CLINICAL TRIAL: A PHASE I TRIAL OF ESCALATING DOSES OF KARENITECIN PLUS CYCLOPHO

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Cyclophosphamide has a broad spectrum of antitumor activity and is extensively used in the treatment of pediatric solid tumors. Cyclophosphamide in combination with the topoisomerase I inhibitor, Hycamtin¿¿ (topotecan, GlaxoSmithKline), has been evaluated in both Phase 1 and Phase 2 pediatric clinical trials. Cyclophosphamide doses were fixed at 250 mg/m2/dose for 5 consecutive days; while topotecan doses in the Phase 1 trial ranged from 0.6 to 0.75 mg/m2/dose; and were fixed at 0.75 mg/m2/dose for 5 consecutive days in the phase 2 trial. Myelosuppression was the predominant toxicity of this combination, and G-CSF support was used for neutrophil recovery in the Phase 2 trial. Responses (complete plus partial) were observed in a variety of pediatric solid tumors including rhabdomyosarcoma (67%), neuroblastoma (46%), and Ewing¿??s sarcoma (35%). Thus, as evidenced by these data, the combination of cyclophosphamide plus a topoisomerase I inhibitor appears to be active. The safety profile of Karenitecin suggests a reduced incidence of severe (NCI-CTCAE grade = 3) hematologic toxicity when compared with that of topotecan. This is of particular importance since an improved hematologic toxicity profile may reduce the need for frequent monitoring of bone marrow function and treatment interventions (for example, treatment delays, dose reductions, red blood cell [RBC] transfusions, growth factor support), thus improving patient safety, compliance, and clinical benefit. Results from 3 Phase 1 studies clearly indicate that Karenitecin can be safely administered to patients at the dose level of 1.0 mg/m2/day IV over one hour for 5 consecutive days in a 3-week treatment cycle. The principal and dose-limiting toxicity is non-cumulative, reversible myelosuppression. Gastrointestinal toxicity is generally = grade 2 and is not dose-limiting. In 4 Phase 2 studies, Karenitecin demonstrated an acceptable safety profile, moderate clinical activity in patients with malignant gliomas, and potentially significant clinical activity in patients with metastatic melanoma, ovarian and peritoneal cancer, and non-small cell lung cancer. Based on these considerations for both agents, it is medically justified to evaluate the combination of Karenitecin co-administered with cyclophosphamide, particularly given the apparent advantages of Karenitecin relative to topotecan. We aim to determine a maximum tolerated dose (MTD) level and determine the recommended Phase 2 dose level for this study, and obtain preliminary information on the antitumor activity of karenitecin in two groups of pediatric subjects with refractory or recurrent pediatric solid tumors. Approximately 25 subjects will be enrolled in each stratum for a total of fifty. Primary Objective: To determine the maximum tolerated dose (MTD) levels and recommended Phase 2 dose levels of Karenitecin when administered intravenously for 5 consecutive days with a fixed dose of cyclophosphamide to children with refractory or recurrent solid tumors stratified according to the presence or absence of bone marrow metastases or treatment with previous intensive myelosuppressive therapy. Secondary Objectives: Secondary objectives include the assessment of toxicity associated with Karenitecin administered in combination with cyclophosphamide; and the assessment of antitumor activity of Karenitecin administered in combination with cyclophosphamide.