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Phase 1 Study of Cabozantinib in Combination with Topotecan- Cyclophosphamide for Patients with Relapsed Ewing Sarcoma or Osteosarcoma
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  • Kevin Campbell,
  • Andrew Posner,
  • Nan Chen,
  • Kerri Cavanaugh,
  • Ketki Bhushan,
  • Katherine Janeway,
  • David Shulman,
  • Suzanne George,
  • Kelly Klega,
  • Brian Crompton,
  • Wendy London,
  • Steven DuBois
Kevin Campbell
Dana-Farber/Boston Children's Cancer and Blood Disorders Center
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Andrew Posner
Dana-Farber/Boston Children's Cancer and Blood Disorders Center
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Nan Chen
Dana-Farber/Boston Children's Cancer and Blood Disorders Center
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Kerri Cavanaugh
Dana-Farber/Boston Children's Cancer and Blood Disorders Center
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Ketki Bhushan
Dana-Farber/Boston Children's Cancer and Blood Disorders Center
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Katherine Janeway
Dana-Farber/Boston Children's Cancer and Blood Disorders Center
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David Shulman
Dana-Farber/Boston Children's Cancer and Blood Disorders Center
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Suzanne George
Dana-Farber/Boston Children's Cancer and Blood Disorders Center
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Kelly Klega
Dana-Farber/Boston Children's Cancer and Blood Disorders Center
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Brian Crompton
Dana-Farber/Boston Children's Cancer and Blood Disorders Center
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Wendy London
Dana-Farber/Boston Children's Cancer and Blood Disorders Center
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Steven DuBois
Dana-Farber/Boston Children's Cancer and Blood Disorders Center

Corresponding Author:steven_dubois@dfci.harvard.edu

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Abstract

Purpose Phase 1 study assessing the safety and toxicity of cabozantinib in combination with topotecan and cyclophosphamide for relapsed osteosarcoma and Ewing sarcoma. Methods Oral cabozantinib (25mg/m 2) was administered daily for 21 (dose level 1) or 14 (dose level -1B) days. Topotecan (0.75mg/m 2) and cyclophosphamide (250mg/m 2) were administered IV on days 1-5. A modified 3+3 design based upon first cycle dose-limiting toxicities (DLT) was used for dose escalation. Results Twelve patients with a median age of 15 (12.9-33.2) years were enrolled (7 with Ewing sarcoma; 5 with osteosarcoma); all were evaluable for toxicity. At dose level 1, three of six patients developed first cycle DLT: grade 3 epistaxis; grade 3 transaminitis; prolonged grade 2 thrombocytopenia. Six patients were enrolled on dose level -1B (interrupted cabozantinib, given days 8-21), with one first cycle DLT (grade 3 pneumothorax) observed. Of the 10 response evaluable patients, one had partial response (Ewing sarcoma), seven had stable disease, and two had progressive disease. Conclusions The recommended phase 2 doses and schedules for this combination are topotecan 0.75mg/m 2 IV days 1-5, cyclophosphamide 250mg/m 2 IV days 1-5, and cabozantinib 25mg/m 2 days 8-21. Non-concomitant administration of cabozantinib with cytotoxic therapy in this population has acceptable toxicity while allowing for potential disease control.
21 Jul 2023Submission Checks Completed
21 Jul 2023Assigned to Editor
21 Jul 2023Submitted to Pediatric Blood & Cancer
25 Jul 2023Review(s) Completed, Editorial Evaluation Pending
27 Jul 2023Reviewer(s) Assigned
08 Aug 2023Editorial Decision: Revise Major
22 Aug 20231st Revision Received
22 Aug 2023Submission Checks Completed
22 Aug 2023Assigned to Editor
22 Aug 2023Review(s) Completed, Editorial Evaluation Pending
23 Aug 2023Reviewer(s) Assigned
01 Sep 2023Editorial Decision: Accept