A phase I trial of temozolomide and lomustine in newly diagnosed high-grade gliomas of childhood

¹ Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
² Ohio State University, Columbus, OH, USA
³ Baylor College of Medicine, Houston, TX, USA
⁴ University of Southern California, Los Angeles, CA, USA; Children’s Oncology Group, Arcadia, CA, USA
⁵ The University of Texas Southwestern Medical Center, Dallas, TX, USA
⁶ Children's Oncology Group, Arcadia, CA, USA
⁷ University of California, San Francisco, San Francisco, CA, USA
⁸ Children's Hospital of Philadelphia, Philadelphia, PA, USA

^* To whom correspondence should be addressed. E-mail: regina.jakacki{at}chp.edu.

	Abstract

A phase I trial was conducted to determine the maximum tolerated dose (MTD) of temozolomide given in combination with lomustine in newly diagnosed pediatric patients with high-grade gliomas. Response was assessed following two courses of therapy at the MTD. Temozolomide was administered to cohorts of patients at doses of 100, 125, 160, or 200 mg/m² on days 1-5, along with 90 mg/m² lomustine on day 1. Two courses of lomustine/temozolomide were given prior to radiation therapy (RT) and up to six courses were administered afterward. Thirty-two patients were enrolled. Dose-limiting myelosuppression was seen in two of three patients enrolled at the 200 mg/m² dose level. One of 14 patients in the expanded MTD cohort (160 mg/m²) experienced dose-limiting thrombocytopenia. After two courses at the MTD, one patient with a 5-mm enhancing nodule postoperatively had a complete response, one patient with a large residual temporal lobe glioblastoma had a partial response, and eight patients had stable disease. Several patients developed transient radiographic worsening after completing RT. Median 1- and 2-year overall survivals at the MTD were 60% ± 13% and 40% ± 13% with a median of 17.6 months. Thirteen of 20 patients (65%) who underwent MRI scans within 6 months prior to death developed metastatic disease. In conclusion, when administered with 90 mg/m² lomustine on day 1, the MTD of temozolomide is 160 mg/m²/day x 5. Radiographic changes following RT make determination of early tumor progression difficult. Metastatic disease is common prior to death.

Key Words: CCNU (lomustine), malignant glioma, pediatrics, temozolomide

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