TRLS-16. RESULTS FROM SJDAWN: A ST JUDE CHILDREN’S RESEARCH HOSPITAL PHASE 1 STUDY EVALUATING MOLECULARLY DRIVEN DOUBLET THERAPIES FOR ALL CHILDREN WITH REFRACTORY OR RECURRENT CENTRAL NERVOUS SYSTEM (CNS) MALIGNANT NEOPLASMS AND YOUNG ADULTS WITH SHH MEDULLOBLASTOMA Open Access

Pediatric CNS tumors have recurring molecular aberrations that modulate the cell cycle. We hypothesized that ribociclib, a brain-penetrant CDK4/6 inhibitor, given in doublet combinations could benefit patients with CNS malignancies. SJDAWN (NCT03434262) was launched to determine the recommended phase 2 dose (RP2D), safety, pharmacokinetics, and early efficacy of doublets.

Patients >1 and <40 years with recurrent/refractory CNS malignancy were stratified into 3 strata. Escalating dose-levels in 28-day cycles were evaluated in each stratum by rolling-6 design with an expansion cohort at the highest tolerated dose-level. RP2D was declared if ≤3 dose-limiting toxicities (DLTs) occurred in 12 patients. Stratum A evaluated ribociclib/gemcitabine in group3/group4 (Grp3/4) MB and ependymoma (EPN). Stratum B evaluated ribociclib/trametinib in malignancies not eligible for stratum A or C. Stratum C evaluated ribociclib/sonidegib in skeletally mature patients with SHH-MB, TP53 wildtype with chr9q loss and/or PTCH1 mutation. Tumor, blood, and CSF samples were analyzed.

From 2018-2022, 68 patients enrolled: 33 in A (22 Grp3/4-MB, 11 EPN); 28 in B (15 HGG, 13 other); 7 SHH-MB in C. The RP2D was gemcitabine 1250mg/m² IV day 1, 15 and ribociclib 350mg/m² PO 1-21 days for A; trametinib 0.025mg/kg PO days 1-14 and ribociclib 280mg/m² PO days 7-21 for B; and not established for C. DLTs included neutropenia (A), thrombocytopenia (B), mucositis (B), and rash (C). The 6-, 12-, and 24-month progression-free survival (PFS) was 42%(26%-58%), 18%(8%-33%), and 12%(4%-26%) in A, 18%(7%-34%), 4%(1%-15%), and 0% in B, 71%(30%-92%), 43%(13%-73%), and 0% in C. PFS beyond 2-years was observed in 3 Grp3/4-Subgroup3 MBs and 1 EPN. Amplification of CDK6, CCND2, and MYCN in serial CSF samples suggested a mechanism of resistance.

Ribociclib doublets are tolerated, and the lengthy survival of some patients suggests a selective benefit.