Official Title: “Outpatient Chemotherapy in Pediatric Osteosarcoma: Doxorubicin With Cisplatin, High-Dose Methotrexate, and Additional Risk-Adapted Outpatient Chemotherapy”

Primary Objectives:

1. Develop an outpatient thoracic treatment paradigm by reducing the number of hospitalizations during front-line osteosarcoma therapy and to improve Quality of Life (QOL) and quality of care by providing state-of the art osteosarcoma treatment in the pediatric outpatient clinic (e.g. Pediatric Ambulatory Therapy Center, PATC) except for intra-arterial chemotherapy, surgery, significant illness, or if requested by the patient and/or caregiver.

Secondary Objectives:

1. To document incidence of lung metastases on therapy and after completion of therapy.

2. Monitor safety profile and determine efficacy (PFS) of a lung-directed therapy in higher-risk patients using gemcitabine and aerosol GM-CSF.

3. Collect data on local control including: type of procedure(s) for control of primary tumor, type of procedure(s) for control of metastases, time interval from start of chemotherapy to achieve no evidence of disease (NED) status, wound complications and infections, and percent necrosis of surgical specimens.

4. Compare PFS for non-metastatic extremity (standard-risk) and higher-risk cohorts.

5. Analyze FAS expression on surgical specimens (lung metastases and primary tumors).

6. Monitor incidence of ototoxicity (>40 dB loss at 4000 Hz and/or >30dB at 2000Hz) and cardiotoxicity (EF decrease>10 % or <50% EF).

Study Type: Interventional

Study Design: Treatment, Non-Randomized, Open Label, Uncontrolled, Parallel Assignment, Safety/Efficacy Study

Study Primary Completion Date: January 2010

THE STUDY DRUGS:

The standard treatment combination used to treat patients with osteosarcoma is doxorubicin, cisplatin, and methotrexate with or without ifosfamide. When this treatment combination is given in the hospital, it can require around 18-22 hospital stays. Somewhat recently, chemotherapy for osteosarcoma has become possible to give in the outpatient clinic.

Researchers want to learn if giving 4 certain drugs (the combination of doxorubicin, cisplatin, and methotrexate with or without ifosfamide) in the outpatient setting to eligible patients will help to decrease the number of hospital stays.

During this study, all study participants whose tumor(s) can be taken out with surgery will be offered routine surgery to remove the tumor(s). After surgery, if the doctor believes the tumor(s) have responded well enough, the standard treatment combination is again doxorubicin, cisplatin, and methotrexate. If the tumor(s) have not responded well enough, however, the standard treatment combination is methotrexate and ifosfamide.

In this study, participants are considered at "higher risk" for the tumor(s) spreading to the lungs in the following cases: if the participant's tumor(s) are large at the time of joining this study, if the cancer has spread to other organs, and/or if standard chemotherapy in this study has not killed enough tumor cells.

Researchers want to find out if giving gemcitabine and aerosol sargramostim after surgery (in addition to methotrexate and ifosfamide) to participants in this "higher risk" group can help to prevent the disease from spreading to the lungs.

Participants who are unable to have surgery will also be considered at higher risk for the tumor(s) spreading to the lungs, and will also receive gemcitabine and aerosol sargramostim, in addition to methotrexate and ifosfamide, for this same purpose.

The following drugs are used in this study: - DOXORUBICIN is designed to stop the growth of cancer cells, which may cause the cells to die. - CISPLATIN has an atom at its center that contains a type of metal called platinum. The platinum is supposed to poison the cancer cells. - METHOTREXATE is designed to disrupt cells (including cancer cells) from making and repairing DNA and "copying" themselves. - IFOSFAMIDE is designed to stop the growth of cancer cells, which may cause the cells to die. - SARGRAMOSTIM promotes the growth of white blood cells, which help to fight infections.

