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Phase I study of the safety and pharmacokinetics of trabectedin with docetaxel in patients with advanced malignancies

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Abstract

Purpose

Combination therapy with trabectedin and docetaxel was evaluated in patients with advanced malignancies.

Methods

In this open-label phase 1 study, docetaxel (60 or 75 mg/m2; 1-h intravenous infusion) was given on day 1 of a 21-day cycle in combination with escalating doses of trabectedin (0.4–1.3 mg/m2 by 3-h intravenous infusion, 1 h after docetaxel) and prophylactic granulocyte colony-stimulating factor (G-CSF). Maximum tolerated dose (MTD) as primary objective and safety, plasma pharmacokinetics, and antitumor activity as secondary objectives were assessed.

Results

Patients (N = 49) received a median of four cycles of treatment. MTD was 1.3 mg/m2 trabectedin and 60 mg/m2 docetaxel for patients with limited and 1.1 mg/m2 trabectedin and 60 mg/m2 docetaxel for patients with unlimited prior chemotherapy. Dose-limiting toxicities (during cycle 1) included elevated alanine aminotransferase (ALT) and fatigue in patients with limited prior chemotherapy and elevated ALT and febrile neutropenia in those with unlimited prior chemotherapy. The most common drug-related adverse events were nausea (65 %), fatigue (63 %), and neutropenia (53 %). One patient achieved a complete response. Thirty patients had stable disease, and 11 had stable disease for ≥6 months. Pharmacokinetic results for trabectedin plus docetaxel were similar to those previously reported for the single agents.

Conclusion

In patients with previously treated, advanced malignancies, the combination of therapeutic doses of trabectedin and docetaxel showed clinical activity and was tolerable with prophylactic G-CSF, with no evidence of clinically important drug interactions.

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Acknowledgments

We thank the trial participants; Sue Brown, RN, and Monica Davey, BSN, MEd, MBA, for expert study coordination; and Peter Zannikos, Martha Gonzalez, and Tom Verhaeghe, of Janssen Research & Development, LLC, for contributions, respectively, in study design and data interpretation; data interpretation; and bioanalysis of the study samples, and Akhilesh Singh, PhD (SIRO Clinpharm Pvt. Ltd.) and Namit Ghildyal, PhD (Janssen Research & Development, LLC) for providing editorial support. This clinical trial (ET-743-USA-2) was supported by Janssen, LLC, Raritan, NJ, USA, and PharmaMar, Madrid, Spain. This study was supported in part by Grant 5P30CA006927 from the US National Cancer Institute to Fox Chase Cancer Center.

Conflict of interest

M. von Mehren is a consultant/advisor for Janssen, LLC, and PharmaMar. M. Bookman has participated in ad hoc advisory boards for Janssen, LLC. J. Li, R. Knoblauch, T. Parekh are employees of Janssen Research & Development, LLC. During the conduct of the study, M. von Mehren, M. Bookman, N. J. Meropol, L. M. Weiner, E. Sherman, and R. B. Cohen were affiliated with the Fox Chase Cancer Center.

Funding

Janssen, LLC, provided funding for this study.

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Authors and Affiliations

  1. Department of Medical Oncology, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA

    Margaret von Mehren

  2. Arizona Oncology, US Oncology Research, Tucson, AZ, USA

    Michael Bookman

  3. Hematology and Oncology, University Hospitals Case Medical Center, Seidman Cancer Center, Cleveland, OH, USA

    Neal J. Meropol

  4. Georgetown University Medical Center, Washington, DC, USA

    Louis M. Weiner

  5. Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    Eric Sherman

  6. Janssen Research & Development, LLC, Raritan, NJ, USA

    Jinhui Li, Roland Knoblauch & Trilok Parekh

  7. University of Pennsylvania, Philadelphia, PA, USA

    Roger B. Cohen

  8. Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA

    Neal J. Meropol

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  1. Margaret von Mehren
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  2. Michael Bookman
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  3. Neal J. Meropol
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  6. Jinhui Li
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Correspondence to Margaret von Mehren.

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von Mehren, M., Bookman, M., Meropol, N.J. et al. Phase I study of the safety and pharmacokinetics of trabectedin with docetaxel in patients with advanced malignancies. Cancer Chemother Pharmacol 75, 1047–1055 (2015). https://doi.org/10.1007/s00280-015-2705-z

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  • DOI: https://doi.org/10.1007/s00280-015-2705-z

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