Phase II NCCTG trial of RT + irinotecan and adjuvant BCNU plus irinotecan for newly diagnosed GBM

Kurt A. Jaeckle; Karla V. Ballman; Caterina Giannini; Paula J. Schomberg; Matthew M. Ames; Joel M. Reid; Renee M. McGovern; Stephanie L. Safgren; Evanthia Galanis; Joon H. Uhm; Paul D. Brown; Julie E. Hammack; Robert Arusell; Daniel A. Nikcevich; Roscoe F. Morton; Donald B. Wender; Jan C. Buckner

doi:10.1007/s11060-009-0103-2

Phase II NCCTG trial of RT + irinotecan and adjuvant BCNU plus irinotecan for newly diagnosed GBM

Kurt A. Jaeckle, Karla V. Ballman, Caterina Giannini, Paula J. Schomberg, Matthew M. Ames, Joel M. Reid, Renee M. McGovern, Stephanie L. Safgren, Evanthia Galanis, Joon H. Uhm, Paul D. Brown, Julie E. Hammack, Robert Arusell, Daniel A. Nikcevich, Roscoe F. Morton, Donald B. Wender, Jan C. Buckner

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7 Scopus citations

Abstract

Irinotecan has radiosensitizing effects and shows synergism with nitrosoureas. We performed a Phase II study of RT and irinotecan, followed by BCNU plus irinotecan in newly-diagnosed GBM. The MTD for patients receiving enzyme-inducing anticonvulsants (EIAC) was as follows: irinotecan 400 mg/m ²/week on Days 1, 8, 22 and 29 during RT, followed by BCNU 100 mg/m² Day 1, and irinotecan, 400 mg/m² on Days 1, 8, 22 and 29, every 6 weeks. The MTD for non-EIAC patients was as follows: irinotecan 125 mg/m²/week on Days 1, 8, 22 and 29 during RT, followed by BCNU 100 mg/m² Day 1 and irinotecan 75 mg/m² Days 1, 8, 22 and 29, every 6 weeks. Median OS was 10.8 mos. (95% CI: 7.7-14.9); OS at 12 months was 44.6% (95% CI: 33.3-59.8) and PFS 6 was 28.6% (95% CI: 18.9-43.2). Patients went off treatment due to adverse events (7%), refusal (11%), progressive disease (48%), death (9%), and other (9%); 16% completed protocol treatment. Survival was similar in patients with variant (6/7 or 7/7) and wild-type (6/6) UGT1A1*28 genotypic alleles. Grade 3-4 toxicity was more common in non-EIAC patients with variant alleles. SN-38 C_max and AUC in EIAC patients receiving 400 mg/m² irinotecan were 20.9 ng/ml and 212 ng/ml h, and in non-EIAC patients receiving 125 mg/m², 15.5 ng/ml and 207 ng/ml h. SN-38 AUC varied by UGT1A1*28 status in non-EIAC patients. This regimen was not significantly active and radiosensitization was not observed. Non-EIAC patients with UGT1A1*28 variant alleles appear particularly sensitive to toxicity from irinotecan.

Original language	English (US)
Pages (from-to)	73-80
Number of pages	8
Journal	Journal of neuro-oncology
Volume	99
Issue number	1
DOIs	https://doi.org/10.1007/s11060-009-0103-2
State	Published - Aug 2010

Keywords

BCNU
Enzyme-inducing anticonvulsant
Glioblastoma
Irinotecan
NCCTG
Nitrosourea
UGT1A1

ASJC Scopus subject areas

Oncology
Neurology
Clinical Neurology
Cancer Research

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10.1007/s11060-009-0103-2

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Jaeckle, K. A., Ballman, K. V., Giannini, C., Schomberg, P. J., Ames, M. M., Reid, J. M., McGovern, R. M., Safgren, S. L., Galanis, E., Uhm, J. H., Brown, P. D., Hammack, J. E., Arusell, R., Nikcevich, D. A., Morton, R. F., Wender, D. B., & Buckner, J. C. (2010). Phase II NCCTG trial of RT + irinotecan and adjuvant BCNU plus irinotecan for newly diagnosed GBM. Journal of neuro-oncology, 99(1), 73-80. https://doi.org/10.1007/s11060-009-0103-2

Jaeckle, KA, Ballman, KV, Giannini, C, Schomberg, PJ, Ames, MM, Reid, JM, McGovern, RM, Safgren, SL, Galanis, E, Uhm, JH, Brown, PD, Hammack, JE, Arusell, R, Nikcevich, DA, Morton, RF, Wender, DB & Buckner, JC 2010, 'Phase II NCCTG trial of RT + irinotecan and adjuvant BCNU plus irinotecan for newly diagnosed GBM', Journal of neuro-oncology, vol. 99, no. 1, pp. 73-80. https://doi.org/10.1007/s11060-009-0103-2

