Cycles 1 and 2: HDMTX administered as a 4-hour infusion and pantoprazole is administered with cisplatin Cycles 3 and 4: HDMTX administered as a 12-hour infusion and cisplatin is administered alone

Cycles 1 and 2: HDMTX administered as a 4-hour infusion and cisplatin is administered alone Cycles 3 and 4: HDMTX administered as a 12-hour infusion and pantoprazole is administered with cisplatin

Cycles 1 and 2: HDMTX administered as a 12-hour infusion and pantoprazole is administered with cisplatin Cycles 3 and 4: HDMTX administered as a 4-hour infusion and cisplatin is administered alone

Cycles 1 and 2: HDMTX administered as a 12-hour infusion and cisplatin is administered alone Cycles 3 and 4: HDMTX administered as a 4-hour infusion and pantoprazole is administered with cisplatin

Cycles 1 and 2: HDMTX administered as a 4-hour infusion and pantoprazole is administered with cisplatin Cycles 3 and 4: HDMTX administered as a 12-hour infusion and cisplatin is administered alone
Pantoprazole: 0.3 mg/kg IV over 15 min immediately prior to cisplatin as a loading dose on days 1 & 2 followed by 1.3 mg/kg IV infused over 4 h concurrent with the 4 h cisplatin infusion on days 1 & 2 of treatment Cycles 1 & 2 (Treatment Arms 1, 3) OR Cycles 3 & 4 (Treatment Arms 2, 4)
High-dose methotrexate infusion duration: High-dose methotrexate (12 g/sq m, maximum dose 20 g) will be infused over 4 hours or 12 hours

Arm 1

Cycles 1 and 2: HDMTX administered as a 4-hour infusion and cisplatin is administered alone Cycles 3 and 4: HDMTX administered as a 12-hour infusion and pantoprazole is administered with cisplatin
Pantoprazole: 0.3 mg/kg IV over 15 min immediately prior to cisplatin as a loading dose on days 1 & 2 followed by 1.3 mg/kg IV infused over 4 h concurrent with the 4 h cisplatin infusion on days 1 & 2 of treatment Cycles 1 & 2 (Treatment Arms 1, 3) OR Cycles 3 & 4 (Treatment Arms 2, 4)
High-dose methotrexate infusion duration: High-dose methotrexate (12 g/sq m, maximum dose 20 g) will be infused over 4 hours or 12 hours

Arm 2

Cycles 1 and 2: HDMTX administered as a 12-hour infusion and pantoprazole is administered with cisplatin Cycles 3 and 4: HDMTX administered as a 4-hour infusion and cisplatin is administered alone
Pantoprazole: 0.3 mg/kg IV over 15 min immediately prior to cisplatin as a loading dose on days 1 & 2 followed by 1.3 mg/kg IV infused over 4 h concurrent with the 4 h cisplatin infusion on days 1 & 2 of treatment Cycles 1 & 2 (Treatment Arms 1, 3) OR Cycles 3 & 4 (Treatment Arms 2, 4)
High-dose methotrexate infusion duration: High-dose methotrexate (12 g/sq m, maximum dose 20 g) will be infused over 4 hours or 12 hours

Arm 3

Cycles 1 and 2: HDMTX administered as a 12-hour infusion and cisplatin is administered alone Cycles 3 and 4: HDMTX administered as a 4-hour infusion and pantoprazole is administered with cisplatin
Pantoprazole: 0.3 mg/kg IV over 15 min immediately prior to cisplatin as a loading dose on days 1 & 2 followed by 1.3 mg/kg IV infused over 4 h concurrent with the 4 h cisplatin infusion on days 1 & 2 of treatment Cycles 1 & 2 (Treatment Arms 1, 3) OR Cycles 3 & 4 (Treatment Arms 2, 4)
High-dose methotrexate infusion duration: High-dose methotrexate (12 g/sq m, maximum dose 20 g) will be infused over 4 hours or 12 hours

Arm 4

Total

Sex: Female, Male

Ethnicity (NIH/OMB)

Region of Enrollment

This measure describes the urinary biomarkers of AKI after each course of C throughout Cycles 1-2, compared to baseline (pre-infusion) values.
Biomarkers of AKI, include: Kidney Injury Molecule-1 (KIM-1), and Neutrophil Gelatinase-Associated Lipocalin (NGAL).

