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Phase I and pharmacokinetic study of the novel redox-active agent, motexafin gadolinium, with concurrent radiation therapy in patients with locally advanced pancreatic or biliary cancers

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Abstract

Purpose: To determine the maximum tolerated dose and dose-limiting toxicity (DLT) of the novel anticancer agent, motexafin gadolinium (MGd), administered concurrently with radiation therapy (RT) in patients with locally advanced pancreatic or biliary tumors. The pharmacokinetics of MGd were also evaluated. Methods: Cohorts of three to six patients were treated with escalating doses of MGd, administered three times per week for a total of 16 doses concurrent with RT. The dose of RT was fixed at 5,040 cGy, and given in 28 fractions, from Monday to Friday of every week. Plasma MGd concentrations were measured by high performance liquid chromatography. Results: Eight patients were treated at dose level 1 (2.9 mg/kg), with one DLT (grade 3 fever). Three patients were treated at dose level 2 (3.6 mg/kg), and two DLTs were noted. One DLT was grade 3 nausea and vomiting (N/V), and the other was grade 3 skin toxicity. The most common toxicity was N/V. There were no objective responses. The median survival was 6 months. The MGd plasma concentration versus time profile in each patient was best fit by a two-compartment, open, linear model. There was minimal accumulation of MGd in plasma with the three-times/week dosing schedule. Simulation of the time course of MGd in the peripheral compartment indicated that maximal MGd concentrations of 1–2 μmol/kg occurred between 4 and 6 h after MGd infusion. Conclusion: Dose level 1 (2.9 mg/kg of MGd) is the recommended dose for combination with (RT) in phase II studies for locally advanced pancreatic and biliary cancers. Patient tolerance might be improved by modification of the RT schedule and antiemetic prophylaxis.

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Acknowledgments

We thank Ms. Alicia Depastino and Mr. Jeremy Hedges for excellent secretarial support and the UPCI Hematology/Oncology Writing Group for constructive criticisms regarding this manuscript. This study was sponsored by the Cancer Therapy and Evaluation Program of the National Cancer Institute, Bethesda, MD, USA. Presented, in part, at the 37th Annual Meeting of the American Society of Clinical Oncology, San Francisco, CA, 2001. Supported, in part, by grants UO1-CA69855, P30CA47904, NIH/NCCR/GCRC#5M01 RR 00056 to the University of Pittsburgh Cancer Institute and Medical Center. U01-CA069852-11 to University of Chicago Medical Center, NIH grants K24 CA84081 and P30CA23108 to Dartmouth College and U01-CA62491/CA/NCI to the University of Wisconsin Comprehensive Cancer Center.

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Author notes

  1. Marwan Fakih & Donald L. Trump

    Present address: Department of Medicine, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY, 14263, USA

  2. Sridhar Mani

    Present address: Montefiore Medical Ctr, 1825 East Chester Rd, Rm 2S-49, Bronx, NY, 10461, USA

Authors and Affiliations

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

    Ramesh K. Ramanathan, Marwan Fakih, Donald L. Trump, Chandra P. Belani & Merrill J. Egorin

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

    Ramesh K. Ramanathan, Marwan Fakih, Julie L. Eiseman, Donald L. Trump, Chandra P. Belani, Robert A. Parise & Merrill J. Egorin

  3. Division of Hematology/Oncology, Department of Medicine, University of Chicago School of Medicine, Chicago, IL, 60637, USA

    Sridhar Mani

  4. Department of Radiation Oncology, University of Pittsburgh Medical Center, Pittsburgh, PA, 15213, USA

    Melvin Deutsch

  5. Molecular Therapeutics Research Program, Norris Cotton Cancer Center, Dartmouth-Hitchock Medical Center, Lebanon, NH, 03756, USA

    Raymond P. Perez

  6. Department of Human Oncology, University of Wisconsin School of Medicine, Madison, WI, 53792, USA

    Mark A. Ritter

  7. Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA

    Julie L. Eiseman & Merrill J. Egorin

  8. Investigational Drug Branch, Cancer Therapy Evaluation Program, Division of Cancer Treatment and Centers, National Cancer Institute, Bethesda, MD, 20892, USA

    S. Percy Ivy

  9. Biostatistics Department, Graduate School of Public Health, and Biostatistics Facility, University of Pittsburgh Cancer Institute, Pittsburgh, PA, 15213, USA

    Douglas M. Potter

  10. UPMC Cancer Pavilion, # 562, 5150 Centre Avenue, Pittsburgh, PA, 15232, USA

    Ramesh K. Ramanathan

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  1. Ramesh K. Ramanathan
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  2. Marwan Fakih
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  4. Melvin Deutsch
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Correspondence to Ramesh K. Ramanathan.

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Ramanathan, R.K., Fakih, M., Mani, S. et al. Phase I and pharmacokinetic study of the novel redox-active agent, motexafin gadolinium, with concurrent radiation therapy in patients with locally advanced pancreatic or biliary cancers. Cancer Chemother Pharmacol 57, 465–474 (2006). https://doi.org/10.1007/s00280-005-0071-y

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