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title = "Phase II NCCTG trial of RT + irinotecan and adjuvant BCNU plus irinotecan for newly diagnosed GBM",

abstract = "Irinotecan has radiosensitizing effects and shows synergism with nitrosoureas. We performed a Phase II study of RT and irinotecan, followed by BCNU plus irinotecan in newly-diagnosed GBM. The MTD for patients receiving enzyme-inducing anticonvulsants (EIAC) was as follows: irinotecan 400 mg/m 2/week on Days 1, 8, 22 and 29 during RT, followed by BCNU 100 mg/m2 Day 1, and irinotecan, 400 mg/m2 on Days 1, 8, 22 and 29, every 6 weeks. The MTD for non-EIAC patients was as follows: irinotecan 125 mg/m2/week on Days 1, 8, 22 and 29 during RT, followed by BCNU 100 mg/m2 Day 1 and irinotecan 75 mg/m2 Days 1, 8, 22 and 29, every 6 weeks. Median OS was 10.8 mos. (95% CI: 7.7-14.9); OS at 12 months was 44.6% (95% CI: 33.3-59.8) and PFS 6 was 28.6% (95% CI: 18.9-43.2). Patients went off treatment due to adverse events (7%), refusal (11%), progressive disease (48%), death (9%), and other (9%); 16% completed protocol treatment. Survival was similar in patients with variant (6/7 or 7/7) and wild-type (6/6) UGT1A1*28 genotypic alleles. Grade 3-4 toxicity was more common in non-EIAC patients with variant alleles. SN-38 Cmax and AUC in EIAC patients receiving 400 mg/m2 irinotecan were 20.9 ng/ml and 212 ng/ml h, and in non-EIAC patients receiving 125 mg/m2, 15.5 ng/ml and 207 ng/ml h. SN-38 AUC varied by UGT1A1*28 status in non-EIAC patients. This regimen was not significantly active and radiosensitization was not observed. Non-EIAC patients with UGT1A1*28 variant alleles appear particularly sensitive to toxicity from irinotecan.",

keywords = "BCNU, Enzyme-inducing anticonvulsant, Glioblastoma, Irinotecan, NCCTG, Nitrosourea, UGT1A1",

author = "Jaeckle, {Kurt A.} and Ballman, {Karla V.} and Caterina Giannini and Schomberg, {Paula J.} and Ames, {Matthew M.} and Reid, {Joel M.} and McGovern, {Renee M.} and Safgren, {Stephanie L.} and Evanthia Galanis and Uhm, {Joon H.} and Brown, {Paul D.} and Hammack, {Julie E.} and Robert Arusell and Nikcevich, {Daniel A.} and Morton, {Roscoe F.} and Wender, {Donald B.} and Buckner, {Jan C.}",

note = "Funding Information: This study was conducted as a collaborative trial of the North Central Cancer Treatment Group and Mayo Clinic and was supported in part by Public Health Service grants CA-25224, CA-37404, CA-35269, CA-35101, CA-35103, CA-35113, CA-35431, CA-35267, CA-52352, CA-37417, CA-63848, and by grants from Pharmacia and Upjohn. The content is solely the responsibility of the authors and does not necessarily represent the views of the National Cancer Institute or the National Institute of Health. Additional participating institutions include in Appendix.",

year = "2010",

month = aug,

doi = "10.1007/s11060-009-0103-2",

language = "English (US)",

volume = "99",

pages = "73--80",

journal = "Journal of Neuro-Oncology",

issn = "0167-594X",

publisher = "Kluwer Academic Publishers",

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TY - JOUR

T1 - Phase II NCCTG trial of RT + irinotecan and adjuvant BCNU plus irinotecan for newly diagnosed GBM

AU - Jaeckle, Kurt A.

AU - Ballman, Karla V.

AU - Giannini, Caterina

AU - Schomberg, Paula J.

AU - Ames, Matthew M.

AU - Reid, Joel M.

AU - McGovern, Renee M.

AU - Safgren, Stephanie L.

AU - Galanis, Evanthia

AU - Uhm, Joon H.

AU - Brown, Paul D.

AU - Hammack, Julie E.

AU - Arusell, Robert

AU - Nikcevich, Daniel A.

AU - Morton, Roscoe F.

AU - Wender, Donald B.

AU - Buckner, Jan C.

