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

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.

FIGURE 1

Flow‐chart diagram of Ewing sarcoma phase‐I/II trials selection according to PRISMA recommendations. WHO, World Health Organization; NCT, Clinicaltrials.gov registry; EMA, European Medicines Agency registry; INCa, French Institut National du Cancer; UMIN, Japanese national registry

FIGURE 2

Geographic and temporal distribution of the 146 phase‐II trials in recurrent or refractory Ewing sarcoma. (A) Number of trials opened according to the location. (B) Number of trials opened over time

FIGURE 3

Age eligibility criteria in the 146 selected trials including refractory or recurrent Ewing sarcoma. Each trial is represented by a horizontal bar drawn from the minimal to the maximal age of inclusion. Gray horizontal bars: osteosarcoma specific trials; blue/red horizontal bars: trials with wider eligibility criteria; vertical dark line: 18 years old; vertical green line

FIGURE 4

Therapeutic interventions tested in the 146 selected phase‐I/II trials in recurrent or refractory Ewin sarcoma. (A) Therapeutic intervention type. (B) Therapeutic intervention over time between 2005 and 2018. (C) Targeted pathways in trials for targeted therapy drugs (Orange) and immunotherapy drugs (Green). Signaling pathway: Pi3k/Akt/mTOR, Igfr/ir, Raf‐braf, Tgfβ1, Sonic hedgehog, Alk, Errb, Ntrk, and Pak4. Multisignaling pathway: any multi‐tyrosine kinase Inhibitor. Epigenetic: histone deacetylase, histone demethylase‐Inhibitor, and ezh2. DNA repair: parp inhibitors. Antiangiogenic: vegf and fgf/fgfr. Transcription: anti Ews‐fli1. Metabolism: Aldh, Ascorbate, and Statin. Cell cycle: cdk4/cdk6. Immunity/inflammation: Anti‐COX2. Other: molecular‐targeted trials and Xpo‐1. Checkpoint inhibitors: antibody against PD1, PDL1, CTLA4. Adoptive cell therapy: immunotherapy that uses the patient's own T cells after in vitro treatment. Antiangiogenic antibody targeted VEGF. Anti‐inflammatory immunotherapy: IL2 aerosol. 12 years old

FIGURE 5

Description of phase‐I/II response rate in the 62 published trials according to pharmaceutical class and single drug versus combination