Avasopasem manganese (GC4419) protects against cisplatin-induced chronic kidney disease: An exploratory analysis of renal metrics from a randomized phase 2b clinical trial in head and neck cancer patients
K.A. Mapuskar,
G. Vasquez Martinez,
C.F. Pulliam,
M.S. Petronek,
E.J. Steinbach,
V. Monga,
M. Furqan,
J.G. Jetton,
D.P. Saunders,
A. Pearce,
S. Davidson,
L. Pitre,
N.E. Dunlap,
R. Fairbanks,
C.M. Lee,
S.L. Mott,
K.L. Bodeker,
Huang Cl,
J.M. Buatti,
C.M. Anderson,
R.A. Beardsley,
J.T. Holmlund,
D. Zepeda-Orozco,
D.R. Spitz,
B.G. Allen
Affiliations
K.A. Mapuskar
University of Iowa Hospitals and Clinics, Free Radical and Radiation Biology Program, Department of Radiation Oncology, Iowa City, IA, USA
G. Vasquez Martinez
Kidney and Urinary Tract Center, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, USA
C.F. Pulliam
University of Iowa Hospitals and Clinics, Free Radical and Radiation Biology Program, Department of Radiation Oncology, Iowa City, IA, USA
M.S. Petronek
University of Iowa Hospitals and Clinics, Free Radical and Radiation Biology Program, Department of Radiation Oncology, Iowa City, IA, USA
E.J. Steinbach
The University of Iowa Stead Family Department of Pediatrics, Iowa City, IA, USA
V. Monga
University of Iowa Hospitals and Clinics, Department of Internal Medicine, Iowa City, IA, USA
M. Furqan
University of Iowa Hospitals and Clinics, Department of Internal Medicine, Iowa City, IA, USA
J.G. Jetton
Medical College of Wisconsin, Department of Pediatrics, Milwaukee, WI, USA
D.P. Saunders
Northeast Cancer Centre, Health Sciences North, Northern Ontario School of Medicine, Sudbury, Canada
A. Pearce
Northeast Cancer Centre, Health Sciences North, Northern Ontario School of Medicine, Sudbury, Canada
S. Davidson
Northeast Cancer Centre, Health Sciences North, Northern Ontario School of Medicine, Sudbury, Canada
L. Pitre
Northeast Cancer Centre, Health Sciences North, Northern Ontario School of Medicine, Sudbury, Canada
N.E. Dunlap
University of Louisville, School of Medicine, Louisville, KY, 40202, USA
R. Fairbanks
Cancer Care Northwest, Spokane, WA, USA
C.M. Lee
Cancer Care Northwest, Spokane, WA, USA
S.L. Mott
University of Iowa Holden Comprehensive Cancer Center, Iowa City, IA, USA
K.L. Bodeker
University of Iowa Hospitals and Clinics, Free Radical and Radiation Biology Program, Department of Radiation Oncology, Iowa City, IA, USA
Huang Cl
University of Iowa Carver College of Medicine, Department of Internal Medicine, Iowa City, IA, USA
J.M. Buatti
University of Iowa Hospitals and Clinics, Free Radical and Radiation Biology Program, Department of Radiation Oncology, Iowa City, IA, USA
C.M. Anderson
University of Iowa Hospitals and Clinics, Free Radical and Radiation Biology Program, Department of Radiation Oncology, Iowa City, IA, USA
R.A. Beardsley
Galera Therapeutics, Inc., Malvern, PA, USA
J.T. Holmlund
Galera Therapeutics, Inc., Malvern, PA, USA
D. Zepeda-Orozco
Kidney and Urinary Tract Center, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, USA; Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, USA
D.R. Spitz
University of Iowa Hospitals and Clinics, Free Radical and Radiation Biology Program, Department of Radiation Oncology, Iowa City, IA, USA; Corresponding author. Division of Free Radical and Radiation Biology Department of Radiation Oncology The University of Iowa Hospitals and Clinics, Iowa City, IA, 52242, USA.
B.G. Allen
University of Iowa Hospitals and Clinics, Free Radical and Radiation Biology Program, Department of Radiation Oncology, Iowa City, IA, USA; Corresponding author. Division of Free Radical and Radiation Biology Department of Radiation Oncology The University of Iowa Hospitals and Clinics, Iowa City, IA, 52242-1181, USA.
Head and neck squamous cell carcinoma (HNSCC) patients treated with high-dose cisplatin concurrently with radiotherapy (hdCis-RT) commonly suffer kidney injury leading to acute and chronic kidney disease (AKD and CKD, respectively). We conducted a retrospective analysis of renal function and kidney injury-related plasma biomarkers in a subset of HNSCC subjects receiving hdCis-RT in a double-blinded, placebo-controlled clinical trial (NCT02508389) evaluating the superoxide dismutase mimetic, avasopasem manganese (AVA), an investigational new drug. We found that 90 mg AVA treatment prevented a significant reduction in estimated glomerular filtration rate (eGFR) three months as well as six and twelve months after treatment compared to 30 mg AVA and placebo. Moreover, AVA treatment may have allowed renal repair in the first 22 days following cisplatin treatment as evidenced by an increase in epithelial growth factor (EGF), known to aid in renal recovery. An upward trend was also observed in plasma iron homeostasis proteins including total iron (Fe-blood) and iron saturation (Fe-saturation) in the 90 mg AVA group versus placebo. These data support the hypothesis that treatment with 90 mg AVA mitigates cisplatin-induced CKD by inhibiting hdCis-induced renal changes and promoting renal recovery.
