Pathological response in children and adults with large unresected intermediate-grade or high-grade soft tissue sarcoma receiving preoperative chemoradiotherapy with or without pazopanib (ARST1321): a multicentre, randomised, open-label, phase 2 trial

Aaron R. Weiss, Yen Lin Chen, Thomas J. Scharschmidt, Yueh Yun Chi, Jing Tian, Jennifer O. Black, Jessica L. Davis, Julie C. Fanburg-Smith, Eduardo Zambrano, James Anderson, Robin Arens, Odion Binitie, Edwin Choy, Justin W. Davis, Andrea Hayes-Jordan, Simon C. Kao, Mark L. Kayton, Sandy Kessel, Ruth Lim, William H. MeyerLynn Million, Scott H. Okuno, Andrew Ostrenga, Marguerite T. Parisi, Daniel A. Pryma, R. Lor Randall, Mark A. Rosen, Mary Schlapkohl, Barry L. Shulkin, Ethan A. Smith, Joel I. Sorger, Stephanie Terezakis, Douglas S. Hawkins, Sheri L. Spunt, Dian Wang

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5 Scopus citations

Abstract

Background: Outcomes for children and adults with advanced soft tissue sarcoma are poor with traditional therapy. We investigated whether the addition of pazopanib to preoperative chemoradiotherapy would improve pathological near complete response rate compared with chemoradiotherapy alone. Methods: In this joint Children's Oncology Group and NRG Oncology multicentre, randomised, open-label, phase 2 trial, we enrolled eligible adults (aged ≥18 years) and children (aged between 2 and <18 years) from 57 hospitals in the USA and Canada with unresected, newly diagnosed trunk or extremity chemotherapy-sensitive soft tissue sarcoma, which were larger than 5 cm in diameter and of intermediate or high grade. Eligible patients had Lansky (if aged ≤16 years) or Karnofsky (if aged >16 years) performance status score of at least 70. Patients received ifosfamide (2·5 g/m2 per dose intravenously on days 1–3 with mesna) and doxorubicin (37·5 mg/m2 per dose intravenously on days 1–2) with 45 Gy preoperative radiotherapy, followed by surgical resection at week 13. Patients were randomly assigned (1:1) using a web-based system, in an unmasked manner, to receive oral pazopanib (if patients <18 years 350 mg/m2 once daily; if patients ≥18 years 600 mg once daily) or not (control group), with pazopanib not given immediately before or after surgery at week 13. The study projected 100 randomly assigned patients were needed to show an improvement in the number of participants with a 90% or higher pathological response at week 13 from 40% to 60%. Analysis was done per protocol. This study has completed accrual and is registered with ClinicalTrials.gov, NCT02180867. Findings: Between July 7, 2014, and Oct 1, 2018, 81 eligible patients were enrolled and randomly assigned to the pazopanib group (n=42) or the control group (n=39). At the planned second interim analysis with 42 evaluable patients and a median follow-up of 0·8 years (IQR 0·3–1·6) in the pazopanib group and 1 year (0·3–1·6) in the control group, the number of patients with a 90% pathological response or higher was 14 (58%) of 24 patients in the pazopanib group and four (22%) of 18 patients in the control group, with a between-group difference in the number of 90% or higher pathological response of 36·1% (83·8% CI 16·5–55·8). On the basis of an interim analysis significance level of 0·081 (overall one-sided significance level of 0·20, power of 0·80, and O'Brien-Fleming-type cumulative error spending function), the 83·8% CI for response difference was between 16·5% and 55·8% and thus excluded 0. The improvement in pathological response rate with the addition of pazopanib crossed the predetermined boundary and enrolment was stopped. The most common grade 3–4 adverse events were leukopenia (16 [43%] of 37 patients), neutropenia (15 [41%]), and febrile neutropenia (15 [41%]) in the pazopanib group, and neutropenia (three [9%] of 35 patients) and febrile neutropenia (three [9%]) in the control group. 22 (59%) of 37 patients in the pazopanib group had a pazopanib-related serious adverse event. Paediatric and adult patients had a similar number of grade 3 and 4 toxicity. There were seven deaths (three in the pazopanib group and four in the control group), none of which were treatment related. Interpretation: In this presumed first prospective trial of soft tissue sarcoma spanning nearly the entire age spectrum, adding pazopanib to neoadjuvant chemoradiotherapy improved the rate of pathological near complete response, suggesting that this is a highly active and feasible combination in children and adults with advanced soft tissue sarcoma. The comparison of survival outcomes requires longer follow-up. Funding: National Institutes of Health, St Baldrick's Foundation, Seattle Children's Foundation.

