Muscal, Jodi A.

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: Imetelstat is a covalently-lipidated 13-mer thiophosphoramidate oligonucleotide that acts as a potent specific inhibitor of telomerase. It binds with high affinity to the template region of the RNA component of human telomerase (hTERC) and is a competitive inhibitor of telomerase enzymatic activity. The purpose of this study was to determine the recommended phase II dose of imetelstat in children with recurrent or refractory solid tumors. Experimental Design: Imetelstat was administered intravenously more than two hours on days 1 and 8, every 21 days. Dose levels of 225, 285, and 360 mg/m2 were evaluated, using the rolling-six design. Imetelstat pharmacokinetic and correlative biology studies were also performed during the first cycle. Results: Twenty subjects were enrolled (median age, 14 years; range, 3–21). Seventeen were evaluable for toxicity. The most common toxicities were neutropenia, thrombocytopenia, and lymphopenia, with dose-limiting myelosuppression in 2 of 6 patients at 360 mg/m2. Pharmacokinetics is dose dependent with a lower clearance at the highest dose level. Telomerase inhibition was observed in peripheral blood mononuclear cells at 285 and 360 mg/m2. Two confirmed partial responses, osteosarcoma (n = 1) and Ewing sarcoma (n = 1), were observed. Conclusions: The recommended phase II dose of imetelstat given on days 1 and 8 of a 21-day cycle is 285 mg/m2. Clin Cancer Res; 19(23); 6578–84. ©2013 AACR.