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Phase III Soft Tissue Sarcoma Trials: Success or Failure?

ABSTRACT: Two recently reported phase III randomised control trials (RCTs) have resulted in the registration of two new systemic therapies for advanced soft tissue sarcoma. Both of these trials' designs were informed by phase II data that guided the selection of sensitive STS diagnoses, enabling the demonstration of benefit in certain subtypes. A number of other phase III trials reported in the last 18 months have seemingly fit into a recurrent pattern of failure-promising efficacy signals in earlier phase studies being lost in the survival follow-up of large, highly heterogeneous cohorts. Greater effort is needed to identify histological and molecularly defined subgroups associated with differential treatment response in order to avoid the tremendous disappointment and loss of resources associated with a failed phase III trial. Additionally, improvements in available treatment of advanced STS have underpinned a prolongation in overall survival (OS). Consequently, surrogate efficacy endpoints are of increasing importance to STS drug trials. Whilst progression-free survival (PFS) should arguably replace overall survival as the primary endpoint of choice in first-line studies, more work is required to provide definitive validation of surrogacy, as well as developing more sophisticated techniques of assessing radiological response and expanding the inclusion of quality-of-life-related endpoints.

SUBMITTER: Lee AT

PROVIDER: S-EPMC5362672 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Phase III Soft Tissue Sarcoma Trials: Success or Failure?

Lee Alexander T J AT Pollack Seth M SM Huang Paul P Jones Robin L RL

Current treatment options in oncology 20170301 3

<h4>Opinion statement</h4>Two recently reported phase III randomised control trials (RCTs) have resulted in the registration of two new systemic therapies for advanced soft tissue sarcoma. Both of these trials' designs were informed by phase II data that guided the selection of sensitive STS diagnoses, enabling the demonstration of benefit in certain subtypes. A number of other phase III trials reported in the last 18 months have seemingly fit into a recurrent pattern of failure-promising effica ...[more]

PMID: 28332083

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Project description:BackgroundPatient-reported outcomes (PROs), including health-related quality of life, are recommended to be routinely collected in clinical trials, but data are limited from trials of sarcoma patients. In this analysis, pooled PRO data are reported from patients with advanced or metastatic soft tissue sarcoma (STS) enrolled to the ANNOUNCE phase III trial of doxorubicin-based therapy.MethodsANNOUNCE was a phase III trial that randomized 509 patients with STS to receive up to eight cycles of doxorubicin with olaratumab or placebo, followed by single-agent olaratumab or placebo. Dexrazoxane was allowed at any cycle of treatment. Participants completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30, which is scored 0-100), and Brief Pain Inventory Short Form Modified (mBPI-sf, scored from 0-10) at each treatment cycle. A descriptive analysis of the longitudinal data was conducted overall and by cumulative dose of doxorubicin received to inform the clinical care of patients with STS. Worsening on the QLQ-C30 was defined as a change of 10 points or more at any post-baseline assessment. Worsening on the mPBI-sf was defined as an increase of ≥2 points from baseline.ResultsThe majority of participants completed the baseline and at least one subsequent PRO assessment within the trial (n = 460, 90.4% EORTC QLQ-C30; n = 454, 89.2%, mBPI-sf). Patients with STS enrolled to the ANNOUNCE trial had clinically meaningful problems with physical function and pain before initiating doxorubicin. Overall, those with fewer symptoms or better function at baseline received higher cumulative doxorubicin dose throughout the study. At baseline, mean QLQ-C30 fatigue was 29.9 with a median time to first worsening of 0.9 months, and mean nausea/vomiting was 6.5 with 1.4 months until worsening; mean physical function was 78.3 with median time to worsening of 2.1 months and mean health status was 66.8 with median time to first worsening of 1.6 months. Median time to worsening of pain was 7.9 months.ConclusionPatients with advanced or metastatic sarcoma reported a relatively rapid decline in PROs during doxorubicin-based treatment, with patients with poorer symptoms at baseline (specifically fatigue), subsequently receiving less doxorubicin therapy. The availability of detailed summary data from the patient perspective during doxorubicin-based treatment may inform future care of these patients and can provide a resource for the development of PRO endpoints in future trials.

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Phase III Soft Tissue Sarcoma Trials: Success or Failure?

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Phase III Soft Tissue Sarcoma Trials: Success or Failure?

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