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Abstract
Background OR502 blocks LILRB2 binding to HLA-class I proteins and prevents LILRB2-mediated immune suppression by myeloid cells. It potentiates Th1-like innate immune responses, rescues T-cells from M2c macrophage-mediated immune suppression and restores T-cell proliferation and effector functions. OR502 reduces and prevents immunosuppressive phenotype of existing and new tumor-associated macrophages (TAMs) and amplifies anti-PD-1 activity in M2c/T-cell coculture. By targeting TAMs, OR502 showed preclinical activity as monotherapy and in combination with cemiplimab.1
FDA’s draft guidance on dose optimization (Project Optimus2) has made the Phase 1–2 development of novel immunotherapies like OR502 more challenging, requiring demonstration of dose-response, and identifying the minimal effective dose prior to later-phase trials.
Methods We designed the OR502-101 study to address standard Phase 1 objectives and the new objectives of Project Optimus (figure 1), including expansion cohorts at different doses (NCT06090266). The monotherapy and combination dose escalations used a modified toxicity probability interval-2 design targeting a dose-limiting toxicity (DLT) rate of 25% with an equivalence interval of 20–30%. The DLT definition included most Grade ≥3 hematological or non-hematological toxicities, with standard exceptions.
As Phase 1 neared completion at the highest dose, we realized we lacked data in the tumor types planned for Part B expansion, but we had observed early signals in other tumor types. It also became clear from further FDA interactions that we should first demonstrate objective efficacy rather than pharmacodynamic signals before exploring dose-response in the indication(s) with demonstrated efficacy. Although we had not anticipated this specific scenario, the protocol’s adaptive elements (table 1) provided flexibility to modify the study design without amendment and with Safety Committee oversight. The adaptive design also allowed expansions at different doses, providing valuable additional pharmacokinetic (PK) data.
Results We immediately transitioned into two mini-expansion cohorts (cutaneous melanoma and non-small cell lung cancer) likely to confirm early efficacy signals prior to further dose-response optimization.
Conclusions Adaptive elements are an important design feature of the modern Phase 1 trial, permitting flexibility (with oversight) to execute efficient Phase 1–2 development in immune oncology (IO) without undue delays. Consequently, development of OR502, a novel IO agent, has been particularly rapid in a changing regulatory environment, accelerating a potentially effective new drug towards approval.
Trial Registration NCT06090266.
References
Bouchlaka M, Zuck M, Dinh N, et al. OR502, a best-in-class anti-LILRB2 antibody that enhances both innate and adaptive anti-tumor immune responses. J Immunother Cancer 2023;11(Suppl 1):A556.
Optimizing the dosage of human prescription drugs and biological products for the treatment of oncologic diseases. Draft FDA Guidance for Industry, January 2023.
Original design and modifications using adaptive elements
Adaptive elements providing flexibility in Phase 1–2 design
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