ONITT: A phase I study of nanoliposomal irinotecan with talazoparib or temozolomide in children and young adults with recurrent or refractory solid tumors.

10007 Background: Talazoparib (TAL), a potent PARP inhibitor, demonstrated preclinical activity in Ewing sarcoma when combined with irinotecan (IRN) and temozolomide (TMZ). A phase I study (BMNIRN, NCT02392793) showed clinical benefit of TAL + IRN + TMZ; but dose escalation was limited due to hematologic and gastrointestinal toxicity. We therefore evaluated, for the first time in children, nanoliposomal irinotecan (nal-IRI) in combination with either TAL or TMZ. Methods: Patients (pts) aged 1-30 with recurrent or refractory solid tumors were eligible to receive nal-IRI + TAL (Arm A) or nal-IRI + TMZ (Arm B) using a Bayesian keyboard design. Nal-IRI dosage was escalated with fixed TAL and TMZ doses. Each cycle was 21 days. Maximum tolerated dosage(s) (MTD) and recommended phase 2 dosage(s) (RP2D) were determined. Nal-IRI and TAL plasma pharmacokinetics (PK) were evaluated. Toxicities were assessed using CTCAE v.5 and responses were evaluated by RECIST 1.1. UGT1A1 polymorphisms and serial circulating tumor DNA (ctDNA) samples were evaluated. Results: Forty-six pts enrolled at 5 sites. The first 9 (5 Arm A; 4 Arm B) received nal-IRI days 1, 8. Four pts had dose limiting toxicities (DLTs), so day 8 nal-IRI was removed (Amend 1). After Amend 1, 37 pts (23 male; median age 14 years, range 1-23) enrolled (19 Arm A; 18 Arm B). The most common diagnosis was Ewing sarcoma (n = 16, 35%). Table 1 summarizes DLTs in Cycle 1 and response. The most common serious adverse events included febrile neutropenia (12 Arm A; 2 Arm B), colitis (4 Arm A; 2 Arm B), vomiting (4 Arm A), and diarrhea (3 Arm A). Confirmed responses were seen in five Arm A (1 CR, 4 PR) and five Arm B (1 CR, 4 PR) pts with Ewing sarcoma, CIC-DUX4 sarcoma, synovial sarcoma, and rhabdomyosarcoma. Seven pts (5 Arm A; 2 Arm B) had stable disease. Results of PK, UGT1A1 and ctDNA will be presented. Conclusions: The MTDs were nal-IRI 160mg/m 2 plus TAL (Arm A) and nal-IRI 200mg/m 2 plus TMZ (Arm B). The RP2Ds are pending FDA review. These regimens are feasible with evidence of anti-tumor activity and warrant further investigation. Clinical trial information: NCT04901702 . Dose level Nal-IRImg/m 2 IV Arm ANal-IRI + TAL(po, 600mcg/m 2 /dose)Days (D) # of pts Arm BNal-IRI + TMZ(po, 100mg/m 2 )Days (D) # of pts DLT Cycle 1 (# of pts) Confirmed Response(CR, PR, SD, PD) 1 120 D 1: nal-IRI + TAL divided BIDD 2-6: TAL daily 7 D 1: nal-IRI + TMZD 2-5: TMZ daily 3 Arm A: 1 pt - neutropenia (1) Arm A: CR (1), SD (1), PD (2)Arm B: PR (1), SD (1), PD (1) 2 160 D 1: nal-IRI + TAL divided BIDD 2-6: TAL daily 10 D 1: nal-IRI + TMZD 2-5: TMZ daily 3 Arm A: 3 pts - anemia (1), thrombocytopenia (1), sepsis (1), colitis (1) Arm A: PR (3), SD (4), PD (3)Arm B: PR (1), PD (1) 3 200 D 1: nal-IRI + TAL divided BIDD 2-6: TAL daily 2 D 1: nal-IRI + TMZD 2-5: TMZ daily 12 Arm A: 2 pts – abd pain (1), thrombocytopenia (1), neutropenia (1), diarrhea (1)Arm B: 3 pts – nausea (1), neutropenia (1), sepsis (1), thrombocytopenia (1) Arm A: PR (1)Arm B: CR (1), PR (2), SD (1), PD (6)