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

Summary

This is a pilot study that will allow investigators to collect data related to early and potentially more accurate response assessments using a chemotherapy protocol that eliminates methotrexate to maximize the dose intensity of doxorubicin. The pilot data will be used to seek funding to more fully address the hypotheses in a multi-institutional, Phase II or Phase III trial. The primary and secondary objectives are as follows:

Primary:

1. To evaluate the feasibility and potential usefulness of measuring early changes in tumor metabolic activity, assessed by Fludeoxyglucose-Positron Emission Tomography (FDG-PET) imaging and alkaline phosphatase activity, as early predictors of histological response rate at 12 weeks in osteosarcoma patients.
2. To explore whether histological response can be assessed by a computer algorithm using virtual microscopic images of pathology material, and whether quantifying necrosis in this way correlates with microscope slide-based review.

Secondary:

1\. To gather pilot data on the histological response rate, 3-year event-free survival, and 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).

All patients will receive 4 courses of preoperative chemotherapy courses. With the exception of high-dose methotrexate, which is given weekly, preoperative and postoperative chemotherapy courses are planned to begin every 21 days.

Patients with good histological response (those patients with \> 90% tumor necrosis at time of definitive resection) will receive three postoperative chemotherapy courses. The 1st will consist of doxorubicin, dexrazoxane, cisplatin and Granulocyte-Colony Stimulating Factor (G-CSF)(or Polyethylene Glycol filgrastim). The 2nd course will consist of doxorubicin, dexrazoxane, ifosfamide, MESNA, etoposide, G-CSF (or PEG-filgrastim). The 3rd course will consist of ifosfamide, MESNA, etoposide, G-CSF (or PEG-filgrastrim). The total doxorubicin dose will be 450 mg/m2.

Patients with poor response (those patients with \< 90% tumor necrosis found on pathology at time of definitive resection) will receive five postoperative chemotherapy courses. High Dose-Methotrexate will be administered during the 1st and 3rd postoperative chemotherapy courses as 4-weekly and 2-weekly doses, respectively. The 2nd course will consist of doxorubicin, dexrazoxane, cisplatin and G-CSF (or PEG-filgrastim). The 4th course will consist of doxorubicin, dexrazoxane, ifosfamide, Mesna, etoposide, G-CSF (or PEG-filgrastim). The 5th cycle will consist of ifosfamide, Mesna, etoposide, G-CSF (or PEG-filgrastrim). The total doxorubicin dose will be 450 mg/m2.

Conditions

• Osteosarcoma
• Lung Metastases

Interventions

DRUG

Dexrazoxane

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

DRUG

Doxorubicin

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

DRUG

Cisplatin

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

DRUG

G-CSF

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

DRUG

PEG-filgrastim

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

DRUG

Etoposide

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

DRUG

Ifosfamide

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

DRUG

Mesna

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)

DRUG

Leucovorin

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

Sponsors & Collaborators

• University of Chicago

  lead OTHER

Principal Investigators

• Stephen X. Skapek, MD · University of Chicago

• Andres Morales, MD · University of Chicago

Study Design

Allocation

NA

Purpose

TREATMENT

Masking

NONE

Model

SINGLE_GROUP

Eligibility

Min Age

2 Years

Max Age

35 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2010-07-31

Primary Completion

2011-11-30

Completion

2011-11-30

Countries

• United States

Study Locations