Prolonged Duration Methotrexate, Doxorubicin Hydrochloride, and Cisplatin with or without Pantoprazole Sodium in Reducing or Preventing Chemotherapy Induced Kidney Damage and Hearing Loss in Younger Patients with Previously Untreated Osteosarcoma

Status: Closed to Accrual

Description

This randomized pilot phase II trial studies prolonged duration methotrexate, doxorubicin hydrochloride, and cisplatin with or without pantoprazole sodium in reducing or preventing chemotherapy induced kidney damage and hearing loss in younger patients with previously untreated osteosarcoma. Drugs used in chemotherapy, such as methotrexate, doxorubicin hydrochloride, and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Methotrexate and cisplatin can damage the kidneys and cause hearing loss, which may not be reversible. Slowing the rate of infusion of methotrexate may lower the amount of drug in the urine, which may reduce the risk of methotrexate crystals forming and prevent damage to the kidneys. Pantoprazole sodium may selectively block the uptake of cisplatin into the cells that are damaged in the kidney and inner ear without interfering with the effect of cisplatin on osteosarcoma. It is not yet known whether giving methotrexate over 12 hours instead of 4 hours, with or without pantoprazole sodium, works better to reduce or prevent chemotherapy induced kidney damage and hearing loss.

Eligibility Criteria

Inclusion Criteria

  • 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 (mg/dL): * 1 month (mo) to < 6 months: male: 0.4; female: 0.4 * 6 mo to < 1 year: male: 0.5; female: 0.5 * 1 year to < 2 years: male: 0.6; female: 0.6 * 2 to < 6 years: male: 0.8; female: 0.8 * 6 to < 10 years: male: 1; female: 1 * 10 to < 13 years: male: 1.2; female: 1.2 * 13 to < 16 years: male:1.5; female: 1.4 * >= 16 years: male: 1.7; female: 1.4
  • 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/mcL
  • Platelet count > 100,000/mcL

Exclusion Criteria

  • Receiving histamine type 2 (H2) antagonists (cimetidine, ranitidine, famotidine, nizatidine) or proton pump inhibitors 9lansoprazole, omeprazole, pantoprazole, esomeprazole, raberprazole, 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 proton pump inhibitor (PPI)
  • Pregnant or breastfeeding
  • Unable to cooperate with research procedures

Locations & Contacts

See trial information on ClinicalTrials.gov for a list of participating sites.

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. To identify more rational, pharmacologically-based drug delivery approaches to prevent nephrotoxicity from high-dose methotrexate (HDMTX) and cisplatin and ototoxicity from cisplatin in patients with osteosarcoma (OS) by: comparing biomarkers of acute injury (kidney injury molecule-1 [KIM-1], N-acetyl-beta-D-glucosamidase [NAG], neutrophil gelatinase-associated lipocalin [NGAL]), glomerular function (cystatin C, creatinine) and plasma and urine methotrexate (MTX) concentrations after 12 g/m^2 of MTX infused over 4 and 12 hours, comparing biomarkers of acute injury (KIM-1, NAG, NGAL) and glomerular and tubular function (cystatin C, creatinine, fraction excretion of magnesium [FEMg]) after cisplatin administered with and without the organic cation transporter 2 (OCT2) inhibitor, pantoprazole (pantoprazole sodium), and comparing hearing loss (audiograms) after cisplatin administered with and without the OCT2 inhibitor, pantoprazole.

SECONDARY OBJECTIVES:

I. Comparing the incidence and severity of common toxicities from cisplatin/doxorubicin administered with and without pantoprazole and from HDMTX administered as a 4 and 12 hour (h) infusion.

II. Comparing radiographic response (log ratio of tumor volumes) and histological response (percent tumor necrosis) to two cycles (10 weeks) of neoadjuvant chemotherapy for the two infusion durations of HDMTX and for cisplatin with and without pantoprazole.

III. Correlating urinary biomarkers of acute kidney injury (AKI) and glomerular filtration rate (GFR) estimated from serum cystatin C to standard measures of renal function (serum creatinine, urinalysis, estimated creatinine clearance, FEMg).

IV. Building a tissue microarray from biopsy, primary resection and resected metastatic tumors to evaluate the expression of proteins that are responsible for resistance to the drugs in the methotrexate, adriamycin (doxorubicin), cisplatin (MAP) regimen and to assess expression of proteins that are targeted by new anticancer drugs under development for childhood cancers.

V. Evaluating serum bone-specific alkaline phosphatase (BSAP) as a potential biomarker for OS.

VI. Monitoring nutritional status (weight, arm circumference, skin fold thickness, pre-albumin) in patients receiving the MAP chemotherapy regimen.

VII. Piloting an osteosarcoma-specific patient reported outcomes survey to assess the incidence and severity of tumor-related and treatment-related symptoms.

OUTLINE: Patients are randomized to 1 of 4 treatment arms.

ARM I: Patients receive cisplatin intravenously (IV) over 4 hours on days 1 and 2 of courses 1-4; doxorubicin hydrochloride IV over 15 minutes on days 1 and 2 of courses 1-6; and methotrexate IV over 4 hours on days 22 and 29 of courses 1-2, over 12 hours of days 22 and 29 of courses 3-4, and over 4 or 12 hours on days 15 and 22 of courses 5 and 6 (based on patient tolerance on courses 1-4). Patients also receive pantoprazole sodium IV over 15 minutes followed by a 4 hour infusion concurrent with cisplatin on days 1 and 2 of courses 1 and 2.

ARM II: Patients receive cisplatin and doxorubicin hydrochloride as in Arm I and methotrexate IV over 4 hours on days 22 and 29 of courses 1-2, over 12 hours of days 22 and 29 of courses 3-4, and over 4 or 12 hours on days 15 and 22 of courses 5 and 6 (based on patient tolerance on courses 1-4). Patients also receive pantoprazole sodium IV over 15 minutes followed by a 4 hour infusion concurrent with cisplatin on days 1 and 2 of courses 3 and 4.

ARM III: Patients receive cisplatin and doxorubicin hydrochloride as in Arm I and methotrexate IV over 12 hours on days 22 and 29 of courses 1-2, over 4 hours of days 22 and 29 of courses 3-4, and over 4 or 12 hours on days 15 and 22 of courses 5 and 6 (based on patient tolerance on courses 1-4). Patients also receive pantoprazole sodium IV over 15 minutes followed by a 4 hour infusion concurrent with cisplatin on days 1 and 2 of courses 1 and 2.

ARM IV: Patients receive cisplatin and doxorubicin hydrochloride as in Arm I and methotrexate IV over 12 hours on days 22 and 29 of courses 1-2, over 4 hours of days 22 and 29 of courses 3-4, and over 4 or 12 hours on days 15 and 22 of courses 5 and 6 (based on patient tolerance on courses 1-4). Patients also receive pantoprazole sodium IV over 15 minutes followed by a 4 hour infusion concurrent with cisplatin on days 1 and 2 of courses 3 and 4.

In all arms, treatment repeats every 35 days for courses 1-4 and every 28 days for courses 5 and 6.

After completion of study treatment, patients are followed up for up to 5 years.

Trial Phase & Type

Trial Phase

Phase II

Trial Type

Supportive care

Lead Organization

Lead Organization
Children's Hospital of Philadelphia

Principal Investigator
Frank M. Balis

Trial IDs

Primary ID CHP12ST051
Secondary IDs NCI-2014-01661, 12ST051, 13-009967, CHP12ST051 OS Pilot
Clinicaltrials.gov ID NCT01848457