OMX-0407 in Treatment of Angiosarcoma

0 1 2 3 4 5 6 7 8 9 10 mg BID (n=1) 30 mg BID (n=2) 60 mg BID (n=4) 90 mg BID (n=7) 100 mg BID (n=4) 140 mg BID Sub-cohort A (n=3) 140 mg BID Sub-cohort B (n=3) N=24 Fatigue Vomiting Anemia Nausea Decreased appetite Diarrhea Skin and subcutaneous tissue disorders • OMX-0407, an orally available spectrum-selective kinase inhibitor that targets key oncology-relevant tyrosine kinases and salt-inducible kinases, is being developed as a first-in-class treatment for solid tumor indications with high unmet medical need, such as squamous NSCLC, urothelial bladder cancer, RCC and AS. • OMX-0407 has demonstrated a dual mode of action by directly inducing cell cycle arrest in tumor cells (through potent inhibition of downstream signaling cascades necessary for cancer cell proliferation; Figure 1) and sensitizing the tumor environment to immune cell-mediated tumor cell killing.1 • Treatment with OMX-0407 in experimental animals has shown dose-responsive, de-phosphorylation, single-agent efficacy in multiple tumor types. Ex vivo analyses showed a dose-responsive, de-phosphorylation of SFKs associated with cell proliferation and cell cycle proteins. Furthermore, the anti-tumor activity of OMX-0407 has been evaluated in an in vivo PDX model of human AS, derived from a 9-year-old female diagnosed with epithelioid AS. OMX-0407 demonstrated dose-dependent efficacy in the PDX model, with significant tumor growth inhibition at both doses tested (25 mg/kg and 50 mg/kg), resulting also in intra-tumoral de-phosphorylation of SFKs. • Functional kinase activity analysis demonstrated dose-dependent downregulation of several SFK-specific phosphorylation sites associated with cancer cell proliferation and regulation of the tumor cell cycle. OMX-0407-mediated pharmacodynamic modulation of Src phosphorylation site pSFK-Y530 was confirmed by Simple Western analysis.2 • Here, we report findings from the dose-escalation part of a Phase 1a/1b study. OMX-0407: A novel spectrum-selective small molecule kinase inhibitor is active in the treatment of angiosarcoma • In our study, OMX-0407, a potent and spectrum-selective kinase inhibitor, was well tolerated and demonstrated anti-tumor activity, with one patient with AS achieving a durable complete response. • Our preclinical findings support inhibition of tumor cell proliferation by OMX-0407 as a highly relevant mode of action, with significant impact on AS in an in vivo model. • OMX-0407 will be further evaluated clinically in the dose-expansion Phase 1b part of this study in all subtypes of AS, as well as other indications preclinically identified as sensitive to OMX-0407. Steven M. Yule1, Valentina Boni2, Tiantom Jarutat1, Ilona-Petra Maser1, Marisa Stebegg-Wagner1, Stefan Bissinger1, Emiliano Calvo3, Omar Saavedra4, Victor Moreno5, Filomena Mazzeo6, Nadia Hindi7, Hannes Loferer1 CTOS 2024 Authors and affiliations 1 iOmx Therapeutics AG, Martinsried/Munich, Germany; 2 NEXT Oncology, Universitary Hospital Quironsalud, Madrid, Spain; 3 START Madrid-HM CIOCC, Madrid, Spain; 4 NEXT Oncology, Barcelona, Spain; 5 START Madrid-FJD, Madrid, Spain; 6 Saint-Luc UCLouvain, Brussels, Belgium; 7 Fundación Jimenez Díaz University Hospital, Madrid, Spain Background Conclusions M G1 S G2 Results Baseline Characteristics • At data cutoff (30 Oct 2024) for the total safety population, mean age was 60.79 years and half of the enrolled participants were female (Table 1). Abbreviations AE, adverse event; AS, angiosarcoma; BID, twice daily; CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group Performance status; MTD, maximum tolerated dose; NA, not applicable; NC, not calculated; NSCLC, non-small cell lung cancer; RCC, renal cell carcinoma; PDX, patient-derived xenograft; RECIST, Response Evaluation Criteria in Solid Tumours; SD, standard deviation; SFK, Src family kinase; TRAE, treatment-related adverse event; UC, urothelial cancer. Acknowledgments This study was funded by iOmx Therapeutics. The authors would like to thank the patients and their families/carers for participating in this ongoing study. Editorial assistance was provided by Jaya Shumoogam at Cancer Communications & Consultancy Ltd (part of Bioscript Group, Macclesfield, UK), funded by iOmx Therapeutics. Study contact: Tiantom (Dom) Jarutat ([email protected]). Safety • Treatment was well tolerated: TRAEs were mild to moderate, with the most common being gastrointestinal in nature (Figure 5); only 1 Grade ≥3 TRAE of anemia was reported in 1 patient at the 140 mg BID dose in sub-cohort A. • Dose-limiting toxicities: One case of facial swelling secondary to drug allergy at the 90 mg BID dose, and one case of fatigue at the 140 mg BID dose in sub-cohort B. 10 mg BID (n=1) 30 mg BID (n=2) 60 mg BID (n=4) 90 mg BID (n=7) 100 mg BID (n=4) 140 mg BID Total (N=24)Sub-cohort A (n=3) Sub-cohort B (n=3) Age (years) Mean (SD) 95% CI 70.00 (NC) NA 70.50 (2.121) 51.44, 89.56 53.25 (9.777) 37.69, 68.81 59.57 (15.884) 44.88, 74.26 55.25 (24.240) 16.68, 93.82 67.33 (7.095) 49.71, 84.96 65.00 (9.000) 42.64, 87.36 60.79 (14.213) 54.79, 66.79 Sex Female (n, %) 1 (100) 2 (100) 3 (75) 2 (28.6) 2 (50) 1 (33.3) 1 (33.3) 12 (50) Table 1. Baseline patient characteristics Figure 5. Grades 1–2 TRAEs occurring in >10% of patients (safety population) Abstract ID: 1863100 Figure 1. OMX-0407 targets oncology-relevant tyrosine kinases, namely SFK, which are associated with cell proliferation and cell cycle proteins References 1. Maser IP , et al. OMX-0407, a spectrum selective kinase inhibitor shows preclinical and clinical efficacy in Angiosarcoma, an indication of high unmet medical need. Poster presented at the 36th EORTC-NCI-AACR Symposium, October 2024, Barcelona, Spain; 2. A Study of OMX-0407 in Patients With Previously Treated Solid Tumours That Can't be Removed Surgically (NCT05826600). Available at https://clinicaltrials.gov/study/NCT05826600?term=OMX-0407&rank=1 (last accessed November 2024). Figure 4. Patient with secondary cutaneous AS resistant to previous chemotherapy (doxorubicin, cyclophosphamide, paclitaxel) treated with OMX-0407. A) Baseline. B) Cycle 2/Day 1: Dose escalation from 10 mg to 30 mg/BID. C) Cycle 4/Day 1: 30 mg/BID dose. D) Cycle 10/Day 1: 60 mg/BID dose (since C9D1) A B C D Response • One patient with secondary radiation-induced metastatic cutaneous AS (Figure 4), treated at doses of 10 to 60 mg BID, achieved a complete response at 30 mg BID: o This was ongoing at the time of data cut, with a current duration of response of 16 months. o The patient had received previous chemotherapy with doxorubicin, cyclophosphamide and paclitaxel. OMX-0407 Shows Anti-Tumor Efficacy in Human AS PDX Model • OMX-0407 exhibits dose-dependent anti-tumor efficacy in a human AS PDX model from a 9-year-old female with epithelioid AS, as a single-agent (Figure 2A). • OMX-0407 therapy in AS PDX tumors results in intra-tumoral de-phosphorylation of SFKs, as seen in protein expression levels of pSFK Y530 (Figure 2B), but also in a functional kinase activity screen, where all SFK-specific phosphorylation sites were dose-dependently downregulated upon treatment with OMX-0407 (Figure 2C). Figure 2. A) Human AS PDX tumor fragments were transplanted into immunodeficient NOG mice, randomized at an average tumor volume of ~150 mm³. Tumor-bearing mice were treated twice daily with OMX-0407 (25 mg/kg or 50 mg/kg) or vehicle control via oral gavage. Average tumor growth is presented as mean ± SEM for six mice per group. Statistical analysis was performed using one-way ANOVA with Tukey's multiple comparison test. B) Semiquantitative analysis of phospho-SFK-Y530 in AS PDX tumors (sampled on the day of necropsy, 26 days after therapy initiation) after Simple Western, normalized to vehicle control-treated animals. C) Log fold change of all significant downregulated SFK phosphosites in tumor lysates of OMX-0407 treated animals relative to vehicle control. Incidence of TRAEs (number of patients) • In this Phase 1a/1b dose-escalation and dose-expansion study (NCT05826600), patients received continuous treatment with OMX-0407 administered in 28-day cycles (10 mg, 30 mg, 60 mg, 90 mg, 100mg and 140 mg BID doses; Figure 3). • Key inclusion criteria: Patients were required to have previously treated unresectable solid tumors (at least one previous line of therapy), ECOG PS of 0 to 2, and tumors evaluable by RECIST 1.1 criteria. • Primary outcomes were incidence of dose-limiting toxicities (at each dose level) in the dose-escalation (Phase 1a part) and objective response rate with OMX-0407 in patients with RCC, NSCLC, UC and AS in the dose expansion (Phase 1b part); secondary outcomes included MTD and recommended dose for Phase 2 based on toxicities, pharmacokinetics, duration of response and progression-free survival. • The dose-escalation part utilized a 3+3 design to characterize the safety profile of OMX-0407 and determine the MTD. Study design2 Patients with unselected tumor types who received previous systemic therapy (N=24) Figure 3. Study cohort schema 10 mg BID dose (n=1) 30 mg BID dose (n=2) 60 mg BID dose (n=4) 90 mg BID dose (n=7) 140 mg BID dose (n=6) 100 mg BID dose (n=4) Expansion A B C -80 -60 -40 -20 0 20 SFK phosphosite Y530 % C h a n g e o f p S F K -Y 5 3 0 r e l. to c tr l. Vehicle ctrl. 25 mg/kg OMX-0407 50 mg/kg OMX-0407 -5 -4 -3 -2 -1 0 SFK phosphosites L o g fo ld c h a n g e r e l. to c t r l. 25mg/kg OMX-0407 50mg/kg OMX-0407

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