SB221: A proof-of-concept study to assess the combination of SON-1010 (IL12-FHAB) and atezolizumab in patients with platinum-resistant ovarian cancer.

person Sant P. Chawla Sarcoma Oncology Center, Santa Monica, CA info_outline Sant P. Chawla, Bo Gao, Carolyn L. Bampton, Brett Hamilton, John K. Cini, Susan Dexter, Richard T. Kenney, Robert Michael Wenham

Authors person Sant P. Chawla Sarcoma Oncology Center, Santa Monica, CA info_outline Sant P. Chawla, Bo Gao, Carolyn L. Bampton, Brett Hamilton, John K. Cini, Susan Dexter, Richard T. Kenney, Robert Michael Wenham Organizations Sarcoma Oncology Center, Santa Monica, CA, Blacktown Cancer and Hematology Centre, Blacktown, NSW, Australia, Ashford Cancer Centre Research, Adelaide, Australia, Albury Wodonga Cancer Care, West Albury, Australia, Sonnet Biotherapeutics, Princeton, NJ, Sonnet BioTherapeutics, Princeton, NJ, Department of Gynecologic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL Abstract Disclosures Research Funding Sonnet BioTherapeutics Background: Recombinant interleukins (rIL) have had limited clinical success due to inefficient tumor targeting and short PK, requiring frequent dosing that leads to aberrant immunostimulation and toxicity. IL-12 potently activates T and NK cells to produce IFNγ and kill tumor cells, yet dosing strategies have failed to provide adequate therapeutic benefit in humans. We developed a novel platform that delivers immunomodulator(s) linked to a fully-human albumin binding (F H AB) domain (Cini, Front Immunol 2023). Single-chain native IL-12 genetically linked to the F H AB provides enhanced tumor targeting and retention through albumin binding to over-expressed FcRn, GP60, and SPARC in the tumor microenvironment (TME), with an improved PK profile, a dose-sparing effect that decreases the toxicity risk, and a broader therapeutic index. Tumor growth inhibition in an immunologically ‘cold’ B16-F10 mouse melanoma model showed the efficacy of IL12-F H AB compared with rIL-12, resulting in significant increases in activated NK, NKT, Th1, and cytotoxic CD8 T cells. SON-1010 is being studied clinically as monotherapy (study SB101) in advanced solid tumors and in healthy volunteers (study SB102) (Chawla, AACR 2023). Atezolizumab (Tecentriq), an anti-PD-L1 immune checkpoint inhibitor (ICI), has shown preliminary clinical activity in Phase 1 studies of patients with platinum-resistant ovarian cancer (PROC) (Liu, Gyn Onc 2019; Moroney, Clin Canc Res 2020). SON-1010 may ‘warm up’ the TME to improve ICI effectiveness in these immunologically-active tumors that have high levels of SPARC. Methods: Study SB221 is a Phase 1b/2a multicenter, dose-escalation and proof-of-concept study to assess the safety, tolerability, PK, PD, and efficacy of SON-1010 administered SC, either alone or in combination with a fixed dose of atezolizumab given IV (NCT05756907). The study is designed in Part 1 to rapidly establish the maximum tolerated dose (MTD) of the combination in patients with advanced solid tumors with up to 5 dose-escalation groups and to expand the dataset using patients with PROC to establish the Recommended Phase 2 Dose (RP2D). Once the likelihood of efficacy is shown in a Simon 2-stage design, this will be followed in Part 2 by an assessment of the potential for improved efficacy of the combination in patients with PROC over SON-1010 alone or the standard of care (SOC). The first dose-escalation cohorts have been enrolled and additional sites are being added to help with recruitment of patients with PROC. Combination of SON-1010 with an ICI offers a unique opportunity to use this extended PK version of IL-12 to augment the potential for tumor control in PROC, which represents a significant unmet medical need. Clinical trial information: NCT05756907.

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