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

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)465-474
Number of pages10
JournalCancer Chemotherapy and Pharmacology
Volume57
Issue number4
DOIs
StatePublished - Apr 2006

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Biliary Tract Neoplasms
Pharmacokinetics
Radiotherapy
Oxidation-Reduction
Toxicity
Dosimetry
Plasmas
Appointments and Schedules
motexafin gadolinium
Antiemetics
Maximum Tolerated Dose
High performance liquid chromatography
Pancreatic Neoplasms
Antineoplastic Agents
Nausea
Vomiting
Tumors
Linear Models
Skin
Fever

Keywords

  • Motexafin gadolinium
  • Pancreatic cancer
  • Phase I study
  • Radiation therapy

ASJC Scopus subject areas

  • Cancer Research
  • Pharmacology
  • Oncology

Cite this

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

In: Cancer Chemotherapy and Pharmacology, Vol. 57, No. 4, 04.2006, p. 465-474.

Research output: Contribution to journalArticle

Ramanathan, RK, Fakih, M, Mani, S, Deutsch, M, Perez, RP, Ritter, MA, Eiseman, JL, Ivy, SP, Trump, DL, Belani, CP, Parise, RA, Potter, DM & Egorin, MJ 2006, '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 Chemotherapy and Pharmacology, vol. 57, no. 4, pp. 465-474. https://doi.org/10.1007/s00280-005-0071-y
Ramanathan, Ramesh K. ; Fakih, Marwan ; Mani, Sridhar ; Deutsch, Melvin ; Perez, Raymond P. ; Ritter, Mark A. ; Eiseman, Julie L. ; Ivy, S. Percy ; Trump, Donald L. ; Belani, Chandra P. ; Parise, Robert A. ; Potter, Douglas M. ; Egorin, Merrill J. / 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. In: Cancer Chemotherapy and Pharmacology. 2006 ; Vol. 57, No. 4. pp. 465-474.
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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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AU - Ramanathan, Ramesh K.

AU - Fakih, Marwan

AU - Mani, Sridhar

AU - Deutsch, Melvin

AU - Perez, Raymond P.

AU - Ritter, Mark A.

AU - Eiseman, Julie L.

AU - Ivy, S. Percy

AU - Trump, Donald L.

AU - Belani, Chandra P.

AU - Parise, Robert A.

AU - Potter, Douglas M.

AU - Egorin, Merrill J.

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N2 - 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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