Prediction of Excretion and Toxicity of High Dose Methotrexate in Children and Adolescents With ALL

NCT02133599 | Completed DMC

• 1 other identifier: CMH 14CC06
• Study Type: interventional
• Target: 23
• Locations: 1 country
• Sites: 1

Brief Summary

Each year approximately 2,900 children and adolescents less than 20 years old are diagnosed with acute lymphoblastic leukemia or acute lymphoblastic lymphoma in the United States. (For the purposes of this protocol, ALL will be used to refer to patients with either acute lymphoblastic leukemia or acute lymphoblastic lymphoma as patients are treated in the same manner.) High-dose methotrexate (HDMTX; 5 g/m2) remains an important component of standard treatment for most ALL patients. However, high plasma and intracellular MTX concentrations (defined as a MTX level of \>1 µmol/L at 42 hours and \> 0.40 µmol/L at 48 hours) can quickly lead to acute kidney, bone marrow, liver, skin, central nervous system, and gastrointestinal toxicities requiring extended hospitalization and delays in subsequent chemotherapy treatments. This study seeks to identify more sensitive markers of kidney injury that could serve as better predictors of delayed excretion and/or toxicity of HDMTX. This study is a pilot repeated-measures feasibility study. Hypothesis 1: Directly measured GFR (mGFR, a type of test to measure the filtering rate of kidneys) by iohexol clearance obtained prior to HDMTX will demonstrate greater sensitivity and specificity for prediction of delayed MTX excretion and/or toxicity in children and adolescents with ALL than serum creatinine (sCr) alone or sCr used for eGFR calculation. If this study proves that mGFR is a better predictor of delayed MTX excretion and/or toxicity, then another study will be developed in the future to determine if modifying the HDMTX dose or adjusting supportive care based on mGFR will prevent delayed clearance and toxicity without impacting patient survival. Hypothesis 2: Those participants prospectively demonstrating delayed MTX excretion or toxicity will exhibit elevation of kidney injury biomarkers less than 24 hours following initiation of HDMTX infusion compared to pre-chemotherapy measurements. These biomarkers will increase prior to a measurable sCr elevation.

Conditions

ALL

Outcome Measures

Primary Outcomes (1)

• Change in Iohexol clearance results

  A change from baseline Iohexol clearance results after about six weeks

  An expected average of 6 weeks or more between the two Iohexol clearances

Secondary Outcomes (1)

• Change in serum creatinine

  An expected average of about 6 weeks between measures

Study Arms (1)

Iohexol

OTHER

All patients will receive two Iohexol clearance tests, 5 mL each time before cycle 1 and 4 of HDMTX

Drug: IOHEXOL

Interventions

IOHEXOL DRUG

Patients receive 5 mL of Iohexol prior to cycle 1 and 4 of HDMTX

Also known as: Iohexol, Omnipaque 300

Iohexol

Eligibility Criteria

• Age: 2 Years - 21 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Histologically confirmed Acute Lymphoblastic Leukemia or Acute Lymphoblastic Lymphoma (ALL) in patients in first remission at the start of Interim Maintenance I. HDMTX is administered during the phase of chemotherapy referred to as "Interim Maintenance I". Interim maintenance I occurs after induction and consolidation, is approximately 64 days in duration, and involves administration of four doses of HDMTX, with a dose given approximately every two weeks.
• Age 2-21 years with a weight of ≥ 13.2 lbs. and a hemoglobin ≥ 7.0
• Karnofsky/Lansky performance score of ≥ 50 (See Appendix II).
• Patients must receive high-dose Methotrexate (HDMTX; 5g/m2) as part of their standard or COG study chemotherapy. The current COG protocols which involve HDMTX include the following: AALL0232, AALL0434, and AALL1131.
• Patients must have a negative urine pregnancy test prior to enrollment and cannot be lactating.
• All subjects must have given signed, informed consent prior to registration on study.

You may not qualify if:

• Hypersensitivity to iohexol, iodine, other contrast material
• Hypersensitivity to shellfish
• Prior treatment with HDMTX

Sponsors & Collaborators

• Ann & Robert H Lurie Children's Hospital of Chicago: lead

Study Sites (1)

Ann & Robert H. Lurie Children's Hosptial of Chicago

Chicago, Illinois, 60611, United States

Location

Related Publications (15)

• Nguyen MT, Devarajan P. Biomarkers for the early detection of acute kidney injury. Pediatr Nephrol. 2008 Dec;23(12):2151-7. doi: 10.1007/s00467-007-0470-x. Epub 2007 Mar 30.

  PMID: 17394022 BACKGROUND

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  PMID: 19158356 BACKGROUND

• Berg UB, Back R, Celsi G, Halling SE, Homberg I, Krmar RT, Monemi KA, Oborn H, Herthelius M. Comparison of plasma clearance of iohexol and urinary clearance of inulin for measurement of GFR in children. Am J Kidney Dis. 2011 Jan;57(1):55-61. doi: 10.1053/j.ajkd.2010.07.013. Epub 2010 Sep 25.

