Cancer Chemotherapy and Pharmacology

, Volume 57, Issue 4, pp 465–474 | Cite as

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

  • Ramesh K. Ramanathan
  • Marwan Fakih
  • Sridhar Mani
  • Melvin Deutsch
  • Raymond P. Perez
  • Mark A. Ritter
  • Julie L. Eiseman
  • S. Percy Ivy
  • Donald L. Trump
  • Chandra P. Belani
  • Robert A. Parise
  • Douglas M. Potter
  • Merrill J. Egorin
Original Article

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.

Keywords

Phase I study Motexafin gadolinium Radiation therapy Pancreatic cancer 

References

  1. 1.
    Moertel CG, Frytak S, Hahn RG, O’Connell MJ et al (1981) Therapy of locally unresectable pancreatic carcinoma: a randomized comparison of high dose (6000 rads) radiation alone, moderate dose radiation (4000 rads + 5-fluorouracil), and high dose radiation + 5-fluorouracil: The Gastrointestinal Tumor Study Group. Cancer 48:1705–1710PubMedCrossRefGoogle Scholar
  2. 2.
    Anonymous (1988) Treatment of locally unresectable carcinoma of the pancreas: comparison of combined-modality therapy (chemotherapy plus radiotherapy) to chemotherapy alone. Gastrointestinal Tumor Study Group. J Natl Cancer Inst 80:751–755CrossRefGoogle Scholar
  3. 3.
    Crane CH, Abbruzzese JL, Evans DB et al (2002) Is the therapeutic index better with gemcitabine-based chemoradiation than with 5-fluorouracil-based chemoradiation in locally advanced pancreatic cancer? Int J Radiat Oncol Biol Phys 52:1293–1302CrossRefPubMedGoogle Scholar
  4. 4.
    Muler J, McGinn C, Normolle D, Lawrence T, Brown D, Hejna G, Zalupski M (2004) Phase I trial using a time-to-event continual reassessment strategy for dose escalation of cisplatin combined with gemcitabine and radiation therapy in pancreatic cancer. J Clin Oncol 22:238–243CrossRefPubMedGoogle Scholar
  5. 5.
    Safran H, Dipetrillo T, Iannitti D et al (2002) Gemcitabine, paclitaxel, and radiation for locally advanced pancreatic cancer: a Phase I trial. Int J Radiat Oncol Biol Phys 54:137–141CrossRefPubMedGoogle Scholar
  6. 6.
    McGinn C, Zalupski M, Shureiqi I et al (2001) Phase I trial of radiation dose escalation with concurrent weekly full-dose gemcitabine in patients with advanced pancreatic cancer. J Clin Oncol 19:4202–4208PubMedGoogle Scholar
  7. 7.
    Rich T, Harris J, Abrams R et al (2004) Phase II study of external irradiation and weekly paclitaxel for nonmetastatic, unresectable pancreatic cancer: RTOG-98-12. J Clin Oncol 27:51–56CrossRefGoogle Scholar
  8. 8.
    Erickson BA, Nag S (1998) Biliary tree malignancies. J Surg Oncol 67:203–210CrossRefPubMedGoogle Scholar
  9. 9.
    Miller RA, Woodburn K, Fan Q et al (1999) In vivo animal studies with gadolinium(III) texaphyrin as a radiation enhancer. Int J Radiat Oncol Biol Phys 45:981–989CrossRefPubMedGoogle Scholar
  10. 10.
    Sessler JL, Miller RA (2000) Texaphyrins: new drugs with diverse clinical applications in radiation and photodynamic therapy. Biochem Pharmacol 59:733–739CrossRefPubMedGoogle Scholar
  11. 11.
    Magda D, Lepp C, Gerasimchuk N et al (2001) Redox cycling by motexafin gadolinium enhances cellular response to ionizing radiation by forming reactive oxygen species. Int J Radiat Oncol Biol Phys 51:1025–1036CrossRefPubMedGoogle Scholar
  12. 12.
    Young SW, Quing F, Harriman A et al (1996) Gadolinium(III) texaphyrin: a tumor selective radiation sensitizer that is detectable by MRI. Proc Natl Acad Sci USA 93:6610–6615CrossRefPubMedGoogle Scholar
  13. 13.
    Carde P, Timmerman R, Mehta MP et al (2001) Multicenter phase Ib/II trial of the radiation enhancer motexafin gadolinium in patients with brain metastases. J Clin Oncol 19:2074–2083PubMedGoogle Scholar
  14. 14.
    Mehta MP, Shapiro WR, Glantz MJ (2002) Lead-in phase to randomized trial of motexafin gadolinium and whole-brain radiation for patients with brain metastases: centralized assessment of magnetic resonance imaging, neurocognitive, and neurologic end points. J Clin Oncol 20:3445–3453CrossRefPubMedGoogle Scholar
  15. 15.
    Rosenthal DI, Nurenberg P, Becerra CR (1999) A phase I single-dose trial of gadolinium texaphyrin (Gd-Tex), a tumor selective radiation sensitizer detectable by magnetic resonance imaging. Clin Cancer Res 5:739–745PubMedGoogle Scholar
  16. 16.
