A first-in-human phase 1 trial of nx-1607, a first-in-class oral CBL-B inhibitor, in patients with advanced solid tumor malignancies.

Abstract

TPS2691 Background: Casitas B-lineage lymphoma proto-oncogene B (CBL-B) is an E3 ubiquitin ligase expressed in multiple immune cell lineages, which in contrast to cell surface immune checkpoints, acts as a regulator of both T and NK cell activation. Inhibition of CBL-B enhances T-cell response, increases response to suboptimal priming, and restores response in exhausted T cells. Thus CBL-B is a promising immune-oncology target and may overcome challenges seen with other T-cell directed therapies. NX-1607 is an oral small molecule inhibitor of CBL-B that has demonstrated anti-tumor activity and long-term survival in murine models as both a single agent and in combination with programmed cell death protein-1 (PD-1) antibodies. Further, NX-1607 elicits dose-dependent increases in cytokine secretion and proliferation in T-cell receptor-stimulated primary human T cells with enhanced tumor antigen-specific T-cell and NK cell anti-tumor responses. Thus, NX-1607 may be effective as a single agent or it may significantly enhance efficacy of other anti-tumor agents. Methods: NX-1607-101 is a first-in-human, multicenter, open-label, Phase 1 dose escalation and expansion trial evaluating NX-1607 in a variety of indications including platinum-resistant epithelial ovarian cancer (EOC), gastric cancer, squamous cell carcinoma of the head and neck (HNSCC), metastatic melanoma, non-small cell lung cancer (NSCLC), metastatic castration-resistant prostate cancer (mCRPC), malignant pleural mesothelioma (MPM), triple-negative breast cancer (TNBC), locally advanced or metastatic urothelial cancer, cervical cancer, microsatellite stable colorectal cancer (MSS CRC), and diffuse large B-cell lymphoma with Richter transformation (DLBCL-RT). The main objective is to establish the safety and tolerability of NX-1607, characterize PK/PD, and determine the recommended Phase 1b dose. NX-1607 will be given orally once daily at doses ranging from 5 to 100 mg in up to 6 dose levels. Dose escalation will proceed using an accelerated modified Fibonacci dose escalation design that transitions to a standard 3 + 3 design based on protocol-specific criteria. Up to 8 expansion cohorts in Phase 1b will be composed of patients with subsets of advanced cancers. Key eligibility criteria include patients with metastatic or unresectable disease that have progressed after prior therapy and for whom standard therapy with proven clinical benefit does not exist, is no longer effective, or is not appropriate. Prior treatment with immune checkpoint inhibitors or CAR-T cells with washout is allowed, but a history of active autoimmune disease is not. Up to 336 patients (60 in Phase 1a, 276 in Phase 1b using a Simon 2-stage design) will be enrolled at approximately 20 sites in the UK and US and treated until disease progression or unacceptable toxicity. Dose escalation is ongoing. Clinical trial information: NCT05107674.