A phase 1 study of 131I-CLR1404 in patients with relapsed or refractory advanced solid tumors: Dosimetry, biodistribution, pharmacokinetics, and safety

Joseph J. Grudzinski; Benjamin Titz; Kevin Kozak; William Clarke; Ernest Allen; Lisaann Trembath; Michael Stabin; John Marshall; Steve Y. Cho; Terence Z. Wong; Joanne Mortimer; Jamey P. Weichert

doi:10.1371/journal.pone.0111652

A phase 1 study of ¹³¹I-CLR1404 in patients with relapsed or refractory advanced solid tumors: Dosimetry, biodistribution, pharmacokinetics, and safety

Joseph J. Grudzinski, Benjamin Titz, Kevin Kozak, William Clarke, Ernest Allen, Lisaann Trembath, Michael Stabin, John Marshall, Steve Y. Cho, Terence Z. Wong, Joanne Mortimer, Jamey P. Weichert

School of Medicine

Research output: Contribution to journal › Article

Abstract

Methods: Eight subjects with refractory or relapsed advanced solid tumors were treated with a single injection of 370 MBq of ¹³¹I-CLR1404. Whole body planar nuclear medicine scans were performed at 15-35 minutes, 4-6, 18-24, 48, 72, 144 hours, and 14 days post injection. Optional single photon emission computed tomography imaging was performed on two patients 6 days post injection. Clinical laboratory parameters were evaluated in blood and urine. Plasma PK was evaluated on ¹²⁷I-CLR1404 mass measurements. To evaluate renal clearance of ¹³¹I-CLR1404, urine was collected for 14 days post injection. Absorbed dose estimates for target organs were determined using the RADAR method with OLINDA/EXM software.

Results: Single administrations of 370 MBq of ¹³¹I-CLR1404 were well tolerated by all subjects. No severe adverse events were reported and no adverse event was dose-limiting. Plasma ¹²⁷I-CLR1404 concentrations declined in a bi-exponential manner with a mean tK value of 822 hours. Mean Cmax and AUC(0-t) values were 72.2 ng/mL and 15753 ngNhr/mL, respectively. An administered activity of approximately 740 MBq is predicted to deliver 400 mSv to marrow.

Conclusions: Preliminary data suggest that ¹³¹I-CLR1404 is well tolerated and may have unique potential as an anti-cancer agent.

Introduction: ¹³¹I-CLR1404 is a small molecule that combines a tumor-targeting moiety with a therapeutic radioisotope. The primary aim of this phase 1 study was to determine the administered radioactivity expected to deliver 400 mSv to the bone marrow. The secondary aims were to determine the pharmacokinetic (PK) and safety profiles of ¹³¹I-CLR1404.

Original language	English (US)
Article number	0111652
Journal	PloS one
Volume	9
Issue number	11
DOIs	https://doi.org/10.1371/journal.pone.0111652
State	Published - Nov 17 2014

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)
Agricultural and Biological Sciences(all)
General

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Grudzinski, J. J., Titz, B., Kozak, K., Clarke, W., Allen, E., Trembath, L., Stabin, M., Marshall, J., Cho, S. Y., Wong, T. Z., Mortimer, J., & Weichert, J. P. (2014). A phase 1 study of ¹³¹I-CLR1404 in patients with relapsed or refractory advanced solid tumors: Dosimetry, biodistribution, pharmacokinetics, and safety. PloS one, 9(11), [0111652]. https://doi.org/10.1371/journal.pone.0111652

A phase 1 study of ¹³¹I-CLR1404 in patients with relapsed or refractory advanced solid tumors : Dosimetry, biodistribution, pharmacokinetics, and safety. / Grudzinski, Joseph J.; Titz, Benjamin; Kozak, Kevin; Clarke, William; Allen, Ernest; Trembath, Lisaann; Stabin, Michael; Marshall, John; Cho, Steve Y.; Wong, Terence Z.; Mortimer, Joanne; Weichert, Jamey P.

In: PloS one, Vol. 9, No. 11, 0111652, 17.11.2014.

Research output: Contribution to journal › Article

Grudzinski, JJ, Titz, B, Kozak, K, Clarke, W, Allen, E, Trembath, L, Stabin, M, Marshall, J, Cho, SY, Wong, TZ, Mortimer, J & Weichert, JP 2014, 'A phase 1 study of ¹³¹I-CLR1404 in patients with relapsed or refractory advanced solid tumors: Dosimetry, biodistribution, pharmacokinetics, and safety', PloS one, vol. 9, no. 11, 0111652. https://doi.org/10.1371/journal.pone.0111652

Grudzinski, Joseph J. ; Titz, Benjamin ; Kozak, Kevin ; Clarke, William ; Allen, Ernest ; Trembath, Lisaann ; Stabin, Michael ; Marshall, John ; Cho, Steve Y. ; Wong, Terence Z. ; Mortimer, Joanne ; Weichert, Jamey P. / A phase 1 study of ¹³¹I-CLR1404 in patients with relapsed or refractory advanced solid tumors : Dosimetry, biodistribution, pharmacokinetics, and safety. In: PloS one. 2014 ; Vol. 9, No. 11.

