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

A. Felix; Pablo Berlanga; Maud Toulmonde; Judith Landman‐Parker; Sarah Dumont; Gilles Vassal; Marie‐Cécile Le Deley; Nathalie Gaspar

doi:10.1002/cam4.3712

January 15, 2021Cancer MedicineOpen Access

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

View Full Paper

Ask AI

Bookmark

Share

Figures

Graphical abstract published by Cancer Medicine — Graphical abstract · Published by Cancer Medicine · CC BY

Why the study?

The optimal Phase-II design to evaluate new therapies in refractory or relapsed Ewing sarcoma remains imperfectly defined.

What are the characteristics and outcomes of phase-I/II trials in recurrent/refractory Ewing sarcoma?

Key Points

To evaluate phase-I/II clinical trial designs in recurrent and refractory Ewing sarcoma and identify strategies to optimize future trial methodologies.
Systematic review of therapeutic trials registered across five trial registries (including clinicaltrials.gov and clinicaltrialsregister.eu) or published in PubMed/ASCO/ESMO between 2005 and 2018.
Screened studies testing targeted therapies, chemotherapies, immunotherapies, or combinations using terms for Ewing sarcoma or bone sarcoma in phase-I or phase-II designs.
Among 146 identified trials (88% multicentric, 30% international, 5% randomized), single-arm designs dominated (88%), and response rate was the most common primary endpoint (79%) rather than progression-free survival (16%) or overall survival (3%).
In the 62 published trials enrolling 827 patients, overall response rate was poor at 10% (1.7% complete response, 8.3% partial response), with 25% achieving stable disease, a median progression-free survival of 1.9 months (range 1.3–14.7), and a median overall survival of 7.6 months (range 5–30).
Only 11 published trials (18%) were considered positive, demonstrating a median response rate of 15% (range 7%–30%), median progression-free survival of 4.5 months (range 1.3–10), and median overall survival of 16.6 months (range 6.9–30).

Structured PICO

What are the characteristics and outcomes of phase-I/II trials in recurrent/refractory Ewing sarcoma?

P

Population

146 phase-I/II trials (62 published trials enrolling 827 patients) evaluating therapies for refractory and recurrent Ewing sarcoma.

I

Intervention

Targeted therapies (34%), chemotherapies (23%), immune therapies (19%), or combined therapies (24%)

C

Comparator

Mostly single-arm trials (88%); 5% randomized

O

Outcome

Response rate (RR=CR+PR) in 79% of trials, progression-free survival (16%), or overall survival (3%)surrogate

This systematic review highlights the poor outcomes in phase I/II trials for recurrent/refractory Ewing sarcoma and emphasizes the need for international randomized phase II trials using PFS as the primary endpoint.

Implication

Supports randomized international Phase II trials with PFS endpoint in refractory ES; leaves open optimal design parameters pending prospective data.

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.

Discussion

No takes yet. Share an insight, caveat, or question.

Cite This Study

Felix et al. (2021) studied this question.

synapsesocial.com/papers/6a73bb121c100ebba7fb6e53 https://doi.org/10.1002/cam4.3712

View Full Paper

Ask AI

Bookmark

Share

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

Figures

Key Points

Structured PICO

Implication

Abstract

Discussion

Cite This Study

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

Figures

Key Points

Structured PICO

Implication

Abstract

Discussion

Cite This Study

Keep reading

More related papers

More from Cancer Medicine

Keep reading

More related papers

More from Cancer Medicine