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Low-Dose Metronomic Topotecan and Pazopanib (TOPAZ) in Children with Relapsed or Refractory Solid Tumors: A C17 Canadian Phase I Clinical Trial

Arif Manji , Yvan Samson , Rebecca J. Deyell , Donna L. Johnston , Victor A. Lewis , Alexandra P. Zorzi , Jason N. Berman , Kathy Brodeur-Robb , Ellen Morrison , Lynn Kee , Sushil Kumar , Sylvain Baruchel , James A. Whitlock and Daniel A. Morgenstern from the Hospital for Sick Children, University of Toronto, the CHU Sainte-Justine, Montréal, the BC Children’s Hospital, Vancouver, the Children’s Hospital of Eastern Ontario, Ottawa, the Alberta Children’s Hospital, Calgary, the Children’s Hospital, London Health Sciences Centre, London, the C17 Council for Children’s Cancer and Blood Disorders, Edmonton and Drug Metabolism & Pharmacokinetics, QPS Holdings LLC, Newark.

Following their initial pre-clinical work on the combination of pazopanib and metronomic toptecan in pediatric refractory malignancies, the C17 canadian consortium has Just published the results of a phase 1 trial entitled : Low-Dose Metronomic Topotecan and Pazopanib (TOPAZ) in Children with Relapsed or Refractory Solid Tumors: A C17 Canadian Phase I Clinical Trial. The article is freely available to all here on the Cancers website.

Oral metronomic topotecan represents a novel approach to chemotherapy delivery which, in preclinical models, may work synergistically with pazopanib in targeting angiogenesis.

A phase I and pharmacokinetic (PK) study of this combination was performed in children with relapsed/refractory solid tumors.

Oral topotecan and pazopanib were each administered daily without interruption in 28-day cycles at five dose levels (0.12 to 0.3 mg/m2 topotecan and 125 to 160 mg/m2 pazopanib powder for oral suspension (PfOS)), with dose escalation in accordance with the rolling-six design. PK studies were performed on day 1 and at steady state.

Thirty patients were enrolled, with 26 evaluable for dose-limiting toxicity (DLT), with median age 12 years (3–20). Toxicities were generally mild; the most common grade 3/4 adverse events related to protocol therapy were neutropenia (18%), thrombocytopenia (11%), lymphopenia (11%), AST elevation (11%), and lipase elevation (11%). Only two cycle 1 DLTs were observed on study, both at the 0.3/160 mg/m2 dose level comprising persistent grade 3 thrombocytopenia and grade 3 ALT elevation. No AEs experienced beyond cycle 1 required treatment discontinuation. The best response was stable disease in 10/25 patients (40%) for a median duration of 6.4 (1.7–45.1) months.

The combination of oral metronomic topotecan and pazopanib is safe and tolerable in pediatric patients with solid tumors, with a recommended phase 2 dose of 0.22 mg/m2 topotecan and 160 mg/m2 pazopanib. No objective responses were observed in this heavily pre-treated patient population, although 40% did achieve stable disease for a median of 6 months. While this combination is likely of limited benefit for relapsed disease, it may play a role in the maintenance setting.