Arm 1 receives a 4-hour infusion of HDTX, and Arm 3 receives a 12-hour infusion of HDTMX, during Cycles 1 & 2. Both arms also receive C and PTZ during Cycles 1 & 2.

Treatments Arms 1 & 3 (Groups With PTZ in Cycles 1 & 2)

Am 2 receives a 4-hour infusion of HDTMX, and Arm 4 receives a 12-hour infusion of HDTMX during Cycles 1 & 2. Both arms also receive the C doses, but without PTZ.

Treatments Arms 2 & 4 (Groups Without PTZ in Cycles 1 & 2)

Change in Urinary Biomarkers of Acute Kidney Injury (AKI) Between Pre-Treatment (Baseline), After CISplatin (C) Treatments, and After HDTMX Treatments

Response of the primary tumor to the first two treatment cycles (Cycles 1 and 2) will be assessed by quantifying the change in tumor volume on MRI, after treatment (pre-operative) relative to the pre-treatment tumor volume. By using the log ratio of the tumor volume post-treatment, to the tumor volume pre-treatment. The larger the change, the more effective the treatment.

Localized Disease at Baseline

Metastatic Disease at Baseline

Change in Tumor Volume

Urinary biomarkers of acute kidney injury (AKI) and glomerular filtration rate (GFR) estimated from serum cystatin C will be compared to standard measures of renal function (serum creatinine, urinalysis, estimated creatinine clearance, fractional excretion of Mg). Single reported values are averaged and reported with full ranges.

Treatment Arms 1, 3 (w/ Pantoprazole)

Treatment Arms 2, 4 (w/o Pantoprazole)

Validating Urinary Biomarkers

Tissue microarray will be constructed from biopsy specimens, primary resection and resected metastatic tumors to evaluate the expression of proteins that are responsible for resistance to the drugs in the MAP regimen and to assess expression of proteins that are targeted by new anticancer drugs under development for childhood cancers.

Tissue Microarray

Serum BSAP will be longitudinally evaluated as a potential biomarker for osteosarcoma

Bone Specific Alkaline Phosphatase (BSAP)

Nutritional status (weight, arm circumference, skin fold thickness, pre-albumin) will be throughout the course of treatment

Individual Subjects

Nutritional Status

PROS survey measures quality of life for pediatric oncology patients, in 17 scaled questions. Each question scaled 0-4 (0 = Never, 1 = Rarely, 2 = Sometimes, 3 = Often, 4 = Almost Always). The higher the final sum of the questions, the lower the quality of life/more severe the side effects of oncology treatment. Total scores can range between 0 = highest quality of life, and 100 = experiencing most severe side effects of oncology treatment/worst quality of life experience.

All participants in the study, regardless of which arm or order they were randomized to receive the study treatment.

All Study Participants (Arms 1-4)

Patient Reported Outcome Survey (PROS)

Average hearing level (HL) threshold in decibels (dB) over the frequency range of 4,000-8,000 hertz (Hz) will be derived separately for each ear from audiograms performed before each dose of cisplatin.