Original languageEnglish (US)
Pages (from-to)1110-1122
Number of pages13
JournalThe Lancet Oncology
Volume21
Issue number8
DOIs
StatePublished - Aug 2020

Bibliographical note

Funding Information:
This study was funded by National Clinical Trials Network Operations Center Grant U10CA180886, National Clinical Trials Network Statistics & Data Center Grant U10CA180899, National Cancer Institute IROC Operations Grant CA180803, St Baldrick's Foundation, and Seattle Children's Foundation, from Kat's Crew Guild through the Sarcoma Research Fund. We gratefully acknowledge all the patients and their families, care providers, and research personnel who participated in this study, and a special thank you to the staff at the Operations Center of the Children's Oncology Group for all of their assistance in shepherding this study through from inception to completion.

Funding Information:
ARW reports grants from the National Cancer Institute and Children's Oncology Group, during the conduct of the study and non-financial support from SpringWorks Therapeutics, outside the submitted work. TJS reports personal fees from Stryker Orthopedics and Daiichi-Sanko, outside the submitted work. JA reports salary support from Merck and Co during the study, outside the submitted work. EC reports a grant from Novartis during the study. JLD reports personal fees from Bayer, Loxo Oncology, and Lilly, outside the submitted work. MLK is a co-inventor on US patents 5641867, 6228837, 6734168, 9125959, 9339574, and 9839709, none of which are directly related to this work and none of which are currently under licensure. DAP reports grants and personal fees from Siemens, Progenics, and 511 Pharma; personal fees from Actinium Pharmaceuticals and Bayer; and grants from Nordic Nanovector, outside the submitted work. ST reports a grant from NIH NCTN Grant (2U01CA180886) for Radiation Oncology Review, during the study. DSH reports grants and non-financial support from Loxo Oncology, Bayer, and Bristol Myers Squibb; non-financial support from AstraZeneca and Celgene; and grants from Merck Sharpe & Dohme, Lilly, Eisai, Glaxo Smith Kline, Novartis, Sanofi, Amgen, Seattle Genetics, Jazz Pharmaceuticals, and Incyte, outside the submitted work. SLS reports grants from National Cancer Institute and Children's Oncology Group, during the study and grants from F Hoffman-La Roche, Novartis, Alex's Lemonade Stand Foundation, Cookies for Kids' Cancer, Bayer, Sanofi, Loxo Oncology, Incyte Corporation, Bristol Myers Squibb, St Baldrick's Foundation, Pfizer, and University of California, Santa Cruz, outside the submitted work. All other co-authors declare no competing interests.

Funding Information:
This study was funded by National Clinical Trials Network Operations Center Grant U10CA180886, National Clinical Trials Network Statistics & Data Center Grant U10CA180899, National Cancer Institute IROC Operations Grant CA180803, St Baldrick's Foundation, and Seattle Children's Foundation, from Kat's Crew Guild through the Sarcoma Research Fund. We gratefully acknowledge all the patients and their families, care providers, and research personnel who participated in this study, and a special thank you to the staff at the Operations Center of the Children's Oncology Group for all of their assistance in shepherding this study through from inception to completion.

Publisher Copyright:
© 2020 Elsevier Ltd

PubMed: MeSH publication types

  • Clinical Trial, Phase II
  • Journal Article
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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