N1 - Funding Information: This study was conducted as a collaborative trial of the North Central Cancer Treatment Group and Mayo Clinic and was supported in part by Public Health Service grants CA-25224, CA-37404, CA-35269, CA-35101, CA-35103, CA-35113, CA-35431, CA-35267, CA-52352, CA-37417, CA-63848, and by grants from Pharmacia and Upjohn. The content is solely the responsibility of the authors and does not necessarily represent the views of the National Cancer Institute or the National Institute of Health. Additional participating institutions include in Appendix.

PY - 2010/8

Y1 - 2010/8

N2 - Irinotecan has radiosensitizing effects and shows synergism with nitrosoureas. We performed a Phase II study of RT and irinotecan, followed by BCNU plus irinotecan in newly-diagnosed GBM. The MTD for patients receiving enzyme-inducing anticonvulsants (EIAC) was as follows: irinotecan 400 mg/m 2/week on Days 1, 8, 22 and 29 during RT, followed by BCNU 100 mg/m2 Day 1, and irinotecan, 400 mg/m2 on Days 1, 8, 22 and 29, every 6 weeks. The MTD for non-EIAC patients was as follows: irinotecan 125 mg/m2/week on Days 1, 8, 22 and 29 during RT, followed by BCNU 100 mg/m2 Day 1 and irinotecan 75 mg/m2 Days 1, 8, 22 and 29, every 6 weeks. Median OS was 10.8 mos. (95% CI: 7.7-14.9); OS at 12 months was 44.6% (95% CI: 33.3-59.8) and PFS 6 was 28.6% (95% CI: 18.9-43.2). Patients went off treatment due to adverse events (7%), refusal (11%), progressive disease (48%), death (9%), and other (9%); 16% completed protocol treatment. Survival was similar in patients with variant (6/7 or 7/7) and wild-type (6/6) UGT1A1*28 genotypic alleles. Grade 3-4 toxicity was more common in non-EIAC patients with variant alleles. SN-38 Cmax and AUC in EIAC patients receiving 400 mg/m2 irinotecan were 20.9 ng/ml and 212 ng/ml h, and in non-EIAC patients receiving 125 mg/m2, 15.5 ng/ml and 207 ng/ml h. SN-38 AUC varied by UGT1A1*28 status in non-EIAC patients. This regimen was not significantly active and radiosensitization was not observed. Non-EIAC patients with UGT1A1*28 variant alleles appear particularly sensitive to toxicity from irinotecan.

AB - Irinotecan has radiosensitizing effects and shows synergism with nitrosoureas. We performed a Phase II study of RT and irinotecan, followed by BCNU plus irinotecan in newly-diagnosed GBM. The MTD for patients receiving enzyme-inducing anticonvulsants (EIAC) was as follows: irinotecan 400 mg/m 2/week on Days 1, 8, 22 and 29 during RT, followed by BCNU 100 mg/m2 Day 1, and irinotecan, 400 mg/m2 on Days 1, 8, 22 and 29, every 6 weeks. The MTD for non-EIAC patients was as follows: irinotecan 125 mg/m2/week on Days 1, 8, 22 and 29 during RT, followed by BCNU 100 mg/m2 Day 1 and irinotecan 75 mg/m2 Days 1, 8, 22 and 29, every 6 weeks. Median OS was 10.8 mos. (95% CI: 7.7-14.9); OS at 12 months was 44.6% (95% CI: 33.3-59.8) and PFS 6 was 28.6% (95% CI: 18.9-43.2). Patients went off treatment due to adverse events (7%), refusal (11%), progressive disease (48%), death (9%), and other (9%); 16% completed protocol treatment. Survival was similar in patients with variant (6/7 or 7/7) and wild-type (6/6) UGT1A1*28 genotypic alleles. Grade 3-4 toxicity was more common in non-EIAC patients with variant alleles. SN-38 Cmax and AUC in EIAC patients receiving 400 mg/m2 irinotecan were 20.9 ng/ml and 212 ng/ml h, and in non-EIAC patients receiving 125 mg/m2, 15.5 ng/ml and 207 ng/ml h. SN-38 AUC varied by UGT1A1*28 status in non-EIAC patients. This regimen was not significantly active and radiosensitization was not observed. Non-EIAC patients with UGT1A1*28 variant alleles appear particularly sensitive to toxicity from irinotecan.

KW - BCNU

KW - Enzyme-inducing anticonvulsant

KW - Glioblastoma

KW - Irinotecan

KW - NCCTG

KW - Nitrosourea

KW - UGT1A1

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Phase II NCCTG trial of RT + irinotecan and adjuvant BCNU plus irinotecan for newly diagnosed GBM

Abstract

Keywords

ASJC Scopus subject areas

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