A study of the safety, efficacy, and pharmacokinetics of SPJ-101CA as maintenance therapy for newly diagnosed high-risk neuroblastoma.

10038 Background: Isotretinoin (ISO), an oral vitamin A derivative, induces differentiation of neuroblastoma (NB) cells and is used as maintenance therapy. SPJ-101CA (Sun Pharma Ltd.), a novel ISO formulation developed with microparticle technology to enhance absorption, is designed to achieve adequate systemic exposure at 80% of the conventional dose. As ISO is an off-label treatment for NB worldwide, the present, registration-directed clinical trial was conducted to evaluate the safety, efficacy, and pharmacokinetics (PK) of SPJ-101CA in pediatric patients. Methods: This open-label, multicenter phase 2 trial enrolled 16 patients aged 1-18 years with newly diagnosed, high-risk NB who had completed the standard, multidisciplinary therapy without progression. Eligibility required an ECOG performance status of 0-2 and adequate organ function. The exclusion criteria were other active malignancies, gelatin allergy, pregnancy or breastfeeding, psychiatric disorder, and intolerance to the study treatment. Written informed consent was obtained from the patients’ legal guardians, and assent was provided by the patients when appropriate. The patients received oral SPJ-101CA 64 mg/m² twice daily for 14 days in each, 28-day course for a total of six courses. Dinutuximab was permitted only before or after, but not during, SPJ-101CA administration. The primary endpoint was the incidence of serious adverse events (AEs). The secondary endpoints included 1-year event-free and overall survival, the AE incidence, and PK properties. Blood samples were collected on day 14 of the first course at predefined intervals to measure the plasma concentration of ISO and 4-oxo-isotretinoin, and the standard PK parameters were evaluated. Results: All 16 patients were included in the full analysis and per-protocol sets. Three serious AEs related to SPJ-101CA occurred in three patients (two and one case of hypertriglyceridemia and hypercalcemia, respectively), for a total incidence of 18.8%. Common, non-serious AEs included upper respiratory inflammation (75.0%), dry skin (62.5%), hypercalcemia (56.3%), eczema (50.0%), hypertriglyceridemia (43.8%), cheilitis (37.5%), pruritus (31.3%), and neutropenia (31.3%). The 1-year event-free survival rate was 93.8%, and the overall survival rate was 100%. PK analysis of 15 patients found that the mean T max of ISO was 3.9 hours and that the 4-oxo-isotretinoin level remained constant and exhibited no distinct peak. The mean ISO C max was approximately 2.3 µg/mL, with a half-life of about 5 hours; 4-oxo-ISO had a higher C max and longer half-life. Conclusions: SPJ-101CA was well-tolerated and effective as maintenance therapy following multidisciplinary treatment for high-risk NB. The PK findings were consistent with the known profile of ISO and indicated good absorption of the formulation. Clinical trial information: jRCT2031220687.