A Phase 1 Study of Pevonedistat (MLN4924), a NEDD8 Activating Enzyme (NAE) Inhibitor, in Combination with Temozolomide and Irinotecan in Pediatric Patients with Recurrent or Refractory Solid Tumors
6 Months - 21 Years, Male and Female
This phase I trial studies the side effects and best dose of pevonedistat when giving together with irinotecan hydrochloride and temozolomide in treating patients with solid tumors or lymphoma that have come back after a period of improvement or that do not respond to treatment. Pevonedistat and irinotecan hydrochloride may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving pevonedistat, irinotecan hydrochloride, and temozolomide may work better in treating patients with solid tumors or lymphoma.
I. To estimate the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of pevonedistat administered as an intravenous infusion on days 1, 8, 10, and 12 of a 28-day cycle (cycle 1), and on days 1, 3, and 5 of a 21-day cycle (cycle 2 and beyond) in combination with irinotecan (irinotecan) (administered as an intravenous infusion on days 8-12 of cycle 1 and days 1-5 of cycles 2+) and temozolomide (administered orally on days 8-12 in cycle 1 and days 1-5 of cycles 2+) in children with recurrent or refractory solid tumors, including central nervous system (CNS) tumors and lymphoma.
II. To define and describe the toxicities of pevonedistat administered on this schedule.
III. To characterize the pharmacokinetics of pevonedistat in children with recurrent or refractory cancer.
I. To preliminarily define the antitumor activity of pevonedistat within the confines of a phase 1 study.
II. To assess the biologic activity of pevonedistat.
OUTLINE: This is a dose escalation study of pevonedistat.
Patients receive pevonedistat intravenously (IV) over 60 minutes on days 1, 8, 10, and 12, temozolomide orally (PO) daily on days 8-12, and irinotecan hydrochloride IV over 90 minutes on days 8-12 of course 1. Beginning at course 2, patients receive pevonedistat IV over 60 minutes on days 1, 3, and 5, temozolomide PO daily on days 1-5, and irinotecan hydrochloride IV over 90 minutes on days 1-5. Treatment repeats every 28 days for course 1 and 21 days for subsequent courses for up to 17 courses in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up periodically.