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Systematic review of phase-I/II trials enrolling refractory and recurrent Ewing sarcoma: Actual knowledge and future
Arthur Felix1, Pablo Berlanga1, Maud Toulmonde2
1Department of Oncology for Child and Adolescent, Gustave Roussy Cancer Campus, Villejuif cedex, France.
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.
Insights
Optimal Phase-II trial designs for refractory/relapsed Ewing sarcomas (ES) are needed. Analysis of past trials suggests international, randomized Phase-II studies with progression-free survival as the primary endpoint are crucial for better outcomes.
Area of Science:
- Oncology
- Clinical Trial Design
- Ewing Sarcoma Research
Background:
- Optimal Phase-II trial designs for refractory/relapsed Ewing sarcomas (ES) are not well-defined.
- Current trial designs often lack international collaboration and diverse age group inclusion.
Purpose of the Study:
- To analyze phase-I/II trials for recurrent/refractory ES to inform improved trial design.
- To identify limitations in existing therapeutic trial methodologies for Ewing sarcoma.
Main Methods:
- A comprehensive review of therapeutic trials for Ewing sarcoma (ES) and related sarcomas was conducted.
- Data from 146 trials registered between 2005-2018 across five major databases and publications were analyzed.
Main Results:
- Most trials (88%) were single-arm, testing targeted, chemo-, or immune therapies, with few international collaborations (30%).
- Inclusion criteria often excluded younger patients and only allowed measurable diseases.
- Published trials showed poor response rates (10%) and limited median progression-free survival (1.9 months).
Conclusions:
- There is a critical need for international, randomized Phase-II trials in Ewing sarcoma.
- Future trials should include all age ranges and utilize progression-free survival as the primary endpoint.
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