Background Despite advances made in management of patients with HER2-driven solid tumors, unmet need remains for novel approaches to improve patient outcomes. BDC-1001 is an ISAC consisting of a trastuzumab biosimilar conjugated to a proprietary cell membrane impermeable TLR7/8 agonist via a non-cleavable linker. It is designed to trigger the innate immune system and generate a durable tumor-targeted adaptive immune response. Preclinical studies indicate that HER2-targeted ISACs elicit potent and durable immune-mediated antitumor efficacy, leading to complete tumor regression in a TLR- and Fc receptor-dependent manner.¹

The phase 1 dose escalation of the phase 1/2, first-in-human study BBI-20201001 (NCT04278144), was completed and determined 20 mg/kg every 2 weeks (q2w) of BDC-1001 as the recommended phase 2 dose (RP2D) for monotherapy (mono)/combination (combo) regimens,² leading to the phase 2 portion of the trial. The phase 1 portion showed that BDC-1001 was well tolerated as mono/combo, with grade 1/2 infusion-related reactions as the most common adverse events (29%). Clinical activity was observed in multiple tumor types; outcomes improved as targeted C_min ≥10mg/mL was reached, particularly at the q2w RP2D. 6 pts (3 mono) had partial response (PR); 12 pts (10 mono) achieved stable disease (SD) ≥24 wks. 14 pts with evaluable HER2+ tumors treated at the RP2D had a clinical benefit rate of 50% (29% confirmed PR, additional 21% SD ≥24wks), tumor shrinkage occurred in 64%, and 36% of pts remain on active Tx. Pharmacodynamic responses in plasma and paired tumor biopsies (protein/gene analyses) demonstrated immune activation consistent with the ISAC technology, and not expected by trastuzumab alone.

This phase 2 (dose expansion) portion of the study is ongoing evaluating BDC-1001 alone and in combination with nivolumab in patients with HER2+ (protein or gene) advanced/metastatic colorectal, endometrial, and gastroesophageal cancers.

Methods This multiarm phase 2 trial will evaluate 20 mg/kg q2w of BDC-1001 as monotherapy (Part 3) and combination with nivolumab (Part 4) using Simon’s 2-stage design in up to 231 patients. The primary objective of the phase 2 will be preliminary antitumor activity of BDC-1001 alone and in combination with nivolumab. Secondary objectives will be safety, pharmacokinetics, and immunogenicity of BDC-1001 alone and in combination with nivolumab. Exploratory objectives will be pharmacodynamic biomarkers in tumor tissue and in peripheral blood, to help elucidate the mechanism of action and identify biomarkers associated with BDC-1001’s biological activity. Enrollment is ongoing in the United States, Europe, and South Korea.

Trial Registration ClinicalTrials.gov (NCT04278144)

References

1. Ackerman SE, Pearson CI, Gregorio JD, et al. Immune-stimulating antibody conjugates elicit robust myeloid activation and durable antitumor immunity. Nat Cancer 2021;2:18–33.

2. Li BT, Pegram MD, Lee KW, Sharma M, Lee J, Spira AI, Hanna GJ, Kang YK, Rasco DW, Moore KN, Weinberg BA, 2023. A phase 1/2 study of a first-in-human immune-stimulating antibody conjugate (ISAC) BDC-1001 in patients with advanced HER2-expressing solid tumors, 2538.

Ethics Approval Protocols, protocol amendments, and informed consents are approved by Institutional review boards or independent ethics committees of participating sites. The study will be conducted in compliance with the Declaration of Helsinki and International Conference on Harmonization Guidelines for Good Clinical Practice. All patients will provide written informed consent.