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Phase II study of dacarbazine given with modern prophylactic anti-emetics and growth factor support to patients with metastatic, resistant soft tissue, and bone sarcoma.

ABSTRACT: Historically, administration of dacarbazine to sarcoma patients was limited by frequent treat-ment-related nausea/vomiting and neutropenia. These toxicities are now largely preventable with contemporary antiemetics and growth factor support. In this single-arm, phase II study, dacarbazine 850 mg/m² was given on day 1 of each 3-week cycle until disease progression or intolerance with prophylactic serotonin-3 receptor, neurokinin-1 antagonists, corticosteroids, and pegfilgrastim. Coprimary endpoints included clinical benefit rate (CBR), and any grade of nausea/vomiting and/or grade 3-4 neutropenia. With a sample size of 80 patients, >24 patients with clinical benefit would indicate that the CBR exceeds the historical (<20%) [Power 0.80; alpha 0.05]. In addition, we hypothesized that the rates of nausea/vomiting would be 27% and grade 3-4 neutropenia would be 1% (historical: 90% and 36%, respectively) [power 0.95; alpha 0.05]. The CBR was 30% (24 patients: PR-2 and stable-22). The rate of nausea/vomiting was 37.5% (31 patients) and grades 3-4 neutropenia was 10% (8 patients). Median time-to-progression was 8.1 weeks (95% CI 8-9.7) and median overall survival was 35.8 weeks (95% CI 26.2-55.4). PET scans demonstrated no association with response. Modern prophylactic anti-emetics and pegfilgrastim given with dacarbazine reduced the rates of treatment related nausea/vomiting and serious neutropenia.

SUBMITTER: Van Tine BA

PROVIDER: S-EPMC8504645 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Phase II study of dacarbazine given with modern prophylactic anti-emetics and growth factor support to patients with metastatic, resistant soft tissue, and bone sarcoma.

Van Tine Brian A BA Weiss Mia C MC Hirbe Angela C AC Oppelt Peter J PJ Abaricia Sarah S Trinkaus Kathryn K Luo Jingqin J Berry Shellie S Ruff Tyler T Callahan Cheryl C Toensikoetter Jacqui J Ley Jessica J Siegel Marilyn J MJ Dehdashti Farrokh F Siegel Barry A BA Adkins Douglas R DR

Rare tumors 20211008

Historically, administration of dacarbazine to sarcoma patients was limited by frequent treat-ment-related nausea/vomiting and neutropenia. These toxicities are now largely preventable with contemporary antiemetics and growth factor support. In this single-arm, phase II study, dacarbazine 850 mg/m<sup>2</sup> was given on day 1 of each 3-week cycle until disease progression or intolerance with prophylactic serotonin-3 receptor, neurokinin-1 antagonists, corticosteroids, and pegfilgrastim. Coprim ...[more]

PMID: 34646430

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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.

Dataset Information

Phase II study of dacarbazine given with modern prophylactic anti-emetics and growth factor support to patients with metastatic, resistant soft tissue, and bone sarcoma.

Publications

Phase II study of dacarbazine given with modern prophylactic anti-emetics and growth factor support to patients with metastatic, resistant soft tissue, and bone sarcoma.

Similar Datasets

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