A pediatric phase 1 trial of vorinostat and temozolomide in relapsed or refractory primary brain or spinal cord tumors: a Children's Oncology Group phase 1 consortium study

Abstract

Purpose: We conducted a pediatric phase I study to estimate the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), and pharmacokinetic properties of vorinostat, a histone deacetylase (HDAC) inhibitor, when given in combination with temozolomide in children with refractory or recurrent CNS malignancies.

Patients and methods: Vorinostat, followed by temozolomide approximately 1 hour later, was orally administered, once daily, for 5 consecutive days every 28 days at three dose levels using the rolling six design. Studies of histone accumulation in peripheral blood mononuclear cells were performed on Day 1 at 0, 6, and 24 hours after vorinostat dosing. Vorinostat pharmacokinetics (PK) and serum MGMT promoter status were also assessed.

Results: Nineteen eligible patients were enrolled and 18 patients were evaluable for toxicity. There were no DLTs observed at dose level 1 or 2. DLTs occurred in four patients at dose level 3: thrombocytopenia (4), neutropenia (3), and leucopenia (1). Non-dose limiting grade 3 or 4 toxicities related to protocol therapy were also hematologic and included neutropenia, lymphopenia, thrombocytopenia, anemia, and leucopenia. Three patients exhibited stable disease and one patient had a partial response. There was no clear relationship between vorinostat dosage and drug exposure over the dose range studied. Accumulation of acetylated H3 histone in PBMC was observed after administration of vorinostat.

Conclusion: Five-day cycles of vorinostat in combination with temozolomide are well tolerated in children with recurrent CNS malignancies with myelosuppression as the DLT. The recommended phase II combination doses are vorinostat, 300 mg/m(2) /day and temozolomide, 150 mg/m(2) /day.

Trial registration: ClinicalTrials.gov NCT01076530.

Keywords: Children's Oncology Group; pediatric cancer; temozolomide phase I trial; vorinostat.

Figure 1. O⁶- Methylguanine-DNA methyltransferase (MGMT) promoter methylation in patient plasma

Genomic DNA was extracted before TMZ/SAHA treatment and MGMT promoter methylation was determined by methylation-specific polymerase chain reaction (PCR). Peripheral blood monouclear cells (WBC) from each patient served as an internal control, and was unmethylated in all patients. Markers (Mar): 100bp (upper) and 75bp (lower). U, unmethylated, M, methylated. NL = WBC from individual without cancer (unmethylated control), SA48-colon cancer (methylated control).