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II study of an oral epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), ZD 1839 (Iressa), with radiation therapy in glioblastoma multiforme (GBM)
Proceedings of the 45th Annual ASTRO Meeting
1113
Phase I Results from RTOG BR-0211, A Phase I/II Study of an Oral Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR-TKI), ZD 1839 (Iressa), with Radiation Therapy in Glioblastoma Multiforme (GBM)
A. Chakravarti,1,9 W. Seiferheld,2,9 I. Robbins,3,9 A. Guha,4,9 P. Sperduto,5,9 A. Choucair,6,9 D. Brachman,7,9 M. Mehta8,9 1
Radiation Oncology, Massachusetts General Hospital, Boston, MA, 2Biostatistics, RTOG, Philadelphia, PA, 3Medical Oncology, University of Wisconsin, Madison, WI, 4Neurosurgery, Hospital for Sick Children, Toronto, ON, Canada, 5 Radiation Oncology, Metro-MN CCOP, Minneapolis, MN, 6Radiation Oncology, LDS Hospital, Salt Lake City, UT, 7 Radiation Oncology, Foundation for Cancer, Phoenix, AZ, 8Radiation Oncology, University of Wisconsin, Madison, WI, 9 Radiation Therapy Oncology Group, Philadelphia, PA Purpose/Objective: EGFR protein overexpression and gene amplification has been associated with adverse outcome in the GBM patient population. There is accumulating preclinical evidence that EGFR can directly mediate resistance to radiation. Therefore, the RTOG has designed a Phase I/II study to determine whether radiation in combination with Iressa, a potent and selective EGFR-TKI, can safely enhance radiation response in GBM patients. This is a report from the Phase I component of RTOG 0211. Materials/Methods: Dose escalation of Iressa has been conducted separately for patients receiving enzyme-inducing anticonvulsants (EIACD) and for non-EIACD patients. EIACD dose escalations are being examined in the range from 250 to 750mg during RT (two escalations), followed by maintenance dose levels of 500mg, with escalation permitted up to 750mg. Non-EIACD dose escalations are being examined in the range of 250 to 500mg (one escalation), followed by maintenance dose levels of 500mg. As of 2/18/03, 23 patients have been accrued: 12 patients in the EIACD group and 11 patients in the non-EIACD group. Of these 23 patients, 16 have been evaluated to date for toxicity. Results: Using the standard 3⫹3 design, Iressa doses have been permitted to be safely escalated to 750mg in the EIACD group and to 500mg in the non-EIACD group, with these respective arms presently open for accrual. No Grade 4 non-hematologic toxicity attributable for Iressa ⫹ RT has been reported for either group. Grade 3 toxicities to date are as follows: One case of metabolic abnormalities (elevated liver enzymes) in the EIACD group at 500mg; and two cases of skin rash and one case of elevated liver enzymes in the non-EIACD group at 250mg. Conclusions: The combination of Iressa ⫹ RT appears to be well tolerated in both EIACD and non-EIACD patients in the dose levels examined thus far. Data for the 750mg arm in the EIACD group and 500mg arm in the non-EIACD group will be available at the time of the RTOG Annual Meeting. The Phase II component will then proceed at the maximum tolerated doses of Iressa for the EIACD and non-EIACD patients, respectively. This publication was supported by grant number (RTOG U10 CA21661, CCOP U10 CA37422, Stat U10 CA32115) from the National Cancer Institute. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute.
