Background: MYC has a key role in driving and maintaining human tumors. However, MYC has long been perceived as an “undruggable” target and, to date, there is still no MYC inhibitor approved for clinical use. Omomyc is a MYC dominant negative mini-protein, previously used to inhibit MYC function both in vitro and in vivo, demonstrating a potent therapeutic impact in various mouse models of cancer. Here we present the dose escalation results of a Phase 1 study testing OMO-103, an Omomyc-based mini-protein developed by Peptomyc S.L.
Material and Methods: Phase I dose escalation study used the conventional 3 + 3 design, with 6 dose levels ranging from 0.48 to 9.72 mg/kg, as a weekly 30-min i.v. infusion. The primary objectives were safety and tolerability, while secondary ones were preliminary efficacy according to RECIST 1.1, PK and RP2D. Tumor biopsies were collected at screening and at the end of the dose limiting toxicity (DLT) period (3 weeks) to assess MYC-levels, Ki67, CC3 and transcriptomics, among other indicators.
Results: 22 patients with advanced solid tumors were included. 50% women and men, pts had a range of 3–13 prior treatment lines. ECOG 0 and 1 were equally distributed. The most common treatment related adverse events (TRAE) were mainly grade 1 infusion related reactions (IRR) like chills, fever, nausea, rash, hypotension. 58 TRAEs (80.5%) were grade 1, 12 (16.6%) grade 2 and 1 (1.4%) grade 3. Higher dose levels were associated with more IRRs but easily treated with (pre)medication. 1 DLT was observed: grade 2 pancreatitis (DL 5). 18 SAE, only one considered related. At the time of data cut-off (June22) 4 patients where non evaluable for response. 7 patients achieved SD. 2 pts with PDAC, 2 CRC, 1 NSCLC, 1 Sarcoma, 1 Salivary Gland Carcinoma. Remarkably, 1 PDAC patient stayed in the study for more than 6 months with tumor shrinkage of 8% of target lesions and a reduction of ctDNA. A sarcoma patient was on treatment for more than 7 months and the salivary gland carcinoma patient is still ongoing after 11 months.
The PK analysis revealed a plasma half-life of approximately 50 h. No ADAs were detected in any of the patients, even after long term treatment. Drug activity is supported by a strong association of stable disease with a distinctive dose-dependent cytokine signature. Moreover, patients responding to the drug display modulation of the bona fide MYC target CD47 as well as of anti-tumor immune related markers such as calprotectin and OX-40. Further intratumoral PK data and target engagement evidence will be presented.
Conclusion: OMO-103 demonstrates a favorable safety profile, with early signs of activity that merit further investigation. RP2D has been determined to be DL5 with 6.48 mg/kg. Dose expansion cohorts (Phase 2a) are already planned.
Conflict of interest:
Ownership: M. Niewel: Peptomyc S.L. L. Soucek: Peptomyc S.L. E.Calvo: START and OnCoart Associated.
Advisory Board: E.Garralda has Consulting fees from: Roche/Genentech - F. Hoffmann/La Roche, Ellipses Pharma, Neomed Therapeutics1 Inc, Boehringer Ingelheim, Janssen Global Services, SeaGen, Alkermes, Thermo Fisher, Bristol-Mayers Squibb, MabDiscovery, Anaveon, F-Star Therapeutics, Hengrui, Lilly and Novartis. V.Moreno from: Roche, Bayer, BMS, Janssen and Basilea. E.Calvo from: Nanobiotix, anssen-Cilag, Roche/ Genentech, TargImmune Therapeutics, Servier, Bristol-Myers Squibb, Amunix, Adcendo, Anaveon, AstraZeneca/MedImmune, Chugai Pharma, MonTa, MSD Oncology, Nouscom, Novartis, OncoDNA, T-Knife, Elevation Oncology, PharmaMar, Ellipses Pharma.
Board of Directors: E.Calvo: START, PharmaMar, EORTC, Sanofi, BeiGene, Novartis.
Corporate-sponsored Research: E.Garralda has institutional research funding from: Novartis/Roche/Thermo Fisher/AstraZeneca/Taiho/BeiGene. E.Calvo has personal research funding from: START.
Other Substantive Relationships: PI or Co-PI, institutional. E.Garralda: Novartis/Roche/Thermo Fisher/AstraZeneca/Taiho/BeiGene. V.Moreno: AbbVie, AceaBio, Adaptimmune, ADC Therapeutics, Aduro, Agenus, Amcure, Amgen, Astellas, AstraZeneca Bayer Beigene BioInvent International AB, BMS, Boehringer, Boheringer, Boston, Celgene, Daichii Sankyo, DEBIOPHARM, Eisai, e-Terapeutics, Exelisis, Forma Therapeutics, Genmab, GSK, Harpoon, Hutchison, Immutep, Incyte, Inovio, Iovance, Janssen, Kyowa Kirin, Lilly, Loxo, MedSir, Menarini, Merck, Merus, Millennium, MSD, Nanobiotix, Nektar, Novartis, Odonate Therapeutics, Pfizer, Pharma Mar, PharmaMar, Principia, PsiOxus, Puma, Regeneron, Rigontec, Roche, Sanofi, Sierra Oncology, Synthon, Taiho, Takeda, Tesaro, Transgene, Turning Point Therapeutics, Upshersmith.