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 - 04/08/20

Doi : 10.1016/S1470-2045(20)30325-9

Aaron R Weiss, DO ^a,^{*
Study co-chair}⁎ , Yen-Lin Chen, MD ^b,^{*
Study co-chair}, Thomas J Scharschmidt, MD ^e,^{*
Study co-chair}, Yueh-Yun Chi, PhD ^f, Jing Tian, MS ^g, Jennifer O Black, MD ^h, Jessica L Davis, MD ⁱ, Julie C Fanburg-Smith, ProfMD ^j, Eduardo Zambrano, MD ^k, James Anderson, PhD ^l, Robin Arens, AAS ^m, Odion Binitie, MD ⁿ, Edwin Choy, MD ^c, Justin W Davis ^o, Andrea Hayes-Jordan, ProfMD ^p, Simon C Kao, ProfMD ^q, Mark L Kayton, MD ^r, Sandy Kessel, BA ^s, Ruth Lim, MD ^d, William H Meyer, ProfMD ^t, Lynn Million, ProfMD ^v, Scott H Okuno, ProfMD ^w, Andrew Ostrenga, PharmD ^x, Marguerite T Parisi, ProfMD ^z, Daniel A Pryma, MD ^aa, R Lor Randall, ProfMD ^ab, Mark A Rosen, MD ^aa, Mary Schlapkohl, BSN ^ac, Barry L Shulkin, MD ^ad, Ethan A Smith, MD ^ae, Joel I Sorger, MD ^af, Stephanie Terezakis, ProfMD ^ag, Douglas S Hawkins, ProfMD ^y,^{^{†
Study co-senior leader}}, Sheri L Spunt, ProfMD ^u,^{^{†
Study co-senior leader}}, Dian Wang, ProfMD ^ah,^{^{†
Study co-senior leader}}

^a Department of Pediatrics, Maine Medical Center, Portland, ME, USA

^b Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA

^c Department of Medical Oncology, Massachusetts General Hospital, Boston, MA, USA

^d Department of Radiology, Massachusetts General Hospital, Boston, MA, USA

^e Department of Orthopaedics, James Cancer Hospital and Nationwide Children’s Hospital, Columbus, OH, USA

^f Department of Pediatrics and Preventative Medicine, University of Southern California, Los Angeles, CA, USA

^g Department of Biostatistics, University of Florida, Gainesville, FL, USA

^h Department of Pathology, Children’s Hospital Colorado, Aurora, CO, USA

ⁱ Department of Pathology, Oregon Health & Science University, Portland, OR, USA

^j Department of Pathology, Penn State Children’s Hospital, Hershey, PA, USA

^k Department of Pathology, Rocky Mountain Hospital for Children, Presbyterian St Luke Medical Centre, Denver, CO, USA

^l Department of Biostatistics and Research Decision Sciences, Merck and Co, North Wales, PA, USA

^m Department of Clinical Trials, Connecticut Children’s Medical Center, Hartford, CT, USA

ⁿ Department of Sarcoma, Moffitt Cancer Center, Tampa, FL, USA

^o Children’s Oncology Group, Monrovia, CA, USA

^p Department of Surgery, University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA

^q Department of Radiology, University of Iowa Carver College of Medicine, Iowa City, IA, USA

^r Department of Surgery, Palm Beach Children’s Hospital, St Mary’s Medical Center, Florida Atlantic University, West Palm Beach, FL, USA

^s Imaging and Radiation Oncology Core Rhode Island, Lincoln, RI, USA

^t Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

^u Department of Pediatrics, Stanford University School of Medicine, Palo Alto, CA, USA

^v Department of Radiation Oncology, Stanford University School of Medicine, Palo Alto, CA, USA

^w Department of Oncology, Mayo Clinic, Rochester, MN, USA

^x Department of Pharmacy, University of Mississippi Medical Center, Jackson, MS, USA

^y Department of Pediatrics, University of Washington School of Medicine and Seattle Children’s Hospital, Seattle, WA, USA

^z Department of Radiology and Pediatrics, University of Washington School of Medicine and Seattle Children’s Hospital, Seattle, WA, USA

^aa Department of Radiology, University of Pennsylvania, Philadelphia, PA, USA

^ab Department of Orthopaedic Surgery, University of California Davis, Sacramento, CA, USA

^ac Department of Pediatrics, University of Iowa Hospitals and Clinics, Iowa City, IA, USA

^ad Department of Diagnostic Imaging, St Jude Children’s Research Hospital, Memphis, TN, USA

^ae Department of Radiology and Medical Imaging, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

^af Department of Orthopaedic Surgery, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

^ag Department of Radiation Oncology, University of Minnesota, Masonic Cancer Center, Minneapolis, MN, USA

^ah Department of Radiation Oncology, Rush University Medical Center, Chicago, IL, USA

^* Correspondence to: Dr Aaron R Weiss, Department of Pediatrics, Maine Medical Center, Portland, ME 04102, USA Department of Pediatrics Maine Medical Center Portland ME 04102 USA

Summary

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.

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Vol 21 - N° 8

P. 1110-1122 - août 2020 Retour au numéro

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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 - 04/08/20

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