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Combination of trabectedin and gemcitabine for advanced soft tissue sarcomas: results of a phase I dose escalating trial of the German Interdisciplinary Sarcoma Group (GISG).

ABSTRACT: Evaluation of the potential efficacy and safety of combination therapies for advanced soft tissue sarcomas (STS) has increased substantially after approval of trabectedin and pazopanib. Trabectedin's introduction in Europe in 2007 depended mainly on its activity in so-called L-sarcomas (liposarcoma and leiomyosarcoma); combination of trabectedin with other chemotherapies used in STS seems of particular interest.We initiated within the German Interdisciplinary Sarcoma Group (GISG) a phase I dose escalating trial evaluating the combination of trabectedin and gemcitabine in patients with advanced and/or metastatic L-sarcomas (GISG-02; ClinicalTrials.gov NCT01426633). Patients were treated with increasing doses of trabectedin and gemcitabine. The primary endpoint was to determine the maximum tolerated dose.Five patients were included in the study. Two patients were treated on dose level 1 comprising trabectedin 0.9 mg/m2 on day 1 and gemcitabine 700 mg/m2 on days 1 + 8, every 3 weeks. Due to dose-limiting toxicity (DLT) in both patients (elevated transaminases and thrombocytopenia), an additional three patients were treated on dose level -1 with trabectedin 0.7 mg/m2 plus gemcitabine 700 mg/m2. Of these three patients, two demonstrated another DLT; therefore, the trial was stopped and none of the dose levels could be recommended for phase II testing.The GISG-02 phase I study was stopped with the conclusion that the combination of gemcitabine and trabectedin is generally not recommended for the treatment of patients with advanced and/or metastatic leiomyosarcoma or liposarcoma. Also, this phase I study strongly supports the necessity for careful evaluation of combination therapies.

SUBMITTER: Kasper B

PROVIDER: S-EPMC4306943 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Combination of trabectedin and gemcitabine for advanced soft tissue sarcomas: results of a phase I dose escalating trial of the German Interdisciplinary Sarcoma Group (GISG).

Kasper Bernd B Reichardt Peter P Pink Daniel D Sommer Michaela M Mathew Monika M Rauch Geraldine G Hohenberger Peter P

Marine drugs 20150113 1

<h4>Background</h4>Evaluation of the potential efficacy and safety of combination therapies for advanced soft tissue sarcomas (STS) has increased substantially after approval of trabectedin and pazopanib. Trabectedin's introduction in Europe in 2007 depended mainly on its activity in so-called L-sarcomas (liposarcoma and leiomyosarcoma); combination of trabectedin with other chemotherapies used in STS seems of particular interest.<h4>Methods</h4>We initiated within the German Interdisciplinary S ...[more]

PMID: 25591040

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Project description:ObjectivesThe choice of drug treatment in advanced soft tissue sarcoma (STS) continues to be a challenge regarding efficacy, quality of life (QoL) and toxicity. Unlike other cancer types, where integrating patient-reported outcomes (PRO) has proven to be beneficial for QoL, there is no such evidence in patients with STS as of now. The YonLife trial aimed to explore the effect of a tailored multistep intervention on QoL, symptoms and survival in patients with advanced STS undergoing treatment with trabectedin as well as identifying predictors of QoL.DesignYonLife is a cluster-randomised, open-label, proof-of-concept study. The intervention incorporates electronic PRO assessment, a case vignette and expert-consented treatment recommendations.ParticipantsSix hospitals were randomised to the control arm (CA) or interventional arm (IA). Seventy-nine patients were included of whom 40 were analysed as per-protocol analysis set.Primary and secondary outcome measuresThe primary end point was the change of Functional Assessment for Cancer Therapy (FACT-G) total score after 9 weeks. Secondary outcomes included QoL (FACT-G subscales), anorexia and cachexia (Functional Assessment of Anorexia/Cachexia Therapy (FAACT)), symptoms (MD Anderson Symptom Inventory (MDASI)), anxiety and depression (HADS), pain intensity and interference (Brief Pain Inventory (BPI)) and survival assessment.ResultsAfter 9 weeks of treatment, QoL declined less in the IA (ΔFACT-G total score: -2.4, 95% CI: -9.2 to 4.5) as compared with CA (ΔFACT-G total score: -3.9; 95% CI:-11.3 to 3.5; p=0.765). In almost all FACT-G subscales, average declines were lower in IA, but without reaching statistical significance. Smaller adverse trends between arms were observed for MDASI, FAACT, HADS and BPI scales. These trends failed to reach statistical significance. Overall mean survival was longer in IA (648 days) than in CA (389 days, p=0.110). QoL was predicted by symptom severity, symptom interference, depression and anxiety.ConclusionOur data suggest a potentially favourable effect of an electronic patient-reported outcomes based intervention on QoL that needs to be reappraised in confirmatory studies.Trial registration numberClinicalTrials.gov Identifier (NCT02204111).