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title = "A phase 1 study of 131I-CLR1404 in patients with relapsed or refractory advanced solid tumors: Dosimetry, biodistribution, pharmacokinetics, and safety",

abstract = "Methods: Eight subjects with refractory or relapsed advanced solid tumors were treated with a single injection of 370 MBq of 131I-CLR1404. Whole body planar nuclear medicine scans were performed at 15-35 minutes, 4-6, 18-24, 48, 72, 144 hours, and 14 days post injection. Optional single photon emission computed tomography imaging was performed on two patients 6 days post injection. Clinical laboratory parameters were evaluated in blood and urine. Plasma PK was evaluated on 127I-CLR1404 mass measurements. To evaluate renal clearance of 131I-CLR1404, urine was collected for 14 days post injection. Absorbed dose estimates for target organs were determined using the RADAR method with OLINDA/EXM software.Results: Single administrations of 370 MBq of 131I-CLR1404 were well tolerated by all subjects. No severe adverse events were reported and no adverse event was dose-limiting. Plasma 127I-CLR1404 concentrations declined in a bi-exponential manner with a mean tK value of 822 hours. Mean Cmax and AUC(0-t) values were 72.2 ng/mL and 15753 ngNhr/mL, respectively. An administered activity of approximately 740 MBq is predicted to deliver 400 mSv to marrow.Conclusions: Preliminary data suggest that 131I-CLR1404 is well tolerated and may have unique potential as an anti-cancer agent.Introduction: 131I-CLR1404 is a small molecule that combines a tumor-targeting moiety with a therapeutic radioisotope. The primary aim of this phase 1 study was to determine the administered radioactivity expected to deliver 400 mSv to the bone marrow. The secondary aims were to determine the pharmacokinetic (PK) and safety profiles of 131I-CLR1404.",

author = "Grudzinski, {Joseph J.} and Benjamin Titz and Kevin Kozak and William Clarke and Ernest Allen and Lisaann Trembath and Michael Stabin and John Marshall and Cho, {Steve Y.} and Wong, {Terence Z.} and Joanne Mortimer and Weichert, {Jamey P.}",

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T1 - A phase 1 study of 131I-CLR1404 in patients with relapsed or refractory advanced solid tumors

T2 - Dosimetry, biodistribution, pharmacokinetics, and safety

AU - Grudzinski, Joseph J.

AU - Titz, Benjamin

AU - Kozak, Kevin

AU - Clarke, William

AU - Allen, Ernest

AU - Trembath, Lisaann

AU - Stabin, Michael

AU - Marshall, John

AU - Cho, Steve Y.

AU - Wong, Terence Z.

AU - Mortimer, Joanne

AU - Weichert, Jamey P.

PY - 2014/11/17

Y1 - 2014/11/17

N2 - Methods: Eight subjects with refractory or relapsed advanced solid tumors were treated with a single injection of 370 MBq of 131I-CLR1404. Whole body planar nuclear medicine scans were performed at 15-35 minutes, 4-6, 18-24, 48, 72, 144 hours, and 14 days post injection. Optional single photon emission computed tomography imaging was performed on two patients 6 days post injection. Clinical laboratory parameters were evaluated in blood and urine. Plasma PK was evaluated on 127I-CLR1404 mass measurements. To evaluate renal clearance of 131I-CLR1404, urine was collected for 14 days post injection. Absorbed dose estimates for target organs were determined using the RADAR method with OLINDA/EXM software.Results: Single administrations of 370 MBq of 131I-CLR1404 were well tolerated by all subjects. No severe adverse events were reported and no adverse event was dose-limiting. Plasma 127I-CLR1404 concentrations declined in a bi-exponential manner with a mean tK value of 822 hours. Mean Cmax and AUC(0-t) values were 72.2 ng/mL and 15753 ngNhr/mL, respectively. An administered activity of approximately 740 MBq is predicted to deliver 400 mSv to marrow.Conclusions: Preliminary data suggest that 131I-CLR1404 is well tolerated and may have unique potential as an anti-cancer agent.Introduction: 131I-CLR1404 is a small molecule that combines a tumor-targeting moiety with a therapeutic radioisotope. The primary aim of this phase 1 study was to determine the administered radioactivity expected to deliver 400 mSv to the bone marrow. The secondary aims were to determine the pharmacokinetic (PK) and safety profiles of 131I-CLR1404.

AB - Methods: Eight subjects with refractory or relapsed advanced solid tumors were treated with a single injection of 370 MBq of 131I-CLR1404. Whole body planar nuclear medicine scans were performed at 15-35 minutes, 4-6, 18-24, 48, 72, 144 hours, and 14 days post injection. Optional single photon emission computed tomography imaging was performed on two patients 6 days post injection. Clinical laboratory parameters were evaluated in blood and urine. Plasma PK was evaluated on 127I-CLR1404 mass measurements. To evaluate renal clearance of 131I-CLR1404, urine was collected for 14 days post injection. Absorbed dose estimates for target organs were determined using the RADAR method with OLINDA/EXM software.Results: Single administrations of 370 MBq of 131I-CLR1404 were well tolerated by all subjects. No severe adverse events were reported and no adverse event was dose-limiting. Plasma 127I-CLR1404 concentrations declined in a bi-exponential manner with a mean tK value of 822 hours. Mean Cmax and AUC(0-t) values were 72.2 ng/mL and 15753 ngNhr/mL, respectively. An administered activity of approximately 740 MBq is predicted to deliver 400 mSv to marrow.Conclusions: Preliminary data suggest that 131I-CLR1404 is well tolerated and may have unique potential as an anti-cancer agent.Introduction: 131I-CLR1404 is a small molecule that combines a tumor-targeting moiety with a therapeutic radioisotope. The primary aim of this phase 1 study was to determine the administered radioactivity expected to deliver 400 mSv to the bone marrow. The secondary aims were to determine the pharmacokinetic (PK) and safety profiles of 131I-CLR1404.

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