Preventing Nephrotoxicity and Ototoxicity From Osteosarcoma Therapy



Status:Active, not recruiting
Conditions:Cancer, Nephrology
Therapuetic Areas:Nephrology / Urology, Oncology
Healthy:No
Age Range:Any - 30
Updated:9/15/2018
Start Date:April 2013
End Date:January 2019

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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

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.

Inclusion Criteria:

- <30 years of age

- histological diagnosis of high-grade osteosarcoma

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

- 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.

- Pregnant or breastfeeding

- Unable to cooperate with research procedures
We found this trial at
1
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South 34th Street
Philadelphia, Pennsylvania 19104
 215-590-1000
Children's Hospital of Philadelphia Since its start in 1855 as the nation's first hospital devoted...
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