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Pilot Study to Prevent Nephrotoxicity of High-Dose Methotrexate by Prolonging the Infusion Duration and Prevent Nephrotoxicity and Ototoxicity of Cisplatin With Pantoprazole in Children, Adolescents and Young Adults With Osteosarcoma

Phase 2
1 Year
30 Years
Open (Enrolling)
Osteosarcoma, Nephrotoxicity, Ototoxicity

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Trial Information

Pilot Study to Prevent Nephrotoxicity of High-Dose Methotrexate by Prolonging the Infusion Duration and Prevent Nephrotoxicity and Ototoxicity of Cisplatin With Pantoprazole in Children, Adolescents and Young Adults With Osteosarcoma

Current osteosarcoma treatment regimens include cisplatin and high-dose methotrexate
(HDMTX), which are nephrotoxic and ototoxic, and the damage to kidneys and cochlear hair
cells may be irreversible. Preventing these toxicities will improve the outcome in long-term
survivors and may also prevent short-term treatment delays and dose reductions that can
compromise the efficacy of the treatment regimen and allow for administration of higher
cumulative doses of cisplatin. This pilot study evaluates pharmacologically-based approaches
to prevent the nephrotoxic effect of HDMTX by prolonging the infusion duration and thereby
lowering the risk of drug precipitation in renal tubules; and to selectively block the
uptake of cisplatin into renal tubular cells and cochlear hair cells by inhibiting the
organic cation transporter 2 (OCT2) with the proton pump inhibitor (PPI), pantoprazole.
Participants with previously untreated biopsy-proven, localized or metastatic osteosarcoma
will receive six cycles of the standard MAP chemotherapy regimen, which includes high-dose
methotrexate, doxorubicin and cisplatin. The first 2 cycles are administered neoadjuvantly
followed by surgery to remove the primary tumor, when feasible.

A novel randomized, crossover, 2 x 2 factorial clinical trial design allows all patients to
receive the new interventions to prevent toxicity and to serve as their own controls. New,
sensitive urinary biomarkers of acute kidney injury serve as primary endpoints for
evaluating treatment-related renal damage. Ototoxicity will be monitored using audiograms.
The effect of these interventions on tumor response (radiographic and histologic) and
toxicity (including a patient reported outcome survey and nutritional status) will be
closely monitored. Other secondary objectives include evaluating bone-specific alkaline
phosphatase as a biomarker of tumor burden and constructing a tissue microarray to evaluate
expression of proteins that are responsible for resistance to the current drugs used to
treat osteosarcoma and assess expression of proteins that are targeted by new anticancer
drugs under development for childhood cancers.

Inclusion Criteria:

- <30 years of age

- histological diagnosis of high-grade osteosarcoma

- Extremity or central axis (including craniofacial) primary tumor; localized or

- No prior chemotherapy or radiation therapy for osteosarcoma. Subjects who develop
osteosarcoma as a second cancer are eligible if they have not previously received
cisplatin, doxorubicin or other anthracyclines, or MTX

- Serum creatinine at or below the upper limit of normal (ULN) for age and gender

- Shortening fraction on echocardiogram >28%

- Hearing level threshold ≤25 dB at all frequencies in both ears to be evaluable for
evaluation of pantoprazole's effect on cisplatin ototoxicity. Patients with hearing
loss can be enrolled but will not be evaluable for ototoxicity objective.

- Absolute neutrophil count >1,000/microliter(mcL) and platelet count >100,000/mcL

Exclusion Criteria:

- Receiving H2 antagonists (cimetidine, ranitidine, famotidine, nizatidine) or proton
pump inhibitors (lansoprazole, omeprazole, pantoprazole, esomeprazole, rabeprazole,
dexlansoprazole) AND unable to hold the drug for 24 h prior to and 24 h after each
cisplatin course on cycles 1-4.

- Inability to tolerate a PPI

- Pregnant or breastfeeding

- Unable to cooperate with research procedures

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Pharmacodynamics Study, Intervention Model: Crossover Assignment, Masking: Open Label, Primary Purpose: Supportive Care

Outcome Measure:

Change of urinary biomarker concentration from pre treatment and 24 hours after cisplatin or High-dose Methotrexate

Outcome Description:

Biomarkers of acute kidney injury (urinary KIM-1, NAG, NGAL), glomerular function (serum creatinine, cystatin C), renal tubular function (fractional excretion of Mg)

Outcome Time Frame:

pretreatment and 24 hours after cisplatin or high-dose methotrexate

Safety Issue:


Principal Investigator

Frank M Balis, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Children's Hospital of Philadelphia


United States: Institutional Review Board

Study ID:




Start Date:

April 2013

Completion Date:

May 2016

Related Keywords:

  • Osteosarcoma
  • Nephrotoxicity
  • Ototoxicity
  • Osteosarcoma
  • Cancer
  • Nephrotoxicity
  • Ototoxicity
  • Cisplatin
  • High-dose methotrexate
  • Biomarkers
  • Patient reported outcomes
  • Osteosarcoma



Children's Hospital of Philadelphia Philadelphia, Pennsylvania  19104