Dataset Information

REGOSARC: Regorafenib versus placebo in doxorubicin-refractory soft-tissue sarcoma-A quality-adjusted time without symptoms of progression or toxicity analysis.

ABSTRACT: BACKGROUND:In a placebo-controlled, randomized phase 2 trial (ClinicalTrials.gov identifier NCT01900743), regorafenib improved progression-free survival (PFS) for patients with doxorubicin-pretreated advanced nonadipocytic sarcoma. A quality-adjusted time without symptoms of progression or toxicity (Q-TWiST) post hoc exploratory analysis was applied to provide an integrated measure of its clinical benefit. METHODS:In the base-case analysis, each patient's overall survival (OS) was partitioned into 3 mutually exclusive health states: the time with a grade 3 or 4 adverse event (TOX), the time without symptoms of disease or grade 3 or 4 toxicity from treatment, and the time after tumor progression or relapse. The time spent in each state was weighted with a health-state utility associated with that state and was summed to calculate the Q-TWiST. The stability of the base-case analysis was explored with several sensitivity analyses. RESULTS:In nonadipocytic sarcoma, the PFS was (4.0 months [2.6-5.5 months] with regorafenib vs 1.0 month [0.9-1.8 months] with a placebo; hazard ratio, 0.36 [0.25-0.53]; P < .0001); the OS was 13.4 months (8.6-17.3 months) with regorafenib and 9.0 months (6.8-12.5 months) with a placebo (hazard ratio, 0.67 [0.44-1.02]). With the classic definition of TOX (including all grade 3 and 4 clinical adverse events), the Q-TWiSTs were 8.0 months (7.0-9.0 months) with regorafenib and 5.7 months (4.9-6.4 months) with a placebo (P?

SUBMITTER: Berry V

PROVIDER: S-EPMC5485075 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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REGOSARC: Regorafenib versus placebo in doxorubicin-refractory soft-tissue sarcoma-A quality-adjusted time without symptoms of progression or toxicity analysis.

Berry Vincent V Basson Laurent L Bogart Emilie E Mir Olivier O Blay Jean-Yves JY Italiano Antoine A Bertucci François F Chevreau Christine C Clisant-Delaine Stéphanie S Liegl-Antzager Bernadette B Tresch-Bruneel Emmanuelle E Wallet Jennifer J Taieb Sophie S Decoupigny Emilie E Le Cesne Axel A Brodowicz Thomas T Penel Nicolas N

Cancer 20170310 12

<h4>Background</h4>In a placebo-controlled, randomized phase 2 trial (ClinicalTrials.gov identifier NCT01900743), regorafenib improved progression-free survival (PFS) for patients with doxorubicin-pretreated advanced nonadipocytic sarcoma. A quality-adjusted time without symptoms of progression or toxicity (Q-TWiST) post hoc exploratory analysis was applied to provide an integrated measure of its clinical benefit.<h4>Methods</h4>In the base-case analysis, each patient's overall survival (OS) was ...[more]

PMID: 28295221

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Project description:BackgroundAngiogenesis, among other signaling pathways, plays a key-role in sarcoma biology. Regorafenib (RE) has recently been shown to be effective in imatinib and sunitinib-refractory GIST in a phase III trial.Methods/designWe are conducting an international trial (France, Austria and Germany) consisting in 4 parallel double-blind placebo-controlled randomized (1/1) phase II trials to assess the activity and safety of RE in doxorubicin-refractory STS (ClinicalTrials.gov: NCT01900743). Each phase II trial is dedicated to one of the 4 following histological subgroups: liposarcoma, leiomyosarcoma, synovial sarcoma and other sarcoma. Within each randomized trial the following stratification factors will be applied: countries and prior exposure to pazopanib. Key-eligibility criteria are: measurable disease, age ≥18, not > 3 previous systemic treatment lines for metastatic disease, metastatic disease not amenable to surgical resection. The primary endpoint is progression-free survival (PFS) according to central radiological review. Secondary endpoints are: Toxicity (NCI-CTC AE V4.0); time to progression; Growth modulation index in pts receiving RE after randomization; 3 and 6 months PFS-Rates, best response rate and overall survival. Each phase II trial will be separately analyzed. In 3 trials, statistical assumptions are: PFS0 = 1.6 & PFS1 = 4.6 months; 1-sided α = 0.1; β = 0.05 with a total sample size of 192 pts. To take into account the rarity of synovial sarcoma, the statistical assumptions are: PFS0 = 1.6 & PFS1 = 4.6 months; 1-sided α = 0.1; β = 0.2 Tumor assessment is done monthly during the 4 first months, and every 3 months thereafter. After central radiological confirmation of tumor progression, an optional open-label option is offered to eligible patients.DiscussionThe design of this trial allows an assessment of regorafenib activity over placebo in four sarcoma strata and might provide evidence for launching a phase III trial. This study includes both integrative and exploratory translational research program. The study is enrolling since June 2013 (TRIAL REGISTRATION NUMBER: EudraCT N°: 2012-005743-24, on the 15(th) February 2012).

Project description:BackgroundThe lenvatinib (LEN) plus everolimus (EVE) combination demonstrated improved progression-free survival over everolimus alone in a phase 2 trial (Study-205).ObjectiveTo compare quality-adjusted time without symptoms of disease progression or toxicity (Q-TWiST) between LEN + EVE and EVE alone among patients with advanced renal cell carcinoma (RCC) following one prior antiangiogenic therapy.Design setting and participantsThis was a post hoc analysis of Study-205.Outcome measurements and statistical analysisSurvival time was partitioned into three mutually exclusive health states: time with grade 3/4 toxicity (TOX); time before disease progression and without grade 3/4 toxicity (TWiST); and time after disease progression (REL). The mean time in each state was weighted by utility measures and summed to calculate Q-TWiST. Nonparametric bootstrapping generated 95% confidence intervals (CIs). In the base case, utility for TWiST, TOX, and REL was assigned as 1.0, 0.5, and 0.5, respectively. Sensitivity analyses applied alternative utility values for REL, TOX, and TWiST. A relative gain in Q-TWiST of ≥10% and ≥15% has been established as clinically important and clearly clinically important, respectively.Results and limitationsPatients receiving LEN + EVE (n = 51) had a significant mean Q-TWiST gain of 3.7 mo (14.7 vs 11.0 mo; 95% CI for difference 1.3-6.3), with a relative gain of 24% compared to EVE alone. In a sensitivity analysis using alternative utility values for TWiST (varied from 0.55 to 0.9) with utility set to 0.5 for both TOX and REL, the relative Q-TWiST gain was maintained (ranging from 11.0% to 21.2%; all significant) across varying utility values. Limitations include the sample size, the absence of utility estimates, and the length of adverse events from the trial.ConclusionsLEN + EVE showed a significant and clearly clinically important improvement in quality-adjusted survival time versus EVE alone.Patient summaryPatients with advanced kidney cancer who had received other previous treatments experienced a clearly clinically important improvement in quality survival time when treated with lenvatinib plus everolimus compared to everolimus alone.

Dataset Information

REGOSARC: Regorafenib versus placebo in doxorubicin-refractory soft-tissue sarcoma-A quality-adjusted time without symptoms of progression or toxicity analysis.

Publications

REGOSARC: Regorafenib versus placebo in doxorubicin-refractory soft-tissue sarcoma-A quality-adjusted time without symptoms of progression or toxicity analysis.

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