This drug is typically given by vein or under the skin as a shot, but in this study it is being given in a different way, by inhaling an aerosol mist containing sargramostim. - GEMCITABINE is designed to stop the growth of cancer cells, which may cause the cells to die. - The combination of sargramostim plus gemcitabine is being tested as a "lung-directed" therapy because gemcitabine is designed to increase the levels of a certain "biomarker" that is found on osteosarcoma cells, and sargramostim can activate ("turn on") white blood cells that can recognize those biomarkers on osteosarcoma cells in the lungs.

This may cause tumor cells in the lungs to die.

SCREENING TESTS:

Before you can start treatment on this study, you will have "screening tests" to help the doctor decide if you are eligible to take part in this study. The following tests and procedures will be performed: - Your medical history will be reviewed. - You will have a physical exam. - Blood (about 2-3 teaspoons) will be drawn for routine tests and tests of your kidney and liver function. This routine blood draw will include a pregnancy test for women who are able to have children. To be eligible to take part in this study, the pregnancy test must be negative. - You will have an echocardiogram (ECHO -- a test to check heart function). - You will have a magnetic resonance imaging (MRI) scan of the disease area, an x-ray of the disease area and the chest, a computed tomography (CT) scan of the chest, and a bone scan. - You will have whole-body scans (such as fluorodeoxyglucose positron emission tomography [FDG-PET] scans) performed. Throughout this study, whenever scans are performed, the purpose is to check the status of the disease. Your MRI, CT scans, and x-rays will not be sent to outside institutions. - You will have a hearing test.

STUDY GROUPS:

If you are found to be eligible to take part in this study, you will be assigned to 1 of 2 groups based on the likelihood that the surgery will be able to control the disease in the arm or leg that has the bone tumor(s).

Group 1 includes participants who are considered to have a "standard" chance that surgery will be able to control the disease in the arm or leg, participants who will have an amputation, or participants with cancer in areas other than in an arm or leg at the time of diagnosis.

Group 2 includes participants who are considered to have a "higher" chance that the tumor(s) will be left behind after having surgery that the doctor considers as "incomplete" to control the disease.

CENTRAL VENOUS LINE:

For drugs to be given by vein, your study doctor will likely recommend that you have a central venous line (CVL) placed. A central venous line is a sterile flexible tube that will be placed into a large vein while you are under local anesthesia. Your doctor will explain this procedure to you in more detail, and you will be required to sign a separate consent form for this procedure.

PRE-SURGERY CHEMOTHERAPY FOR GROUP 1:

Before surgery, Group 1 participants will receive doxorubicin, cisplatin, and methotrexate followed by leucovorin. Leucovorin is given to help prevent and/or treat the side effects that methotrexate may cause. Dexrazoxane is used to decrease the risk of side effects to the heart that doxorubicin may cause. These drugs will be given in an outpatient clinic (without requiring hospitalization), if possible.

DOXORUBICIN will be given by vein over 15 minutes, after dexrazoxane by vein over 15 minutes, on Day 1 of Weeks 1 and 6.

CISPLATIN will be given as a continuous infusion by vein over 48 hours, on Days 1 and 2 of Weeks 1 and 6.

METHOTREXATE will be given by vein, over 4 hours, on Day 1 of Weeks 4, 5, 9, and 10. If you have difficulty recovering from the effects of the methotrexate therapy, you may only receive methotrexate twice before surgery, instead of 4 times.

LEUCOVORIN will be given by vein, over 5 minutes, on the day after each methotrexate dose and then by mouth every 6 hours after that, until the study doctor believes that the methotrexate level in the blood is low. The methotrexate level in the blood will be checked using a blood test (less than 2 teaspoons each time). This test will be performed once a day after each methotrexate infusion, until the methotrexate blood level is low and it is considered safe to stop the leucovorin.

PRE-SURGERY CHEMOTHERAPY FOR GROUP 2:

Before surgery, Group 2 participants will receive dexrazoxane, doxorubicin, and cisplatin.

On Day 1 of Weeks 1, 4, and 7, DEXRAZOXANE will be given by vein over 15 minutes, followed by DOXORUBICIN given by vein over 15 minutes and then CISPLATIN through an artery over 4 hours.