  PMID: 20870329 BACKGROUND

• Back SE, Krutzen E, Nilsson-Ehle P. Contrast media as markers for glomerular filtration: a pharmacokinetic comparison of four agents. Scand J Clin Lab Invest. 1988 May;48(3):247-53. doi: 10.3109/00365518809167491.

  PMID: 3375780 BACKGROUND

• Krutzen E, Back SE, Nilsson-Ehle P. Determination of glomerular filtration rate using iohexol clearance and capillary sampling. Scand J Clin Lab Invest. 1990 May;50(3):279-83. doi: 10.3109/00365519009091579.

  PMID: 2162080 BACKGROUND

• Gaspari F, Perico N, Ruggenenti P, Mosconi L, Amuchastegui CS, Guerini E, Daina E, Remuzzi G. Plasma clearance of nonradioactive iohexol as a measure of glomerular filtration rate. J Am Soc Nephrol. 1995 Aug;6(2):257-63. doi: 10.1681/ASN.V62257.

  PMID: 7579093 BACKGROUND

• Stake G, Monn E, Rootwelt K, Monclair T. The clearance of iohexol as a measure of the glomerular filtration rate in children with chronic renal failure. Scand J Clin Lab Invest. 1991 Dec;51(8):729-34. doi: 10.3109/00365519109104587.

  PMID: 1806987 BACKGROUND

• Holmquist P, Torffvit O, Sjoblad S. Metabolic status in diabetes mellitus affects markers for glomerular filtration rate. Pediatr Nephrol. 2003 Jun;18(6):536-40. doi: 10.1007/s00467-003-1086-4. Epub 2003 Apr 16.

  PMID: 12698326 BACKGROUND

• Adiyanti SS, Loho T. Acute Kidney Injury (AKI) biomarker. Acta Med Indones. 2012 Jul;44(3):246-55.

  PMID: 22983082 BACKGROUND

• Han WK, Bailly V, Abichandani R, Thadhani R, Bonventre JV. Kidney Injury Molecule-1 (KIM-1): a novel biomarker for human renal proximal tubule injury. Kidney Int. 2002 Jul;62(1):237-44. doi: 10.1046/j.1523-1755.2002.00433.x.

  PMID: 12081583 BACKGROUND

• Wunnapuk K, Liu X, Peake P, Gobe G, Endre Z, Grice JE, Roberts MS, Buckley NA. Renal biomarkers predict nephrotoxicity after paraquat. Toxicol Lett. 2013 Oct 9;222(3):280-8. doi: 10.1016/j.toxlet.2013.08.003. Epub 2013 Aug 14.

  PMID: 23954200 BACKGROUND

• Dieterle F, Perentes E, Cordier A, Roth DR, Verdes P, Grenet O, Pantano S, Moulin P, Wahl D, Mahl A, End P, Staedtler F, Legay F, Carl K, Laurie D, Chibout SD, Vonderscher J, Maurer G. Urinary clusterin, cystatin C, beta2-microglobulin and total protein as markers to detect drug-induced kidney injury. Nat Biotechnol. 2010 May;28(5):463-9. doi: 10.1038/nbt.1622.

  PMID: 20458316 BACKGROUND

• Herget-Rosenthal S, Marggraf G, Husing J, Goring F, Pietruck F, Janssen O, Philipp T, Kribben A. Early detection of acute renal failure by serum cystatin C. Kidney Int. 2004 Sep;66(3):1115-22. doi: 10.1111/j.1523-1755.2004.00861.x.

  PMID: 15327406 BACKGROUND

• Christov M, Waikar SS, Pereira RC, Havasi A, Leaf DE, Goltzman D, Pajevic PD, Wolf M, Juppner H. Plasma FGF23 levels increase rapidly after acute kidney injury. Kidney Int. 2013 Oct;84(4):776-85. doi: 10.1038/ki.2013.150. Epub 2013 May 8.

  PMID: 23657144 BACKGROUND

• Leaf DE, Wolf M, Waikar SS, Chase H, Christov M, Cremers S, Stern L. FGF-23 levels in patients with AKI and risk of adverse outcomes. Clin J Am Soc Nephrol. 2012 Aug;7(8):1217-23. doi: 10.2215/CJN.00550112. Epub 2012 Jun 14.

  PMID: 22700885 BACKGROUND

MeSH Terms

Interventions

Iohexol

Intervention Hierarchy (Ancestors)

Triiodobenzoic Acids; Iodobenzoates; Benzoates; Acids, Carbocyclic; Carboxylic Acids; Organic Chemicals; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons

Study Officials

• Amy Walz, MD

  Ann & Robert H. Lurie Children's Hosptial of Chicago

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: DIAGNOSTIC
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Attending Physician-Hematology, Oncology, Neuro-Oncology, and Stem Cell Transplant

Study Record Dates

• First Submitted: May 5, 2014
• First Posted: May 8, 2014
• Study Start: July 24, 2014
• Primary Completion: February 26, 2019
• Study Completion: February 27, 2019
• Last Updated: August 2, 2021

Record last verified: 2021-07

Locations

US (1)