Abstract OT3-28-01: A Dose-escalation Study of the Safety and Pharmacology of DAN-222 in Subjects with Metastatic Breast Cancer NCT05261269

Abstract

Abstract Clinical Study: This clinical study is designed to evaluate DAN-222 as a monotherapy and in combination with a PARP inhibitor which is expected to increase efficacy without significant increase in toxicity. DAN-222 is a novel therapeutic nanoparticle with a complimentary mechanism for combination with a PARP inhibitor anticipated for patients with HRD+ and HRD- tumors, and not restricted to BRCAm. This is an ongoing phase 1/2 study to evaluate the safety and pharmacology of DAN-222 in patients with metastatic breast cancer and initial evaluation of efficacy. Here we report on the initial pharmacology. The results in the patients show the expected characteristics of the designed product, including consistency with preclinical models (e.g. T1/2= 28 hours), which is a feature of this platform given the non-enzymatic release mechanism of the payload that allows for improved translation from preclinical species to clinical patients as well low variability between patients (e.g. CV%=16.5). Study Rationale: DAN-222 is a topoisomerase-1 inhibitor (Camptothecin) nanoparticle therapeutic that has been optimized for tumor biodistribution and pharmacokinetics. DAN-222 has a broad therapeutic index in preclinical evaluation and the complementary mechanism of action with PARP inhibitors provides significantly enhanced efficacy while also sparing bone marrow. Importantly, the complementary enhanced efficacy is independent of tumor homologous repair deficiency (HRD) status, including BRCA status. The efficacy of DAN-222 was evaluated alone and in combination with a PARP inhibitor (niraparib) in HRD+ breast cancer (MDA-MB-436) and HRD- ovarian cancer (OVCAR-3) xenograft models. Table 1 highlights the endpoints of the study as measured by partial response, complete response, tumor free survival and median tumor volume at end of study (Day 60). DAN-222 alone had PR effects and reduced median tumor volume compared to niraparib alone. The combination demonstrated enhancement of response as evidenced by an increase in partial response, a shift from partial to complete response, an increase in tumor-free survivors, and significant further reduction in median tumor volume. Conclusion: The clinical pharmacology will be presented and demonstrates the designed behavior of the nanoparticle. A design feature of the nanoparticle is that the payload and linker are sequestered in the core, protecting them from circulatory components. Moreover, the covalent attachment of the payload allows for tunable release kinetics via a hydrolytic linker, preventing burst release and associated toxicities common to physical encapsulation-based nanoparticle systems (e.g., liposomes, micelles). The preliminary PK profile in patients supports the translatability across species and consistency of exposure across patients. Table 1: Efficacy of DAN-222 Alone or Combination with Niraparib Citation Format: Ashley P. Wright, Emily A. Wyatt, Timothy Hagerty. A Dose-escalation Study of the Safety and Pharmacology of DAN-222 in Subjects with Metastatic Breast Cancer NCT05261269 [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT3-28-01.