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A Phase I clinical trial of the combination of imatinib and paclitaxel in patients with advanced or metastatic solid tumors refractory to standard therapy

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Abstract

Purpose

Pre-clinical data suggest that combining imatinib with traditional cytotoxic chemotherapy may improve imatinib efficacy. We conducted a Phase I study of imatinib in combination with paclitaxel in patients with advanced or metastatic solid tumors.

Methods

Patients were accrued to the study in a standard 3 + 3 design. Patients were restaged every two cycles, and those with stable disease (SD), or better, continued study treatment without interruption. Maximally tolerated doses (MTDs) and pharmacokinetic profiles of combination imatinib and paclitaxel were assessed.

Results

Fifty-eight patients were enrolled, including 40 in the Phase I dose escalation portion. Alternating dose escalation of imatinib and paclitaxel on a 28-day cycle resulted in MTDs of 800 mg imatinib daily, on days 1–4, 8–11, 15–18, and 22–25, and 100 mg/m2 paclitaxel weekly, on days 3, 10, and 17. Two expansion cohorts, comprising 10 breast cancer patients and 8 patients with soft-tissue sarcomas, were enrolled at the MTDs. The most common adverse events were flu-like symptoms (64 %) and nausea/vomiting (71 %). The most common Grade 3/4 toxicities were neutropenia (26 %), flu-like symptoms (12 %), and pain (12 %). There were no relevant differences in the pharmacokinetic profiles of either drug when given in combination compared with alone. Thirty-eight subjects were evaluable for response, 18 (47.4 %) of whom experienced clinical benefit. Five patients (13.2 %) had a partial response (PR) and 13 patients (34.2 %) had SD; the average time to progression in those with clinical benefit was 17 weeks (range: 7–28 weeks).

Conclusions

This combination of imatinib and paclitaxel was reasonably safe and tolerable, and demonstrated evidence of anti-tumor activity. Further exploration in disease-specific Phase II trials is warranted.

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Abbreviations

PDGF:

Platelet-derived growth factor

PDGF-R:

Platelet-derived growth factor receptor

CML:

Chronic myelogenous leukemia

GIST:

Gastrointestinal stromal tumor

DFSP:

Dermatofibrosarcoma protuberans

RR:

Response rate

CR:

Complete response

IFP:

Interstitial fluid pressure

ULN:

Upper limit of normal

MTD:

Maximally tolerated doses

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Acknowledgments

We would like to thank Novartis for funding this clinical trial. Jan H. Beumer (JHB) and Merrill J. Egorin (MJE) were supported by grant P30-CA47904 from the National Cancer Institute. JHB is the recipient of a Hillman Fellows for Innovative Cancer Research Award. MJE is the recipient of an American Society of Clinical Oncology Cancer Foundation Translational Research Professorship.

Conflict of interest

None.

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Authors and Affiliations

  1. Lombardi Comprehensive Cancer Center, Developmental Therapeutics Program, Georgetown University Medical Center, Podium B, 3800 Reservoir Road, NW, Washington, DC, 20007, USA

    Michael J. Pishvaian, Rebecca Slack, Eunice Y. Koh, Marion L. Hartley, Ion Cotarla, John Deeken, Aiwu Ruth He, Jimmy Hwang, Shakun Malik, Kashif Firozvi, Minetta Liu, Beth Elston & John L. Marshall

  2. Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, TX, 77230, USA

    Rebecca Slack

  3. Molecular Therapeutics/Drug Discovery Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA, 15213, USA

    Jan H. Beumer & Sandy Strychor

  4. Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, PA, 15213, USA

    Jan H. Beumer

  5. Melanoma Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA, 15213, USA

    Jan H. Beumer

  6. Center for Population Health and Clinic Epidemiology, Brown University, Providence, RI, 02912, USA

    Beth Elston

  7. Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA

    Merrill J. Egorin

  8. Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA

    Merrill J. Egorin

Authors
  1. Michael J. Pishvaian
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  2. Rebecca Slack
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  3. Eunice Y. Koh
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  4. Jan H. Beumer
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  5. Marion L. Hartley
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  6. Ion Cotarla
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  7. John Deeken
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  8. Aiwu Ruth He
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  9. Jimmy Hwang
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  10. Shakun Malik
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  12. Minetta Liu
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  13. Beth Elston
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  14. Sandy Strychor
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  15. Merrill J. Egorin
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  16. John L. Marshall
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Correspondence to Michael J. Pishvaian.

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Pishvaian, M.J., Slack, R., Koh, E.Y. et al. A Phase I clinical trial of the combination of imatinib and paclitaxel in patients with advanced or metastatic solid tumors refractory to standard therapy. Cancer Chemother Pharmacol 70, 843–853 (2012). https://doi.org/10.1007/s00280-012-1969-9

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  • DOI: https://doi.org/10.1007/s00280-012-1969-9

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