Ototoxicity

Cycles 1 & 2: HDMTX 4h, PTZ+C; Then Cycles 3 & 4: HDTMX 12h, C

Cycles 1 & 2: HDMTX 4h, C; Then Cycles 3 & 4: HDTMX 12h, C+PTZ

Cycles 1 & 2: HDMTX 12h, PTZ+C; Then Cycles 3 & 4: HDTMX 4h, C

Cycles 1 & 2: HDMTX 12h, C; Then Cycles 3 & 4: HDTMX 4h, C+PTZ

Overall Study

Frank Balis, MD

Osteosarcoma

Nephrotoxicity

0.3 mg/kg IV over 15 min immediately prior to cisplatin as a loading dose on days 1 & 2 followed by 1.3 mg/kg IV infused over 4 h concurrent with the 4 h cisplatin infusion on days 1 & 2 of treatment Cycles 1 & 2 (Treatment Arms 1, 3) OR Cycles 3 & 4 (Treatment Arms 2, 4)

Pantoprazole

High-dose methotrexate (12 g/sq m, maximum dose 20 g) will be infused over 4 hours or 12 hours

High-dose methotrexate infusion duration

Children's Hospital of Philadelphia

Preventing Nephrotoxicity and Ototoxicity From Osteosarcoma Therapy

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

Gateway for Cancer Research

Lung Metastases

Preoperative Chemotherapy Courses 1, 2, 3, 4: 750mg/m2; IV over 15 minutes on day 1
Postoperative Chemotherapy for Good Responders Courses 1 and 2: 750mg/m2 IV over 15 minutes on Day 1
Postoperative Chemotherapy for Poor Responders Courses 2 and 4: 750mg/m2 IV over 15 minutes on Day 1

Dexrazoxane

Preoperative Chemotherapy Courses 1 and 3: 75mg/m2; IV push day 1 Courses 2 and 4: 75mg/m2; IV push day 1, hour 0
Postoperative Chemotherapy for Good Responders Course 1: 75mg/m2; IV push day 1 Course 2: 75mg/m2; IV push day 1, hour 0
Postoperative Chemotherapy for Poor Responders Course 2: 75mg/m2; IV push day 1 Course 4: 75mg/m2; IV push day 1, hour 0

Doxorubicin

Preoperative Chemotherapy Courses 1 and 3: 60mg/m2 daily x 2 days, in 1000 ml D5W NS + 10g/m2 mannitol
Postoperative Chemotherapy for Good Responders Courses 1 and 2: 60mg/m2 daily x 2 days, in 1000 ml D5W NS + 10g/m2 mannitol
Postoperative Chemotherapy for Poor Responders:
Course 2: 60mg/m2 daily x 2 days, in 1000 ml D5W NS + 10g/m2 mannitol

Cisplatin

Preoperative Chemotherapy Courses 1, 2, 3, and 4: 5mcg/Kg; IV/SQ starting 24 hours after chemotherapy until WBC >10,000
Postoperative Chemotherapy for Good Responders Courses 1, 2, and 3: 5mcg/Kg; IV/SQ starting 24 hours after chemotherapy until WBC >10,000
Postoperative Chemotherapy for Poor Responders Courses 2, 4, and 5: 5mcg/Kg; IV/SQ starting 24 hours after chemotherapy until WBC >10,000

G-CSF

Preoperative Chemotherapy Courses 1, 2, 3, and 4: 6mg; SQ starting 24 hours after chemotherapy
Postoperative Chemotherapy for Good Responders Courses 1, 2, and 3: 6mg; SQ starting 24 hours after chemotherapy
Postoperative Chemotherapy for Poor Responders Courses 2 and 4: 6mg; SQ starting 24 hours after chemotherapy

PEG-filgrastim

Preoperative Chemotherapy Courses 2 and 4: 50mg/m2 on days 1, 2, 3, 4
Postoperative Chemotherapy for Good Responders Course 2: 50mg/m2 on days 1, 2, 3, 4 Course 3: 50mg/m2 on days, 1, 2, 3, 4 Hour 0-1
Postoperative Chemotherapy for Poor Responders Course 4: 50mg/m2 on days 1, 2, 3, 4 Course 5: 50mg/m2 on days 1, 2, 3, 4

