Safety of pioglitazone during and after radiation therapy in patients with brain tumors: a phase I clinical trial

Christina K. Cramer, Natalie Alphonse-Sullivan, Scott Isom, Linda J. Metheny-Barlow, Tiffany L. Cummings, Brandi Page, Doris R. Brown, Arthur W. Blackstock, Ann M. Peiffer, Roy E. Strowd, Stephen Rapp, Glenn J. Lesser, Edward G. Shaw, Michael D. Chan

Research output: Contribution to journalArticle

Abstract

Introduction: Radiation-induced cognitive decline (RICD) is a late effect of radiotherapy (RT) occurring in 30–50% of irradiated brain tumor survivors. In preclinical models, pioglitazone prevents RICD but there are little safety data on its use in non-diabetic patients. We conducted a dose-escalation trial to determine the safety of pioglitazone taken during and after brain irradiation. Methods: We enrolled patients > 18 years old with primary or metastatic brain tumors slated to receive at least 10 treatments of RT (≤ 3 Gy per fraction). We evaluated the safety of pioglitazone at 22.5 mg and 45 mg with a dose-escalation phase and dose-expansion phase. Pioglitazone was taken daily during RT and for 6 months after. Results: 18 patients with a mean age of 54 were enrolled between 2010 and 2014. 14 patients had metastatic brain tumors and were treated with whole brain RT. Four patients had primary brain tumors and received partial brain RT and concurrent chemotherapy. No DLTs were identified. In the dose-escalation phase, there were only three instances of grade ≥ 3 toxicity: one instance of neuropathy in a patient receiving 22.5 mg, one instance of fatigue in a patient receiving 22.5 mg and one instance of dizziness in a patient receiving 45 mg. The attribution in each of these cases was considered “possible.” In the dose-expansion phase, nine patients received 45 mg and there was only one grade 3 toxicity (fatigue) possibly attributable to pioglitazone. Conclusion: Pioglitazone was well tolerated by brain tumor patients undergoing RT. 45 mg is a safe dose to use in future efficacy trials.

Original languageEnglish (US)
JournalJournal of Cancer Research and Clinical Oncology
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

pioglitazone
Clinical Trials, Phase I
Brain Neoplasms
Radiotherapy
Safety
Fatigue
Brain
Radiation

Keywords

  • Neuroprotective
  • Pioglitazone
  • Radiation-induced cognitive decline

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Safety of pioglitazone during and after radiation therapy in patients with brain tumors : a phase I clinical trial. / Cramer, Christina K.; Alphonse-Sullivan, Natalie; Isom, Scott; Metheny-Barlow, Linda J.; Cummings, Tiffany L.; Page, Brandi; Brown, Doris R.; Blackstock, Arthur W.; Peiffer, Ann M.; Strowd, Roy E.; Rapp, Stephen; Lesser, Glenn J.; Shaw, Edward G.; Chan, Michael D.

In: Journal of Cancer Research and Clinical Oncology, 01.01.2018.

Research output: Contribution to journalArticle

Cramer, CK, Alphonse-Sullivan, N, Isom, S, Metheny-Barlow, LJ, Cummings, TL, Page, B, Brown, DR, Blackstock, AW, Peiffer, AM, Strowd, RE, Rapp, S, Lesser, GJ, Shaw, EG & Chan, MD 2018, 'Safety of pioglitazone during and after radiation therapy in patients with brain tumors: a phase I clinical trial', Journal of Cancer Research and Clinical Oncology. https://doi.org/10.1007/s00432-018-2791-5
Cramer, Christina K. ; Alphonse-Sullivan, Natalie ; Isom, Scott ; Metheny-Barlow, Linda J. ; Cummings, Tiffany L. ; Page, Brandi ; Brown, Doris R. ; Blackstock, Arthur W. ; Peiffer, Ann M. ; Strowd, Roy E. ; Rapp, Stephen ; Lesser, Glenn J. ; Shaw, Edward G. ; Chan, Michael D. / Safety of pioglitazone during and after radiation therapy in patients with brain tumors : a phase I clinical trial. In: Journal of Cancer Research and Clinical Oncology. 2018.
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abstract = "Introduction: Radiation-induced cognitive decline (RICD) is a late effect of radiotherapy (RT) occurring in 30–50{\%} of irradiated brain tumor survivors. In preclinical models, pioglitazone prevents RICD but there are little safety data on its use in non-diabetic patients. We conducted a dose-escalation trial to determine the safety of pioglitazone taken during and after brain irradiation. Methods: We enrolled patients > 18 years old with primary or metastatic brain tumors slated to receive at least 10 treatments of RT (≤ 3 Gy per fraction). We evaluated the safety of pioglitazone at 22.5 mg and 45 mg with a dose-escalation phase and dose-expansion phase. Pioglitazone was taken daily during RT and for 6 months after. Results: 18 patients with a mean age of 54 were enrolled between 2010 and 2014. 14 patients had metastatic brain tumors and were treated with whole brain RT. Four patients had primary brain tumors and received partial brain RT and concurrent chemotherapy. No DLTs were identified. In the dose-escalation phase, there were only three instances of grade ≥ 3 toxicity: one instance of neuropathy in a patient receiving 22.5 mg, one instance of fatigue in a patient receiving 22.5 mg and one instance of dizziness in a patient receiving 45 mg. The attribution in each of these cases was considered “possible.” In the dose-expansion phase, nine patients received 45 mg and there was only one grade 3 toxicity (fatigue) possibly attributable to pioglitazone. Conclusion: Pioglitazone was well tolerated by brain tumor patients undergoing RT. 45 mg is a safe dose to use in future efficacy trials.",
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T2 - a phase I clinical trial

