Osteosarcoma Clinical Trial
Official title:
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
Osteosarcoma is the most common type of bone cancer in children, adolescents and young adults. Treatment with surgery and a combination of three conventional chemotherapy drugs can cure nearly two-thirds patients with osteosarcoma, but the treatment can also cause irreversible damage to the kidneys and cause permanent hearing loss. The purpose of this study is to evaluate new approaches to prevent these side effects without interfering with the beneficial effects of the chemotherapy drugs on the cancer by using our knowledge of how the drugs damage the kidney and cochlear hair cells in the ear to selectively block these side effects. Preventing these side effects without interfering with the anti-cancer effect of the drugs will improve the outcome in survivors and may also improve the effectiveness of the chemotherapy regimen by preventing treatment delays and dose reductions that are often caused by the side effects. Patients will be carefully monitored to ensure that the new interventions do not adversely affect response to the treatment and do not increase the other side effects of the chemotherapy. Specifically, we will monitor the nutritional status of the patients closely and ask patients to complete a survey describing the side effects after each treatment cycle. We will also collect a small sample of cancer tissue at the time of biopsy and surgery from each patient on this study for testing to determine new classes of anti-cancer drugs currently under development may have a role in treating osteosarcoma. If effective, these new approaches to prevent kidney damage and hearing loss will be applicable in other types of cancers treated with the same chemotherapy drugs.
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 Methotrexate, Adriamycin (doxorubicin),cisplatin (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.
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