669P - CBX-12-101: Final results of a phase I study of CBX-12, a peptide drug conjugate (PDC) in patients (pts) with metastatic solid tumors

Background

Tumor-targeted drug delivery technologies are urgently needed to overcome conventional chemotherapy’s lack of tumor selectivity. Alphalex conjugates, which contain a pH-low insertion peptide (pHLIP), a linker and a payload are designed to overcome this lack of selectivity. Alphalex PDCs target tumors in an antigen-independent manner. At pH 7.4, the peptide is unstructured. In the low pH tumor microenvironment the peptide forms an alpha helix and inserts directionally into the tumor cell membrane delivering the linker and payload. For CBX-12 the payload is exatecan.

Methods

In this Phase 1 trial, cohorts of pts were treated with escalating doses of CBX-12 in a 3 + 3 design. The primary objectives are safety, tolerability and to determine the MTD/RP2D. Secondary and exploratory objectives include evaluation of plasma PK of CBX-12 and exatecan, anti-tumor activity per RECIST v1.1, and measurement of anti-drug antibodies.

Results

Enrollment is complete with 69 pts having been treated on study. The most frequent treatment-related AEs (TRAEs) were anaemia (53.6%), leukopenia (42.0%), neutropenia (40.6%), nausea (39.1%), and fatigue (36.2%). The most frequent Gr3/4 TRAEs were neutropenia, (27.5%), anaemia (24.6%), leukopenia (21.7%), and thrombocytopenia (13.0%). No ILD or ophthalmic toxicity was reported. There were 5 confirmed responses in ovarian (2), breast (2), and colorectal cancer (1). Evidence of activity was also seen in NSCLC, cholangiocarcinoma, and thymic cancer. Of 12 patients with ovarian cancer there was one confirmed complete response, one confirmed partial response (PR) and tw0 unconfirmed PRs. 8 of 12 saw clinical benefit. The RP2D was established as 125mg/m² every 21 days.

Conclusions

Tumor targeting facilitated by this pH sensitive peptide made possible an improved safety profile despite the administration of a 5-fold increase in the dose of exatecan compared to unconjugated exatecan. The dose limiting toxicity is myelosuppression. CBX-12 demonstrated broad activity with 5 confirmed responses in three malignancies. A randomized Phase 2 study in platinum resistant ovarian cancer is underway comparing two doses on the once every 21 day schedule.

Clinical trial identification

NCT04902872.

Editorial acknowledgement

Legal entity responsible for the study

Cybrexa Inc.

Funding

Cybrexa Inc.

Disclosure

F. Meric-Bernstam: Financial Interests, Personal and Institutional, Funding: Cybrexa, Inc. P. Pearson: Financial Interests, Personal, Financially compensated role, Consultant: Cybrexa, Inc. M.N. Needle: Financial Interests, Personal, Full or part-time Employment: Cybrexa, Inc. All other authors have declared no conflicts of interest.