Foster, Jennifer

10019 Background: Pevonedistat (PEV), a first in class inhibitor of NEDD8 activating enzyme (NAE), prevents the activation of Cullin-RING ligases (CRL) necessary for proteasome mediated degradation of key regulatory proteins important in cell survival. In adults with solid tumors, the maximum tolerated dose (MTD) in combination with chemotherapy is 20-25 mg/m2. Antitumor activity of PEV has been demonstrated in preclinical models of childhood cancer. In vivo additive activity has been demonstrated for PEV in combination with IRN and alkylating agents. The objectives of this study are to determine the MTD and recommended Phase 2 dose of PEV in combination with IRN and TMZ and describe the toxicities, pharmacokinetic (PK), and pharmacodynamics (PD) properties of this combination. Methods: We conducted a phase 1 trial of PEV in combination with IRN and TMZ in pediatric patients (pts) with recurrent or refractory solid tumors and brain tumors. During cycle 1, PEV was administered intravenously on days 1, 8, 10, and 12, with IRN (IV, 50mg/m2) and TMZ (orally, 100mg/m2), on days 8-12 of a 28 day cycle. In subsequent cycles, PEV was administered on days 1, 3, and 5, with IRN and TMZ on days 1-5 of a 21 day cycle. Dose escalation was determined using the Rolling 6 Design. Results: 30 pts enrolled. All pts were eligible and evaluable for cycle 1 dose limiting toxicity (DLT) assessment. Median (range) age was 13 (1-21) years; 19 (63%) were male. Eleven pts had brain tumors, and 19 pts had solid tumors. Six pts each enrolled on PEV dose levels (DL) 1 (15mg/m2), 2 (20mg/m2), 3 (25mg/m2) and 4 (35mg/m2) as well as an expanded PK cohort at DL4. Cycle 1 grade 3/4 toxicities include lymphopenia (n = 5), leukopenia (n = 4), neutropenia (n = 2), elevated ALT (n = 2), elevated AST (n = 1), diarrhea (n = 1), flu-like symptoms (n = 1). The most frequent non-dose limiting AEs in cycle 1 were anemia (87%), WBC decreased (77%), nausea (57%), diarrhea (53%), ALT increased (50%), AST increased (50%), and vomiting (50%). PK analyses showed the mean area under the curve at the 25 mg/m2 dose level on day 8 (in combination with irinotecan and temozolomide) was 1300 hr•ng/mL, half-life (T ½) was 5-6 hours, time to maximum concentration (Tmax) was 1 hour, and mean clearance was 20 L/hr/m2. There were 3 DLTs, 2 of which were related to protocol therapy (diarrhea and thrombocytopenia), among 12 patients on DL4. Thus the MTD was not exceeded at any dose level. PK at the 25 mg/m2 dose level are comparable to those in adult patients. PK from the 12 patients on DL4 (35mg/m2) as well as responses of all patients are pending. Conclusions: PEV in combination with IRN and TMZ is well tolerated in children with solid or brain tumors. PEV PK was not altered by the addition of irinotecan and temozolomide. Further PK and PD analyses are ongoing to establish the recommended phase 2 dose. Clinical trial information: NCT03323034.

e21521 Background: Pevonedistat, a first in class inhibitor of NEDD8 activating enzyme (NAE), prevents the activation of Cullin-RING ligases (CRL) necessary for proteasome mediated degradation of key regulatory proteins important in cell survival. In adults with solid tumors, the maximum tolerated dose (MTD) in combination with chemotherapy is 20-25 mg/m2. Antitumor activity of pevonedistat has been demonstrated in preclinical models of childhood cancer. In vivo additive activity has been demonstrated for pevonedistat in combination with IRN and alkylating agents. The objectives of this study are to determine the MTD and recommended phase 2 dose of pevonedistat in combination with IRN and TMZ and describe the toxicities, pharmacokinetic (PK), and pharmacodynamics (PD) properties of this combination. Methods: Using a rolling six design, we conducted a phase 1 trial of pevonedistat in combination with IRN and TMZ in pediatric patients (pts) with recurrent or refractory solid tumors and brain tumors. During cycle 1, pevonedistat was administered intravenously on days 1, 8, 10, and 12, with IRN (IV, 50mg/m2) and TMZ (orally, 100mg/m2), on days 8-12 of a 28 day cycle. In subsequent cycles, pevonedistat was administered on days 1, 3, and 5, with IRN and TMZ on days 1-5 of a 21 day cycle. Results: 18 pts enrolled. All pts were eligible and evaluable for cycle 1 dose limiting toxicity (DLT) assessment. Median (range) age was 13 (1-21) years; 11 (61%) were male. Six pts had brain tumors, and 12 pts had solid tumors. Six pts each enrolled on pevonedistat dose levels 1 (15mg/m2), 2 (20mg/m2), and 3 (25mg/m2). There were no DLTs; DLT assessment is pending for 1 pt on dose level 3. Grade 3/4 toxicities included grade 4 lymphocyte count decreased (n = 2), grade 3 white blood cell decreased (n = 2), and 1 pt each with grade 3 anemia, elevated AST, and elevated ALT. The most frequent AEs were anemia (83%), nausea (61%), elevated AST (61%), and diarrhea (61%). Pharmacokinetic analysis is pending. Conclusions: Pevonedistat in combination with IRN and TMZ is well tolerated in pts with solid or brain tumors. PK and PD analyses are ongoing to establish the recommended dose. Clinical trial information: NCT03323034.

Abstract Purpose Proton therapy is currently used in the management of pediatric tumors to decrease late toxicities. However, one of the criticisms of proton therapy is the limited data regarding efficacy on disease control. The purpose of this study was to examine local and distant control rates after proton therapy for neuroblastoma. Methods and materials Eighteen patients with high‐risk ( n = 16) and locally recurrent neuroblastoma ( n = 2) were treated with curative intent and received proton therapy to the primary site and up to three post‐induction MIBG‐avid metastatic sites. Primary sites ( n = 18) were treated to 21–36 Gy (relative biological effectiveness [RBE]), and metastatic sites ( n = 16) were treated to 21–24 Gy (RBE). Local control and survival rates were calculated using the Kaplan–Meier method. Results With a median follow‐up of 60.2 months, two‐ and five‐year local control rates at the irradiated primary site were 94% and 87%, respectively. No failures at irradiated distant metastatic sites were observed. The five‐year progression‐free survival (PFS) was 64%, and the five‐year overall survival (OS) was 94%. The extent of surgical resection was not associated with local control, PFS, or OS. No radiation‐related nephropathy or hepatopathy was reported. Conclusions Excellent local control was achieved using proton therapy to the primary and post‐induction MIBG‐positive distant sites. The predominant site of failure is progression in post‐induction non‐MIBG‐avid distant sites. Although proton therapy provides high rates of local control with acceptable toxicity for neuroblastoma, further advances in systemic therapy are needed for the improved control of systemic disease.