    Mehta MP, Rodrigus P, Terhaard CHJ et al (2003) Survival and neurologic outcomes in a randomized trial of motexafin gadolinium and whole-brain radiation therapy in brain metastases. J Clin Oncol 21:2529–2536CrossRefPubMedGoogle Scholar
  17. 17.
    Meyers CA, Smith JA, Bezjak A et al (2004) Neurocognitive function and progression in patients with brain metastases treated with whole-brain radiation and motexafin gadolinium: results of a randomized phase III trial. J Clin Oncol 22:157–165CrossRefPubMedGoogle Scholar
  18. 18.
    Pharmacyclics Corporation (2004) Investigators brochure for Motexfin gadoliniumGoogle Scholar
  19. 19.
    Miller AB, Hoogstraten B, Staquet M et al (1981) Reporting results of cancer treatment. Cancer 47:207–214PubMedCrossRefGoogle Scholar
  20. 20.
    Parise RA, Miles DR, Egorin MJ (2000) Sensitive high-performance liquid chromatographic assay for motexafin gadolinium and motexafin lutetium in human plasma. J Chromatogr B Biomed Sci Appl 749:145–152CrossRefPubMedGoogle Scholar
  21. 21.
    D’Argenio DZ, Schumitzky A (1979) A program package for simulation and parameter estimation in pharmacokinetic systems. Comput Programs Biomed 9:115–134CrossRefPubMedGoogle Scholar
  22. 22.
    Akaike H (1979) A Bayesian extension of the minimal AIC procedures of autoregressive model fitting. Biometrika 66:237–242CrossRefGoogle Scholar
  23. 23.
    Miles DR, Smith JA, Phan SC et al (2005) Population pharmacokinetics of motexafin gadolinium in adults with brain metastases or glioblastoma multiforme. J Clin Pharm 45:299–312CrossRefGoogle Scholar
  24. 24.
    Miller RA, Fan Q, Lee I et al (2002) Motexafin gadolinium (MGd) increases tumor response to chemotherapy in Lewis lung cancer (LLC) animal model. Proc Am Soc Clin Oncol 21: (Abstract#466)Google Scholar
  25. 25.
    Magda D, Lepp C, Fan Q et al (2003) The redox mediator motexafin gadolinium (MGd) enhances the activity of several chemotherapy drugs. Proc Am Soc Clin Oncol 23:229 (Abstract#917)Google Scholar
  26. 26.
    Ramnath N, Chatta G, Egorin MJ, Phan S, Creaven PJ (2004) A phase 1 trial of motexafin gadolinium and docetaxel for advanced solid tumors. Proc Am Soc Clin Oncol 22: (Abstract#3171)Google Scholar
  27. 27.
    Thomas JP, Ramanathan RK, Wilding G et al (2003) A phase I study of motexafin gadolinium (MGd) in combination with doxorubicin (Dox). Proc Am Soc Clin Oncol 22:227 (Abstract#909)Google Scholar
  28. 28.
    Evens AM, Lecane P, Magda D et al (2005) Motexafin gadolinium generates reactive oxygen species and induces apoptosis in sensitive and highly resistant multiple myeloma cells. Blood 105:1265–1273CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Ramesh K. Ramanathan
    • 1
    • 2
    • 10
  • Marwan Fakih
    • 1
    • 2
    • 11
  • Sridhar Mani
    • 3
    • 12
  • Melvin Deutsch
    • 4
  • Raymond P. Perez
    • 5
  • Mark A. Ritter
    • 6
  • Julie L. Eiseman
    • 2
    • 7
  • S. Percy Ivy
    • 8
  • Donald L. Trump
    • 1
    • 2
    • 11
  • Chandra P. Belani
    • 1
    • 2
  • Robert A. Parise
    • 2
  • Douglas M. Potter
    • 9
  • Merrill J. Egorin
    • 1
    • 2
    • 7
  1. 1.Division of Hematology/Oncology, Department of MedicineUniversity of Pittsburgh School of MedicinePittsburghUSA
  2. 2.Molecular Therapeutics/Drug Discovery ProgramUniversity of Pittsburgh Cancer InstitutePittsburghUSA
  3. 3.Division of Hematology/Oncology, Department of MedicineUniversity of Chicago School of MedicineChicagoUSA
  4. 4.Department of Radiation OncologyUniversity of Pittsburgh Medical CenterPittsburghUSA
  5. 5.Molecular Therapeutics Research Program, Norris Cotton Cancer CenterDartmouth-Hitchock Medical CenterLebanonUSA
  6. 6.Department of Human OncologyUniversity of Wisconsin School of MedicineMadisonUSA
  7. 7.Department of PharmacologyUniversity of Pittsburgh School of MedicinePittsburghUSA
  8. 8.Investigational Drug Branch, Cancer Therapy Evaluation Program, Division of Cancer Treatment and CentersNational Cancer InstituteBethesdaUSA
  9. 9.Biostatistics Department, Graduate School of Public Health, and Biostatistics FacilityUniversity of Pittsburgh Cancer InstitutePittsburghUSA
  10. 10.UPMC Cancer Pavilion, # 562PittsburghUSA
  11. 11.Department of MedicineRoswell Park Cancer InstituteBuffaloUSA
  12. 12.Montefiore Medical CtrBronxUSA

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