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Phase I study of 17-allylamino-17 demethoxygeldanamycin, gemcitabine and/or cisplatin in patients with refractory solid tumors

  • PHASE I STUDIES
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Summary

Purpose: To determine the maximum tolerated dose (MTD) and characterize the dose-limiting toxicities (DLT) of 17-AAG, gemcitabine and/or cisplatin. Levels of the proteins Hsp90, Hsp70 and ILK were measured in peripheral blood mononuclear cell (PMBC) lysates to assess the effects of 17-AAG. Experimental design: Phase I dose-escalating trial using a “3 + 3” design performed in patients with advanced solid tumors. Once the MTD of gemcitabine + 17-AAG + cisplatin was determined, dose escalation of 17-AAG with constant doses of gemcitabine and cisplatin was attempted. After significant hematologic toxicity occurred, the protocol was amended to evaluate three cohorts: gemcitabine and 17-AAG; 17-AAG and cisplatin; and gemcitabine, 17-AAG and cisplatin with modified dosing. Results: The 39 patients enrolled were evaluable for toxicity and response. The MTD for cohort A was 154 mg/m2 of 17-AAG, 750 mg/m2 of gemcitabine, and 40 mg/m2 of cisplatin. In cohort A, DLTs were observed at the higher dose level and included neutropenia, hyperbilirubinemia, dehydration, GGT elevation, hyponatremia, nausea, vomiting, and thrombocytopenia. The MTD for cohort C was 154 mg/m2 of 17-AAG and 750 mg/m2 of gemcitabine, with one DLT observed (alkaline phosphatase elevation) observed. In cohort C, DLTs of thrombocytopenia, fever and dyspnea were seen at the higher dose level. The remaining cohorts were closed to accrual due to toxicity. Six patients experienced partial responses. Mean Hsp90 levels were decreased and levels of Hsp70 were increased compared to baseline. Conclusions: 17-AAG in combination with gemcitabine and cisplatin demonstrated antitumor activity, but significant hematologic toxicities were encountered. 17-AAG combined with gemcitabine is tolerable and has demonstrated evidence of activity at the MTD. The recommended phase II dose is defined as 154 mg/m2 of 17-AAG and 750 mg/m2 of gemcitabine, and is currently being investigated in phase II studies in ovarian and pancreatic cancers. There is no recommended phase II dose for the cisplatin-containing combinations.

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Acknowledgments

We thank Patrick Burch M.D. for reviewing and providing thoughtful comments on the manuscript and Barbara Rainville for secretarial support.

Conflicts of interest

The authors have nothing to disclose.

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Authors and Affiliations

  1. Division of Medical Oncology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN, 55905, USA

    Joleen Hubbard, Charles Erlichman, Cynthia Ten Eyck, Gretchen Batzel & Paul Haluska

  2. Division of Biostatistics, Mayo Clinic College of Medicine, Rochester, MN, USA

    Rui Qin & Sara Felten

  3. Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN, USA

    David O. Toft & Bridget A. Stensgard

  4. Cancer Therapy Evaluation Program, National Cancer Institute, Rockville, MD, USA

    S. Percy Ivy

Authors
  1. Joleen Hubbard
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  2. Charles Erlichman
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  3. David O. Toft
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  4. Rui Qin
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  5. Bridget A. Stensgard
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  6. Sara Felten
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  7. Cynthia Ten Eyck
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  8. Gretchen Batzel
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  9. S. Percy Ivy
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  10. Paul Haluska
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Correspondence to Paul Haluska.

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Grant support

CA66912 (C.E.), CA15083, CA090628 (P.H.).

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Hubbard, J., Erlichman, C., Toft, D.O. et al. Phase I study of 17-allylamino-17 demethoxygeldanamycin, gemcitabine and/or cisplatin in patients with refractory solid tumors. Invest New Drugs 29, 473–480 (2011). https://doi.org/10.1007/s10637-009-9381-y

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  • DOI: https://doi.org/10.1007/s10637-009-9381-y

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