Infusion through an artery requires a hospital stay of 2-4 days.

SURGERY:

For all eligible study participants, the surgery to remove the tumor(s) will be performed on either Week 11 or 12. The surgery will be explained to you in detail, and you will be asked to sign a separate consent form for it that will describe its risks.

Before surgery, you will have routine visits with the surgeon. You will have several routine scans performed to help plan the surgery.

CHEMOTHERAPY REGIMENS AFTER SURGERY:

After the surgery (on or around Week 14), you will receive additional "post-surgery" chemotherapy.

After surgery, if you were originally in Group 1, and if the doctor believes the tumor(s) have responded well enough (specifically, if 90% or more of the tumor cells are dead when checked under the microscope), you will receive additional chemotherapy that is similar to what you received before surgery. This is described below as Regimen A. If the doctor does not believe the tumor(s) have responded well enough (if less than 90% of the tumor cells are dead when checked under the microscope), however, you will be assigned to Regimen B.

All participants who started in Group 2 will be assigned to Regimen B.

RADIATION AND CHEMOTHERAPY FOR PATIENTS INELIGIBLE FOR ROUTINE SURGERY:

A small number of participants on this study may need to have radiation therapy to help control the disease, as part of their routine care. This would only be done if the tumor(s) cannot be completely taken out with surgery, or if amputation is necessary but refused by the participant. If needed, and depending on where the tumor(s) are located, your doctor may decide that radiation is needed. All participants needing radiation or having surgery that the doctor considers as "incomplete" to control the disease are considered "higher risk" and will receive Regimen B therapy during and after radiation. (Radiation will usually begin during Weeks 12-14, but it could be anytime during ifosfamide therapy.) Lung-directed chemotherapy, as described below, will also be given. The radiation therapy will be explained to you in detail, and you will be asked to sign a separate consent form for it that will describe its risks.

POST-SURGERY CHEMOTHERAPY FOR REGIMEN A

Regimen A includes the following treatments: - METHOTREXATE will be given over 4 hours on Day 1 of Weeks 14, 15, 19, 20, 24, 25, 29, and 30. - DOXORUBICIN will be given on Day 1 of Weeks 16, 21, and 26. - CISPLATIN will be given as a continuous infusion by vein over 48 hours, on Days 1 and 2 of Weeks 16, 21, and 26. - LEUCOVORIN will be given by vein, over 5 minutes, on the day after each methotrexate dose and then by mouth every 6 hours after that, until the study doctor believes that the methotrexate level in the blood is low. The methotrexate level in the blood will be checked using a blood test (less than 2 teaspoons each time). This test will be performed once a day after each methotrexate infusion, until the methotrexate blood level is low and it is considered safe to stop the leucovorin.

POST-SURGERY CHEMOTHERAPY FOR REGIMEN B

Regimen B includes the following treatments: - METHOTREXATE will be given over 4 hours on Day 1 of Weeks 14, 15, 20, 21, 26, 27, 32, 33, 38, and 39. - LEUCOVORIN will be given by vein, over 5 minutes, on the day after each methotrexate dose and then by mouth every 6 hours after that, until the study doctor believes that the methotrexate level in the blood is low. The methotrexate level in the blood will be checked using a blood test (less than 2 teaspoons each time). This test will be performed once a day after each methotrexate infusion, until the methotrexate blood level is low and it is considered safe to stop the leucovorin. - IFOSFAMIDE will be given by vein, continuously over 5 days each time, on Weeks 16, 22, 28, and 34. - MESNA will be given by vein, continuously over 6 days each time, on Weeks 16, 22, 28, and 34. Mesna is used to decrease the risk of bleeding in the bladder and kidneys while ifosfamide is taken.

STUDY TESTS:

After Week 5 of treatment, and then again before surgery, you will have the following tests performed: - Your medical history will be reviewed. - You will have a physical exam. - Blood (about 2-3 teaspoons each time) will be collected for routine tests and tests of your kidney and liver function. The routine blood tests may be repeated more often during the weeks you are receiving any of the study drugs.

