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

This study has been terminated.
(PI no longer affiliated with institution; only 2 subjects enrolled)
Sponsor:
Information provided by (Responsible Party):
University of Chicago
ClinicalTrials.gov Identifier:
NCT01258634
First received: September 30, 2010
Last updated: December 9, 2013
Last verified: December 2013
  Purpose

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.


Condition Intervention Phase
Osteosarcoma
Lung Metastases
Drug: Dexrazoxane
Drug: Doxorubicin
Drug: Cisplatin
Drug: G-CSF
Drug: PEG-filgrastim
Drug: Etoposide
Drug: Ifosfamide
Drug: Mesna
Drug: Leucovorin
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by University of Chicago:

Primary Outcome Measures:
  • Feasibility and usefulness of measuring early changes in tumor metabolic activity. [ Time Frame: 6 months after last subject has been enrolled ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • Gather pilot data on the histological response rate [ Time Frame: 3 years after last enrolled subject has completed therapy ] [ Designated as safety issue: Yes ]
    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).

  • Explore whether histological response can be measured by a computer algorithm [ Time Frame: 1 year after last enrolled subject has completed therapy ] [ Designated as safety issue: No ]
    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.

  • Gather pilot data on 3-year event-free survival [ Time Frame: 3 years after last subject is enrolled ] [ Designated as safety issue: No ]
    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).

  • Gather pilot data on toxicity [ Time Frame: 3 years after last subject is enrolled on the study. ] [ Designated as safety issue: Yes ]
    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).


Enrollment: 2
Study Start Date: July 2010
Study Completion Date: November 2011
Primary Completion Date: November 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Pre-op treatment 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

  Eligibility

Ages Eligible for Study:   2 Years to 35 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Must be between 2 and 35 years of age at time of diagnosis
  • Must have biopsy-proven, high-grade osteosarcoma.
  • Patients with metastases are eligible as long as the lung is the only site of metastatic disease.
  • The primary tumor and all pulmonary metastases must be deemed to be potentially resectable. There must be a commitment by the surgical team to resect the primary tumor at week 12, and pulmonary nodules at any point, unless the clinical situation indicates these interventions are not in the patient's best interest.
  • Patients must have normal laboratory values and cardiac function as defined below:
  • Creatinine clearance or radioisotope GFR of > or equal to 70ml/min/1.73 m2 OR

A serum creatinine based on age/gender as follows:

Age Maximum Serum Creatinine (mg/dL) Male Female

1 month to < 6 months 0.4 0.4 6 months to < 1 year 0.5 0.5

  1. to < 2 years 0.6 0.6
  2. to < 6 years 0.8 0.8

6 to < 10 years 1 1 10 to < 13 years 1.2 1.2 13 to < 16 years 1.5 1.4

  • or equal to 16 years 1.7 1.4

    • Cardiac: Adequate cardiac function is defined as:

Shortening fraction of > or equal to 28% by echocardiogram OR Ejection fraction of > or equal to 50% by radionuclide angiogram

  • Hepatic: Adequate liver function is described as:

Total bilirubin of < or equal to 1.5 x upper limit of normal (ULN) for age

  • Hematologic function: adequate hematologic function is defined as:

ANC > or equal to 1.5 x 10^9/L and platelet count > or equal to 100 x 10^9/L

  • Female patients must have a negative pregnancy test
  • Female patients who are lactating must agree to stop breast-feeding.
  • Patients must not be known to be HIV positive. Testing for HIV is not mandatory.
  • Sexually active patients of childbearing potential must agree to use effective contraception.
  • Patients must be able to cooperate fully with all planned protocol therapy.
  • Signed informed consent MUST be obtained from patient or parent/legal guardian prior to any study procedures and study entry.

Exclusion Criteria:

  • Patients with any low-grade osteosarcoma, post-radiation osteosarcoma, and osteosarcoma associated with Paget's disease are not eligible.
  • Patients with metastases other than lung metastases are not eligible.
  • Patients may not have received prior chemotherapy.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01258634

Locations
United States, Illinois
University of Chicago Department of Pediatrics Hematology/Oncology
Chicago, Illinois, United States, 60637
Sponsors and Collaborators
University of Chicago
Investigators
Principal Investigator: Stephen X. Skapek, MD University of Chicago
Principal Investigator: Andres Morales, MD University of Chicago
  More Information

No publications provided

Responsible Party: University of Chicago
ClinicalTrials.gov Identifier: NCT01258634     History of Changes
Other Study ID Numbers: 10-186-B
Study First Received: September 30, 2010
Last Updated: December 9, 2013
Health Authority: United States: Institutional Review Board

Keywords provided by University of Chicago:
Osteosarcoma
Surgically Resectable High Grade Osteosarcoma
Lung Metastases Only

Additional relevant MeSH terms:
Osteosarcoma
Neoplasm Metastasis
Lung Neoplasms
Neoplastic Processes
Neoplasms
Pathologic Processes
Neoplasms, Bone Tissue
Neoplasms, Connective Tissue
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Sarcoma
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Lung Diseases
Respiratory Tract Diseases
Liposomal doxorubicin
Etoposide phosphate
Isophosphamide mustard
Cisplatin
Doxorubicin
Etoposide
Ifosfamide
Dexrazoxane
Razoxane
Leucovorin
Levoleucovorin
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions

ClinicalTrials.gov processed this record on July 31, 2014