Cancer Medicine (Mar 2021)

Systematic review of phase‐I/II trials enrolling refractory and recurrent Ewing sarcoma: Actual knowledge and future directions to optimize the research

  • Arthur Felix,
  • Pablo Berlanga,
  • Maud Toulmonde,
  • Judith Landman‐Parker,
  • Sarah Dumont,
  • Gilles Vassal,
  • Marie‐Cécile Le Deley,
  • Nathalie Gaspar

DOI
https://doi.org/10.1002/cam4.3712
Journal volume & issue
Vol. 10, no. 5
pp. 1589 – 1604

Abstract

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Abstract Background Optimal Phase‐II design to evaluate new therapies in refractory/relapsed Ewing sarcomas (ES) remains imperfectly defined. Objectives Recurrent/refractory ES phase‐I/II trials analysis to improve trials design. Methods Comprehensive review of therapeutic trials registered on five databases (who.int/trialsearch, clinicaltrials.gov, clinicaltrialsregister.eu, e‐cancer.fr, and umin.ac.jp) and/or published in PubMed/ASCO/ESMO websites, between 2005 and 2018, using the criterion: (Ewing sarcoma OR bone sarcoma OR sarcoma) AND (Phase‐I or Phase‐II). Results The 146 trials identified (77 phase‐I/II, 67 phase‐II, and 2 phase‐II/III) tested targeted (34%), chemo‐ (23%), immune therapies (19%), or combined therapies (24%). Twenty‐three trials were ES specific and 48 had a specific ES stratum. Usually multicentric (88%), few trials were international (30%). Inclusion criteria cover the recurrent ES age range for only 12% of trials and allowed only accrual of measurable diseases (RECIST criteria). Single‐arm design was the most frequent (88%) testing mainly single drugs (61%), only 5% were randomized. Primary efficacy outcome was response rate (RR=CR+PR; Complete+Partial response) (n = 116/146; 79%), rarely progression‐free or overall survival (16% PFS and 3% OS). H0 and H1 hypotheses were variable (3%–25% and 20%–50%, respectively). The 62 published trials enrolled 827 ES patients. RR was poor (10%; 15 CR=1.7%, 68 PR=8.3%). Stable disease was the best response for 186 patients (25%). Median PFS/OS was of 1.9 (range 1.3–14.7) and 7.6 months (5–30), respectively. Eleven (18%) published trials were considered positive, with median RR/PFS/OS of 15% (7%–30%), 4.5 (1.3–10), and 16.6 months (6.9–30), respectively. Conclusion This review supports the need to develop the international randomized phase‐II trials across all age ranges with PFS as primary endpoint.

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