1114
The Radiation Enhancer Motexafin Gadolinium (MGd) Does Not Penetrate the Blood Brain Barrier in Glioblastoma Multiforme Patients Undergoing Post-Operative Fractionated Radiation Therapy
G.N. Wu,1,3 J.M. Ford,2 J.R. Alger3 1
Biomedical Physics, Univ. of California at Los Angeles, Los Angeles, CA, 2Radiation Oncology, Univ. of California at Los Angeles, Los Angeles, CA, 3Radiology, Univ. of California at Los Angeles, Los Angeles, CA Purpose/Objective: One approach to improving outcome for high grade glioma is to use agents that selectively enhance the antineoplastic effect of ionizing radiation without affecting normal tissue. Motexafin Gadolinium (MGd) is a proposed radiation enhancer, which also acts as an MRI contrast agent. The goal of this work was to quantitatively evaluate whether MGd passes through the intact blood brain barrier, because significant leakage into normal brain tissue may lead to undesirable increase in the effect of radiation on normal tissue. Materials/Methods: In nine post-surgical glioblastoma multiforme (GBM) patients who received daily MGd during fractionated radiation therapy (RT) as part of a phase I clinical trial, T1-weighted MRI was performed 2 to 3 days prior to starting MGd and radiation, and after the 5th daily MGd and radiation administration. During the MRI scans, each patient wore a helmet to which were affixed four tubes containing known MGd concentrations of 0.01, 0.05, 0.1 and 0.2 mg/mL, respectively. Signal intensities from the tubes provided standards that were used for calibration enabling the approximate determination of tissue MGd concentrations. Results: Mean signal intensities from normal appearing white matter and normal appearing gray matter relative to the calibration tubes were measured. The attached table provides mean tube normalized intensity ratios before MGd administration, and on day 5 post MGd administration, as well as post/pre signal ratios for each subject for both white matter and gray matter. A significant signal intensity increase due to MGd was not detected in white matter. However in gray matter a small significant increase was detected with a paired t-test (p ⫽ 0.044). The 2% mean increase in signal intensity resulting from MGd is consistent with an MGd tissue concentration of 0.002 mg/mL based on a calibration curve derived from the tubes containing known MGd concentration. Therefore the gray matter MGd concentration is more than 10-fold lower than the estimates of concentration in tumor from previous data of 0.03 to 0.08mg/ml. Furthermore, part of the observed gray matter signal increase is likely to be the result of MGd in the blood volume, as about 5 to 10% of the gray matter tissue volume is within the vascular space. In this group of 9 patients, assessment of MGd tumor enhancement was complicated by complete surgical resection in many of the patients and by post-surgical hematoma. Conclusions: Data from both white matter and gray matter did not show clinically significant difference between pre- and postMGd administration, suggesting that MGd does not cross the blood brain barrier and is therefore unlikely to enhance any radiation effect on normal tissue.
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1113
Phase I Results from RTOG BR-0211, A Phase I/II Study of an Oral Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR-TKI), ZD 1839 (Iressa), with Radiation Therapy in Glioblastoma Multiforme (GBM)
A. Chakravarti,1,9 W. Seiferheld,2,9 I. Robbins,3,9 A. Guha,4,9 P. Sperduto,5,9 A. Choucair,6,9 D. Brachman,7,9 M. Mehta8,9 1
Radiation Oncology, Massachusetts General Hospital, Boston, MA, 2Biostatistics, RTOG, Philadelphia, PA, 3Medical Oncology, University of Wisconsin, Madison, WI, 4Neurosurgery, Hospital for Sick Children, Toronto, ON, Canada, 5 Radiation Oncology, Metro-MN CCOP, Minneapolis, MN, 6Radiation Oncology, LDS Hospital, Salt Lake City, UT, 7 Radiation Oncology, Foundation for Cancer, Phoenix, AZ, 8Radiation Oncology, University of Wisconsin, Madison, WI, 9 Radiation Therapy Oncology Group, Philadelphia, PA Purpose/Objective: EGFR protein overexpression and gene amplification has been associated with adverse outcome in the GBM patient population. There is accumulating preclinical evidence that EGFR can directly mediate resistance to radiation. Therefore, the RTOG has designed a Phase I/II study to determine whether radiation in combination with Iressa, a potent and selective EGFR-TKI, can safely enhance radiation response in GBM patients. This is a report from the Phase I component of RTOG 0211. Materials/Methods: Dose escalation of Iressa has been conducted separately for patients receiving enzyme-inducing anticonvulsants (EIACD) and for non-EIACD patients. EIACD dose escalations are being examined in the range from 250 