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.