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:10.1002/cam4.3712

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

Cancer Med. 2021 Mar;10(5):1589-1604. doi: 10.1002/cam4.3712. Epub 2021 Jan 15.

Authors

Arthur Felix¹, Pablo Berlanga¹, Maud Toulmonde², Judith Landman-Parker³, Sarah Dumont⁴, Gilles Vassal¹, Marie-Cécile Le Deley⁵, Nathalie Gaspar¹

Affiliations

¹ Department of Oncology for Child and Adolescent, Gustave Roussy Cancer Campus, Villejuif cedex, France.
² Medical Oncology Department, Institut Bergonié, Bordeaux, France.
³ Service d'Hématologie et d'Oncologie Pédiatrique, Hôpital Armand Trousseau, Paris, France.
⁴ Department of Medical Oncology, Gustave Roussy Cancer Campus, Villejuif, France.
⁵ Direction de la Recherche Clinique et de l'Innovation, Centre Oscar Lambret, Lille, France.

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.

Keywords: Ewing sarcoma; new cancer therapies; phase-I/II trials; trial design.

Publication types

Systematic Review

MeSH terms

Antineoplastic Agents / therapeutic use
Bone Neoplasms / therapy*
Clinical Trials, Phase I as Topic / standards*
Clinical Trials, Phase I as Topic / statistics & numerical data
Clinical Trials, Phase II as Topic / standards*
Clinical Trials, Phase II as Topic / statistics & numerical data
Combined Modality Therapy / statistics & numerical data
Databases, Factual / statistics & numerical data
Humans
Immunotherapy / statistics & numerical data
Molecular Targeted Therapy / statistics & numerical data
Multicenter Studies as Topic / statistics & numerical data
Neoplasm Recurrence, Local / therapy*
Progression-Free Survival
Randomized Controlled Trials as Topic / statistics & numerical data
Research Design / standards*
Response Evaluation Criteria in Solid Tumors
Sarcoma, Ewing / therapy*
Treatment Outcome

Substances

Antineoplastic Agents