to 750mg during RT (two escalations), followed by maintenance dose levels of 500mg, with escalation permitted up to 750mg. Non-EIACD dose escalations are being examined in the range of 250 to 500mg (one escalation), followed by maintenance dose levels of 500mg. As of 2/18/03, 23 patients have been accrued: 12 patients in the EIACD group and 11 patients in the non-EIACD group. Of these 23 patients, 16 have been evaluated to date for toxicity. Results: Using the standard 3⫹3 design, Iressa doses have been permitted to be safely escalated to 750mg in the EIACD group and to 500mg in the non-EIACD group, with these respective arms presently open for accrual. No Grade 4 non-hematologic toxicity attributable for Iressa ⫹ RT has been reported for either group. Grade 3 toxicities to date are as follows: One case of metabolic abnormalities (elevated liver enzymes) in the EIACD group at 500mg; and two cases of skin rash and one case of elevated liver enzymes in the non-EIACD group at 250mg. Conclusions: The combination of Iressa ⫹ RT appears to be well tolerated in both EIACD and non-EIACD patients in the dose levels examined thus far. Data for the 750mg arm in the EIACD group and 500mg arm in the non-EIACD group will be available at the time of the RTOG Annual Meeting. The Phase II component will then proceed at the maximum tolerated doses of Iressa for the EIACD and non-EIACD patients, respectively. This publication was supported by grant number (RTOG U10 CA21661, CCOP U10 CA37422, Stat U10 CA32115) from the National Cancer Institute. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute.
1114
The Radiation Enhancer Motexafin Gadolinium (MGd) Does Not Penetrate the Blood Brain Barrier in Glioblastoma Multiforme Patients Undergoing Post-Operative Fractionated Radiation Therapy
G.N. Wu,1,3 J.M. Ford,2 J.R. Alger3 1
Biomedical Physics, Univ. of California at Los Angeles, Los Angeles, CA, 2Radiation Oncology, Univ. of California at Los Angeles, Los Angeles, CA, 3Radiology, Univ. of California at Los Angeles, Los Angeles, CA Purpose/Objective: One approach to improving outcome for high grade glioma is to use agents that selectively enhance the antineoplastic effect of ionizing radiation without affecting normal tissue. Motexafin Gadolinium (MGd) is a proposed radiation enhancer, which also acts as an MRI contrast agent. The goal of this work was to quantitatively evaluate whether MGd passes through the intact blood brain barrier, because significant leakage into normal brain tissue may lead to undesirable increase in the effect of radiation on normal tissue. Materials/Methods: In nine post-surgical glioblastoma multiforme (GBM) patients who received daily MGd during fractionated radiation therapy (RT) as part of a phase I clinical trial, T1-weighted MRI was performed 2 to 3 days prior to starting MGd and radiation, and after the 5th daily MGd and radiation administration. During the MRI scans, each patient wore a helmet to which were affixed four tubes containing known MGd concentrations of 0.01, 0.05, 0.1 and 0.2 mg/mL, respectively. Signal intensities from the tubes provided standards that were used for calibration enabling the approximate determination of tissue MGd concentrations. Results: Mean signal intensities from normal appearing white matter and normal appearing gray matter relative to the calibration tubes were measured. The attached table provides mean tube normalized intensity ratios before MGd administration, and on day 5 post MGd administration, as well as post/pre signal ratios for each subject for both white matter and gray matter. A significant signal intensity increase due to MGd was not detected in white matter. However in gray matter a small significant increase was detected with a paired t-test (p ⫽ 0.044). The 2% mean increase in signal intensity resulting from MGd is consistent with an MGd tissue concentration of 0.002 mg/mL based on a calibration curve derived from the tubes containing known MGd concentration. Therefore the gray matter MGd concentration is more than 10-fold lower than the estimates of concentration in tumor from previous data of 0.03 to 0.08mg/ml. Furthermore, part of the observed gray matter signal increase is likely to be the result of MGd in the blood volume, as about 5 to 10% of the gray matter tissue volume is within the vascular space. In this group of 9 patients, assessment of MGd tumor enhancement was complicated by complete surgical resection in many of the patients and by post-surgical hematoma. Conclusions: Data from both white matter and gray matter did not show clinically significant difference between pre- and postMGd administration, suggesting that MGd does not cross the blood brain barrier and is therefore unlikely to enhance any radiation effect on normal tissue.
S329