Etoposide

Preoperative Chemotherapy Courses 2 and 4: 3g/m2; IV over 1 hour Days 1, 2, 3, 4
Postoperative Chemotherapy for Good Responders Course 2: 3g/m2; IV over 1 hour Days 1, 2, 3, 4 Course 3: 3g/m2; IV over 1 hour Days 1, 2, 3, 4
Postoperative Chemotherapy for Poor Responders Course 4: 3g/m2; IV over 1 hour Days 1, 2, 3, 4 Course 5: 3g/m2; IV over 1 hour Days 1, 2, 3, 4

Ifosfamide

Preoperative Chemotherapy Courses 2 and 4: 600mg/m2, 1st dose in bag with ifosfamide, 2nd dose IV over 3 hours immediately post ifosfamide infusion, Subsequent doses - hour 5, 8, 11, 14 (IV push)
Postoperative Chemotherapy for Good Responders Courses 2 and 3: 600mg/m2, 1st dose in bag with ifosfamide, 2nd dose IV over 3 hours immediately post ifosfamide infusion, Subsequent doses - hour 5, 8, 11, 14 (IV push)
Postoperative Chemotherapy for Poor Responders Courses 4 and 5: 600mg/m2, 1st dose in bag with ifosfamide, 2nd dose IV over 3 hours immediately post ifosfamide infusion, Subsequent doses - hour 5, 8, 11, 14 (IV push)

Mesna

Postoperative Chemotherapy for Poor Responders Courses 1 and 3: 15 mg/m2/dose IV or PO every 6 hours, beginning 24 hours after start of methotrexate infusion and continuing until methotrexate level is <0.1 uM

Leucovorin

University of Chicago Department of Pediatrics Hematology/Oncology

A Study of Pre-Operative Treatment of Newly-Diagnosed, Surgically-Resectable Osteosarcoma With Doxorubicin, Ifosfamide, Etoposide, and Cisplatin With Early Metabolic Assessment of Response

A Pilot Study of Pre-Operative Treatment of Newly-Diagnosed, Surgically-Resectable Osteosarcoma With Doxorubicin, Ifosfamide, Etoposide, and Cisplatin With Early Metabolic Assessment of Response

The feasibility and potential usefulness of measuring early changes in tumor metabolic activity will be assessed by early Fludeoxyglucose-Positron Emission Tomography imaging and alkaline phosphatase activity.

To gather pilot data on the histological response rate when children and young adults with resectable osteosarcoma are treated using a chemotherapy regimen of alternating courses of doxorubicin/cisplatin (DC) and doxorubicin/ifosfamide/etoposide (IDE).

To explore whether histological response can be measured by a computer algorithm using virtual microscopic images of pathology material, and whether quantifying necrosis in this way correlates with microscope slide-based review.

To gather pilot data on the 3-year event-free survival when children and young adults with resectable osteosarcoma are treated using a chemotherapy regimen of alternating courses of doxorubicin/cisplatin (DC) and doxorubicin/ifosfamide/etoposide (IDE).

To gather pilot data on toxicity when children and young adults with resectable osteosarcoma are treated using a chemotherapy regimen of alternating courses of doxorubicin/cisplatin (DC) and doxorubicin/ifosfamide/etoposide (IDE).

University of Chicago

Sarcoma

Bone Tumor

Patients will undergo DCE-MRI prior to, and within 18-24 days of starting chemotherapy. These studies are designed to determine if the DCE-MRI data will provide an a priori or early prognostic marker of tumor response. The dynamic MRI is done on a standard clinical scanner using standard techniques described below.
MR imaging studies will be acquired on a 1.5T GE (Milwaukee,WI) Signa LX scanner.

osteosarcoma/phosphatase

Preventing Nephrotoxicity and Ototoxicity From Osteosarcoma Therapy

A Study of Pre-Operative Treatment of Newly-Diagnosed, Surgically-Resectable Osteosarcoma With Doxorubicin, Ifosfamide, Etoposide, and Cisplatin With Early Metabolic Assessment of Response

Dynamic Contrast Enhanced MRI(DCE-MRI)of Bone Tumors

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