If you are receiving cisplatin, you may have a hearing test performed before each dose of this drug.

You will have an ECHO performed before your fourth dose of doxorubicin on Week 14, and possibly more often if necessary.

QUESTIONNAIRES:

You will be asked to complete 5 brief questionnaires on 5 different days during this study.

The questionnaires ask about the health-related quality of your life, and include questions about how you have felt, physically and emotionally, during cancer treatment. The questionnaires also ask how you and your family have adapted to your having cancer treatments, and what effects the medicines may have had on whether you have felt healthy or sick.

These questionnaires will be completed at Week 1, at about Week 7 (before surgery or radiation), sometime during Weeks 20-22, at the end-of-treatment visit (either the end-of-Regimen-A visit, the end-of-Regimen-B visit, or the end-of-treatment visit), and 1 year after your first diagnosis of cancer. It should take you about 15-20 minutes to fill out the questionnaires each time.

EXTERNAL CARE:

If the study doctor allows and you agree, some of the blood tests in this study may be performed outside of M. D. Anderson. It is also possible that the lung-directed therapy (described below) may be given outside of M. D. Anderson, at a location that is closer to where you live. The study doctor will discuss these options with you, if applicable.

LENGTH OF STUDY PARTICIPATION:

If the disease gets worse or intolerable side effects occur, you will be taken off study.

END-OF-REGIMEN-A VISIT, END-OF-REGIMEN-B VISIT, OR END-OF-TREATMENT VISIT:

If you complete Regimen A or B as planned or you leave the study early for any reason, the following procedures will be performed: - You will have a physical exam. - Urine and blood (about 2-3 teaspoons) will be drawn for routine tests and tests of your kidney and liver function. - You will have an ECHO, x-rays of the disease area and the chest, CT scans of the chest, and a bone scan. - You will also have whole-body scans and a hearing test. - Group B participants will have tests of their breathing function.

FOLLOW-UP VISITS:

After the end-of-Regimen-A visit, the end-of-Regimen-B visit, or the end-of-treatment visit, you will be asked to return for follow-up visits. At these visits, the following procedures will be performed: - CT scans of the chest will be performed every 3 months for the first year after your chemotherapy ends, every 4 months for the 2nd year, every 6 months for the 3rd year, and once a year for the next 2 years. - You will have a bone scan every year for 5 years.

LUNG-DIRECTED CHEMOTHERAPY AFTER COMPLETING REGIMEN B:

After the end-of-Regimen-B visit, Regimen B participants will receive the following lung-directed chemotherapy for 36 additional weeks: - GEMCITABINE will be given by vein over 1 hour, every other week. - You will inhale (breathe in) SARGRAMOSTIM aerosol twice a day for 7 days on, 7 days off, beginning the day you receive gemcitabine.

At the end of lung-directed chemotherapy, all Regimen B participants will have tests of their breathing function.

This is an investigational study. All of the drugs used in this study are commercially available and commonly used in osteosarcoma. This study is designed to look at the drugs' use in the outpatient setting, which is considered research.

You and/or your insurance provider will be responsible for the costs of the study drugs, tests, procedures, and clinical care for this study.

Up to 40 patients will take part in this study. All will be enrolled at M. D. Anderson.

