(P 338) PRECLINICAL EFFICACY OF DAN-222, A NOVEL POLYMERIC NANOPARTICLE, IN PEDIATRIC SOLID TUMOR MODELS

Objective: Nanoparticle technology represents a novel approach for the improved delivery of drug to tumor cells. DAN-222 is a high-capacity nanoparticle covalently conjugated with camptothecin, a topoisomerase I inhibitor. Topoisomerase I inhibition has been shown to be active across a spectrum of pediatric cancers. DAN-222 was shown to be well-tolerated with promising preliminary clinical activity singly and in combination with PARP inhibition (NCT05261269) in heavily pre-treated breast cancer patients. Given promising clinical activity of DAN-222, we explored the preclinical efficacy of DAN-222 both singly and in combination with chemotherapy or PARP inhibition in pediatric solid tumor models.

Methods: Mice were treated with DAN-222 intravenously at 3 dose levels (3 mg/kg, 2.3 mg/kg, and 1.5 mg/kg once weekly for 3 doses) both as single agent and in combination with either temozolomide (mouse equivalent dosing of 33 mg/kg PO daily for 5 days) or olaparib (20 mg/kg IP daily for 5 days) to determine tolerable doses. Weight and clinical appearance were monitored twice weekly. In vivo activity of DAN-222 was evaluated in a Ewing sarcoma (ES), fusion-positive (alveolar) rhabdomyosarcoma (RMS), and a Wilms tumor (WT) patient-derived xenograft (PDX) model using an adaptive trial design. Six treatment arms were tested: (1) Vehicle, (2) Irinotecan + temozolomide (TMZ), (3) DAN-222, (4) DAN-222 + TMZ (or DAN-222 + vincristine in the WT model), (5) DAN-222 + olaparib, and (6) olaparib. Treatment responses were assessed at Day 21 with comparisons of relative tumor volume (TV) across treatments performed using Vardi’s test. Progression free survival (PFS) probabilities, with progression defined as relative TV doubling, and overall survival (OS), defined as time to TV of 1000 mm3, were evaluated using a Kaplan-Meier estimator with treatment comparisons conducted using a logrank test. Evaluation of hematologic toxicity was assessed with serial peripheral blood count monitoring.

Results: The tolerated dose for DAN-222 monotherapy and in combination is 3mg/kg IV weekly x 3 doses (equivalent to the adult recommended phase 2 dose), with no appreciable weight loss observed in treated mice. In ES, DAN-222 with either TMZ or olaparib prolonged disease control compared to vehicle or chemotherapy. Treatment with DAN-222 + TMZ and DAN-222 + olaparib resulted in sustained complete responses through day 60 (Figure 1). In RMS, DAN-222 + TMZ resulted in a significant reduction in average tumor growth rate compared to vehicle control (p=0.03) and improvement in overall survival compared to vehicle (p=0.005) and chemotherapy (irinotecan/TMZ) (p=0.006, Figure 2). Additionally, treatment with DAN-222 monotherapy and DAN-222 in combination with vincristine or olaparib resulted in complete responses in the Wilms tumor model (Figure 3). A modest decrease in hemoglobin was observed in the DAN-222 monotherapy, combination, and chemotherapy treatment arms during the first week with recovery by day 16 from treatment initiation. No thrombocytopenia or neutropenia was observed with DAN-222 singly or in combination (Figure 4).

Conclusion: DAN-222 demonstrates significant preclinical antitumor activity across multiple pediatric solid tumor models, both alone and in combination with chemotherapy or PARP inhibition, providing preclinical rationale for clinical investigation in pediatric solid tumors.