Project description:For resectable soft tissue sarcoma (STS), radical surgery, usually combined with radiotherapy, is the mainstay of treatment and the only potentially curative modality. Since surgery is often complicated by large tumour size and extensive tumour vasculature, preoperative treatment strategies with the aim of devitalising the tumour are being explored. One option is treatment with antiangiogenic drugs. The multikinase inhibitor pazopanib, which possesses pronounced antiangiogenic effects, has shown activity in metastatic and unresectable STS, but has so far not been tested in the preoperative setting.This open-label, multicentre phase II window-of-opportunity trial assesses pazopanib as preoperative treatment of resectable STS. Participants receive a 21-day course of pazopanib 800 mg daily during wait time for surgery. Major eligibility criteria are resectable, high-risk adult STS of any location, or metachronous solitary STS metastasis for which resection is planned, and adequate organ function and performance status. The trial uses an exact single-stage design. The primary end point is metabolic response rate (MRR), that is, the proportion of patients with >50% reduction of the mean standardised uptake value (SUVmean) in post-treatment compared to pre-treatment fluorodeoxyglucose positron emission tomography CT. The MRR below which the treatment is considered ineffective is 0.2. The MRR above which the treatment warrants further exploration is 0.4. With a type I error of 5% and a power of 80%, the sample size is 35 evaluable patients, with 12 or more responders as threshold. Main secondary end points are histopathological and MRI response, resectability, toxicity, recurrence-free and overall survival. In a translational substudy, endothelial progenitor cells and vascular epithelial growth factor receptor are analysed as potential prognostic and predictive markers.Approval by the ethics committee II, University of Heidelberg, Germany (2012-019F-MA), German Federal Institute for Drugs and Medical Devices (61-3910-4038155) and German Federal Institute for Radiation Protection (Z5-22463/2-2012-007).NCT01543802, EudraCT: 2011-003745-18; Pre-results.

Project description:Objective: Trabectedin is an anti-cancer drug commonly used for the treatment of patients with metastatic soft tissue sarcoma (mSTS). Despite its recognized efficacy, significant variability in pharmacological response has been observed among mSTS patients. To address this issue, this pharmacometabolomics study aimed to identify pre-dose plasma metabolomics signatures that can explain individual variations in trabectedin pharmacokinetics and overall clinical response to treatment. Methods: In this study, 40 mSTS patients treated with trabectedin administered by 24 h-intravenous infusion at a dose of 1.5 mg/m2 were enrolled. The patients' baseline plasma metabolomics profiles, which included derivatives of amino acids and bile acids, were analyzed using multiple reaction monitoring LC-MS/MS together with their pharmacokinetics profile of trabectedin. Multivariate Partial least squares regression and univariate statistical analyses were utilized to identify correlations between baseline metabolite concentrations and trabectedin pharmacokinetics, while Partial Least Squares-Discriminant Analysis was employed to evaluate associations with clinical response. Results: The multiple regression model, derived from the correlation between the AUC of trabectedin and pre-dose metabolomics, exhibited the best performance by incorporating cystathionine, hemoglobin, taurocholic acid, citrulline, and the phenylalanine/tyrosine ratio. This model demonstrated a bias of 4.6% and a precision of 17.4% in predicting drug AUC, effectively accounting for up to 70% of the inter-individual pharmacokinetic variability. Through the use of Partial least squares-Discriminant Analysis, cystathionine and hemoglobin were identified as specific metabolic signatures that effectively distinguish patients with stable disease from those with progressive disease. Conclusions: The findings from this study provide compelling evidence to support the utilization of pre-dose metabolomics in uncovering the underlying causes of pharmacokinetic variability of trabectedin, as well as facilitating the identification of patients who are most likely to benefit from this treatment. Graphical Abstract

Project description:BACKGROUND:Alveolar soft part sarcoma (ASPS) is an exceedingly rare and orphan disease, without active drugs approved in the front line. Pazopanib and trabectedin are licensed for sarcoma treatment from second-line, but very little and contradictory data are available on their activity in ASPS. Lacking ongoing and/or planned clinical trials, we conducted a multi-institutional study involving the reference sites for sarcoma in Europe, U.S., and Japan, within the World Sarcoma Network, to investigate the efficacy of pazopanib and trabectedin. MATERIALS AND METHODS:From May 2007, 14 of the 27 centers that were asked to retrospectively review their databases had identified 44 advanced ASPS patients treated with pazopanib and/or trabectedin. Response was evaluated by Response Evaluation Criteria in Solid Tumors 1.1. Progression-free survival (PFS) and overall survival (OS) were computed by Kaplan-Meier method. RESULTS:Among 30 patients who received pazopanib, 18 were pretreated (13 with other antiangiogenics). Response was evaluable in 29/30 patients. Best responses were 1 complete response, 7 partial response (PR), 17 stable disease (SD), and 4 progressions. At a 19-month median follow-up, median PFS was 13.6 months (range: 1.6-32.2+), with 59% of patients progression-free at 1 year. Median OS was not reached.Among 23 patients treated with trabectedin, all were pretreated and evaluable for response. Best responses were 1 PR, 13 SD, and 9 progressions. At a 27-month median follow-up, median PFS was 3.7 months (range: 0.7-109), with 13% of patients progression-free at 1 year. Median OS was 9.1 months. CONCLUSION:The value of pazopanib in advanced ASPS is confirmed, with durable responses, whereas the value of trabectedin appears limited. These results are relevant to defining the best approach to advanced ASPS. IMPLICATIONS FOR PRACTICE:This retrospective study, conducted among the world reference centers for treatment of sarcoma, confirms the value of pazopanib in patients with advanced alveolar soft part sarcoma (ASPS), with dimensional and durable responses, whereas trabectedin shows a limited activity. Alveolar soft part sarcoma is resistant to conventional cytotoxic chemotherapy. Pazopanib and trabectedin are licensed for treatment of sarcoma from second line; in the lack of prospective clinical trials, these results are relevant to defining ASPS best management and strongly support initiatives aimed at obtaining the approval of pazopanib in the front line of the disease.

Dataset Information

Combination of trabectedin and gemcitabine for advanced soft tissue sarcomas: results of a phase I dose escalating trial of the German Interdisciplinary Sarcoma Group (GISG).

Publications

Combination of trabectedin and gemcitabine for advanced soft tissue sarcomas: results of a phase I dose escalating trial of the German Interdisciplinary Sarcoma Group (GISG).

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