Intervention(s) in this Clinical Trial

• Drug: Doxorubicin
  • Pre-Surgery, Arm 1: IV Over 15 Minutes on Day 1 of Weeks 1 and 6; Post-Surgery, Arm 1: IV on Day 1 of Weeks 16, 21, and 26; Pre-Surgery, Arm 2: IV over 15 Minutes on Day 1 of Weeks 1, 4, and 7.
• Drug: Cisplatin
  • Pre-Surgery, Arm 1: IV Over 48 Hours, on Days 1 and 2 of Weeks 1 and 6; Post-Surgery, Arm 1: IV Over 48 Hours, on Days 1 and 2 of Weeks 16, 21, and 26. Pre-Surgery, Arm 2: Infusion through an artery over 4 hours on Day 1 of Weeks 1, 4, and 7.
• Drug: Methotrexate
  • Pre-Surgery, Arm 1: IV Over 4 Hours on Day 1 of Weeks 4, 5, 9, and 10; Post-Surgery, Arm 1: IV Over 4 Hours on Day 1 of Weeks 14, 15, 19, 20, 24, 25, 29, and 30; Post-Surgery, Arm 2: IV Over 4 Hours on Day 1 of Weeks 14, 15, 20, 21, 26, 27, 32, 33, 38, and 39.
• Drug: Leucovorin
  • Pre- and Post-Surgery, Arm 1: IV Over 5 minutes on the day after each methotrexate dose and then by mouth every 6 hours; Post-Surgery, Arm 2: IV Over 5 minutes on the day after each methotrexate dose and then by mouth every 6 hours.
• Drug: Dexrazoxane
  • Pre-Surgery, Arm 2: IV Over 15 minutes on Day 1 of Weeks 1, 4, and 7.
• Drug: Ifosfamide
  • Post-Surgery, Arm 2: IV continuously over 5 days each time, on Weeks 16, 22, 28, and 34.
• Behavioral: Questionnaire
  • Questionnaires to be completed on 5 different days during the study.
• Drug: Gemcitabine
  • IV over 1 hour, every other week.
• Drug: Sargramostim
  • Inhaled aerosol twice a day for 7 days on, 7 days off, beginning the day you receive gemcitabine.

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: 1
  • Pre-Surgery, Arm 1: Doxorubicin, Cisplatin, Methotrexate, Leucovorin; Post-Surgery, Arm 1: Methotrexate, Doxorubicin, Cisplatin, Leucovorin.
• Experimental: 2
  • Pre-Surgery, Arm 2: Dexrazoxane, Doxorubicin, Cisplatin; Post-Surgery, Arm 2: Methotrexate, Leucovorin, Ifosfamide; Lung-Directed Chemotherapy, Arm 2: Gemcitabine, Sargramostim.

Primary Measures

• To learn if giving certain combinations of chemotherapy drugs before and after surgery, mostly in the outpatient clinic instead of in the hospital, can result in fewer hospital stays during treatment for osteosarcoma.
  • Time Frame: 20 Months
    Safety Issue?: No

Secondary Measures

• To find out if giving lung-directed chemotherapy with gemcitabine and inhaled (breathed in) aerosol GM-CSF (sargramostim) to pts. who are at high risk for osteosarcoma spreading to the lungs, can help to prevent the disease from spreading to the lungs.
  • Time Frame: 20 Months
    Safety Issue?: No
• The safety of this continuation therapy will also be studied.
  • Time Frame: 20 Months
    Safety Issue?: Yes

Inclusion Criteria:

• Newly diagnosed high-grade osteosarcoma. Patients with unresectable or metastatic disease ARE eligible.
• Age 5-40 years old on date of diagnostic biopsy.
• Adequate organ function: creatinine 1.6 or lower, bilirubin <2, Hemoglobin 8 gm/dL or greater, ANC 1000 or more, platelets 100,000 or more. Cardiac EF 50% or better, hearing threshold 40 dB at 4000 Hz or better.
• Signed informed consent.
• Negative pregnancy test in females of child bearing potential, and if sexually active, willingness to use effective contraception during chemotherapy.

Exclusion Criteria:

• Diagnosis other than osteosarcoma.
• Pregnant or lactating females, or unwilling to use effective contraception during chemotherapy

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 5 Years

Maximum Age for this Clinical Trial: 40 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: M.D. Anderson Cancer Center

Overall Clinical Trial Officials and Contacts

Peter M. Anderson, MD, PhD Principal Investigator U.T.M.D. Anderson Cancer Center  

Overall Contact: Peter M. Anderson, MD, PhD 713-563-0893 

Information obtained from ClinicalTrials.gov on August 29, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00673179

Study ID Number: 2007-0404

ClinicalTrials.gov Identifier: NCT00673179

Health Authority: United States: Institutional Review Board