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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

Authors :
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
Daniel A. Morgenstern
Source :
Cancers; Volume 14; Issue 12; Pages: 2985
Publication Year :
2022
Publisher :
Multidisciplinary Digital Publishing Institute, 2022.

Abstract

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.

Details

Language :
English
ISSN :
20726694
Database :
OpenAIRE
Journal :
Cancers; Volume 14; Issue 12; Pages: 2985
Accession number :
edsair.doi.dedup.....db5a6dea3132818872c420a8e4da552e
Full Text :
https://doi.org/10.3390/cancers14122985