AU - Cramer, Christina K.

AU - Alphonse-Sullivan, Natalie

AU - Isom, Scott

AU - Metheny-Barlow, Linda J.

AU - Cummings, Tiffany L.

AU - Page, Brandi

AU - Brown, Doris R.

AU - Blackstock, Arthur W.

AU - Peiffer, Ann M.

AU - Strowd, Roy E.

AU - Rapp, Stephen

AU - Lesser, Glenn J.

AU - Shaw, Edward G.

AU - Chan, Michael D.

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N2 - Introduction: Radiation-induced cognitive decline (RICD) is a late effect of radiotherapy (RT) occurring in 30–50% of irradiated brain tumor survivors. In preclinical models, pioglitazone prevents RICD but there are little safety data on its use in non-diabetic patients. We conducted a dose-escalation trial to determine the safety of pioglitazone taken during and after brain irradiation. Methods: We enrolled patients > 18 years old with primary or metastatic brain tumors slated to receive at least 10 treatments of RT (≤ 3 Gy per fraction). We evaluated the safety of pioglitazone at 22.5 mg and 45 mg with a dose-escalation phase and dose-expansion phase. Pioglitazone was taken daily during RT and for 6 months after. Results: 18 patients with a mean age of 54 were enrolled between 2010 and 2014. 14 patients had metastatic brain tumors and were treated with whole brain RT. Four patients had primary brain tumors and received partial brain RT and concurrent chemotherapy. No DLTs were identified. In the dose-escalation phase, there were only three instances of grade ≥ 3 toxicity: one instance of neuropathy in a patient receiving 22.5 mg, one instance of fatigue in a patient receiving 22.5 mg and one instance of dizziness in a patient receiving 45 mg. The attribution in each of these cases was considered “possible.” In the dose-expansion phase, nine patients received 45 mg and there was only one grade 3 toxicity (fatigue) possibly attributable to pioglitazone. Conclusion: Pioglitazone was well tolerated by brain tumor patients undergoing RT. 45 mg is a safe dose to use in future efficacy trials.

AB - Introduction: Radiation-induced cognitive decline (RICD) is a late effect of radiotherapy (RT) occurring in 30–50% of irradiated brain tumor survivors. In preclinical models, pioglitazone prevents RICD but there are little safety data on its use in non-diabetic patients. We conducted a dose-escalation trial to determine the safety of pioglitazone taken during and after brain irradiation. Methods: We enrolled patients > 18 years old with primary or metastatic brain tumors slated to receive at least 10 treatments of RT (≤ 3 Gy per fraction). We evaluated the safety of pioglitazone at 22.5 mg and 45 mg with a dose-escalation phase and dose-expansion phase. Pioglitazone was taken daily during RT and for 6 months after. Results: 18 patients with a mean age of 54 were enrolled between 2010 and 2014. 14 patients had metastatic brain tumors and were treated with whole brain RT. Four patients had primary brain tumors and received partial brain RT and concurrent chemotherapy. No DLTs were identified. In the dose-escalation phase, there were only three instances of grade ≥ 3 toxicity: one instance of neuropathy in a patient receiving 22.5 mg, one instance of fatigue in a patient receiving 22.5 mg and one instance of dizziness in a patient receiving 45 mg. The attribution in each of these cases was considered “possible.” In the dose-expansion phase, nine patients received 45 mg and there was only one grade 3 toxicity (fatigue) possibly attributable to pioglitazone. Conclusion: Pioglitazone was well tolerated by brain tumor patients undergoing RT. 45 mg is a safe dose to use in future efficacy trials.

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