas 
Published: April 2023

Abstract
Purpose: Many cancers suffer from dysfunctional redox status. MTH1 protects cancer cells from oxidative DNA damage by preventing incorporation of oxidized nucleotides. OXC-101 (Karonudib) is a dual-action mitotic disruptor and MTH1 inhibitor, preventing exit from mitosis and sanitation of oxidative damage to DNA subunits in cancer cells. MASTIFF, (MTH1, A Phase I, Study on Tumors Inhibition, First in Human, First in Class), is a first- in- human phase 1 study, with the primary aim to assess safety, tolerability, and pharmacokinetics (PK) of OXC-101 in patients (pts) with advanced solid malignant tumors (NCT03036228).
Methods: Phase 1a study with 3+3 design and intra-patient dose escalation. New cohorts were opened following review of safety and PK data by the safety data monitoring board after the first treatment cycle of 4 weeks (w). All patients had progressive stage IV disease with no treatment options in SOC at inclusion. Radiological tumor response evaluation (RECIST 1.1) was performed 8w of the first 24w, 12w thereafter. The first 29 patients (cohort 1-10) obtained an oral solution. From cohort 11 pts obtained 100mg tablets.
Results: 50 subjects (50% female, 50% male) were enrolled at 16 dose levels of OXC-101 at varying posology: 25-900 mg BID, 800-1000mg QD; every second day, once or twice weekly. Mean age was 52 years (range:20-74). 92% of pts had received previous chemotherapy (mean: 5 lines, range:0-34), 18% endocrine therapy and 52% other therapies (incl immunotherapy). OXC-101 was generally well tolerated and with manageable toxicity for dose levels for an average of 121 days (range:2-513 days), and 43/50 subjects discontinued due to disease progression. A total of 20 SAEs were reported: 8 SAEs in 7 subjects were considered related/possibly related to OXC-101 and included pneumonia (3/8), febrile neutropenia (2/8), ileus (1/8), unspecified infection (1/8) and fever (1/8). There were 14 dose-limiting toxicities (DLTs) reported in 7 subjects. At 510mg every second day (1785mg weekly) 2/5 subjects reported G4 neutropenia; at 500mg BID/1000mg QD, twice per week (2000 mg weekly) 2/9 subjects reported G4 neutropenia; at 900mg BID, once weekly (1800 mg weekly) 3/3 subjects reported decrease in white blood count incl. neutropenia. PK was robust and predictable with good exposure correlation between solution and tablet formulation, with an average half-life of 10 hrs in plasma. 15/49 (31%) of the subjects showed stable disease at first radiological evaluation. One subject had stable disease during 73 weeks on OXC-101 treatment. IHC and western blot analysis on tumor biopsies confirmed mechanism of action. A dose of 900mg (500mg mane, 400mg nocte) twice a week (total weekly dose 1800mg) was determined as the Recommended Phase 2 Dose (RP2D). This will be further explored in tumor specific cohorts.
Conclusion: OXC-101 has a favorable safety profile with an RP2D of 900mg twice a week.
Citation Format: Jeffrey Yachnin, Lars Ny, Teresa Sandvall, Kumar Sanjiv, Martin Scobie, Björn Platzack, Pawel Barancewski, Olof Breuer, Vassilis Gorgoulis, Ioannis S. Pateras, Maria Klockare, Austin Smith, Ulrika Warpman Berglund, Thomas Helleday. OXC-101 shows favorable safety profile in first in human phase 1 trial in patients with advanced solid cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT182.