Combination Chemotherapy Plus Dexrazoxane in Treating Patients With Newly Diagnosed Nonmetastatic Osteosarcoma

This study has been completed.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Children's Oncology Group
ClinicalTrials.gov Identifier:
NCT00003937
First received: November 1, 1999
Last updated: August 4, 2014
Last verified: August 2014
  Purpose

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one drug may kill more tumor cells. Chemoprotective drugs such as dexrazoxane may protect normal cells from the side effects of chemotherapy.

PURPOSE: Phase III trial to study the effectiveness of three combination chemotherapy regimens plus dexrazoxane in treating patients who have newly diagnosed nonmetastatic osteosarcoma.


Condition Intervention Phase
Cardiac Toxicity
Sarcoma
Drug: cisplatin
Drug: dexrazoxane hydrochloride
Drug: doxorubicin hydrochloride
Drug: etoposide
Drug: ifosfamide
Drug: methotrexate
Procedure: conventional surgery
Phase 3

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Protocol for Patients With Newly-Diagnosed Non-Metastatic Osteosarcoma - A POG/CCG Pilot Intergroup Study

Resource links provided by NLM:


Further study details as provided by Children's Oncology Group:

Primary Outcome Measures:
  • Event Free Survival [ Designated as safety issue: No ]

Enrollment: 253
Study Start Date: September 1999
Study Completion Date: June 2008
Primary Completion Date: March 2004 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Pilot 1 - Doxorubicin Intensification without Ifosfamide
Dexrazoxane hydrochloride IV followed by doxorubicin hydrochloride IV plus cisplatin IV on days 1 and 2 of weeks 1 and 6. Methotrexate IV on day 1 of weeks 4, 5, 9, and 10. Patients undergo surgery on week 11. Adjuvant chemotherapy begins on day 1 of week 13. Group 1 (good response to neoadjuvant chemotherapy): Patients receive methotrexate IV over 4 hours every 3 weeks for 6 courses, beginning on week 13. Patients also receive dexrazoxane and doxorubicin hydrochloride every 3 weeks for 4 courses, beginning on week 14. Cisplatin is administered with the first 2 courses of dexrazoxane and doxorubicin. Group 2 (standard response to neoadjuvant chemotherapy): Patients receive methotrexate and cisplatin as in group 1 plus dexrazoxane and doxorubicin hydrochloride for 6 courses.
Drug: cisplatin
Other Names:
  • Cis-diamminedichloroplatinum II
  • CDDP
  • Platinol
  • NSC #119875
Drug: dexrazoxane hydrochloride
Other Names:
  • ADR-529
  • ZINECARD
  • ICRF-187
  • NSC #169780
Drug: doxorubicin hydrochloride
Other Names:
  • Adriamycin
  • NSC #123127
Drug: methotrexate
Other Names:
  • MTX
  • amethopterin
  • NSC #000740
Procedure: conventional surgery
Experimental: Pilot 2 - Doxorubicin Intensification with Ifosfamide
Preoperative therapy comprised of dexrazoxane hydrochloride, doxorubicin hydrochloride, and methotrexate as in pilot 1. Ifosfamide IV on days 1-5 of week 1. Patients undergo surgery on week 11, then begin adjuvant chemotherapy on week 13. Group 1: Patients receive methotrexate, dexrazoxane hydrochloride, and doxorubicin hydrochloride as in pilot 1, group 1. Ifosfamide is also administered on weeks 14 and 20. Cisplatin is administered on weeks 17, 23, and 26. Group 2: Patients receive methotrexate, dexrazoxane hydrochloride, and doxorubicin hydrochloride as in pilot 1, group 2. Ifosfamide is administered on weeks 14, 20, 26, and 31. Cisplatin is administered on weeks 17, 23, and 29
Drug: cisplatin
Other Names:
  • Cis-diamminedichloroplatinum II
  • CDDP
  • Platinol
  • NSC #119875
Drug: dexrazoxane hydrochloride
Other Names:
  • ADR-529
  • ZINECARD
  • ICRF-187
  • NSC #169780
Drug: doxorubicin hydrochloride
Other Names:
  • Adriamycin
  • NSC #123127
Drug: ifosfamide
Other Names:
  • IFX
  • IFOS
  • NSC #109724
Drug: methotrexate
Other Names:
  • MTX
  • amethopterin
  • NSC #000740
Procedure: conventional surgery
Experimental: Pilot 3 - Ifosfamide/Etoposide Intensification
Preoperative therapy comprised of methotrexate, dexrazoxane hydrochloride, doxorubicin, ifosfamide, and cisplatin as in pilot 2. Patients undergo surgery on week 11, then begin adjuvant chemotherapy on week 13. Group 1: Patients receive methotrexate, dexrazoxane hydrochloride, doxorubicin, ifosfamide, and cisplatin as in pilot 2, group 1. Group 2: Patients receive methotrexate on weeks 13, 19, 29, 32, 35, and 36, high dose ifosfamide and etoposide IV over 4 hours on days 1-5 of weeks 14, 23, and 26, and cisplatin on weeks 20, 30, and 33. Dexrazoxane hydrochloride and doxorubicin hydrochloride are administered on weeks 17, 20, 30, and 33
Drug: cisplatin
Other Names:
  • Cis-diamminedichloroplatinum II
  • CDDP
  • Platinol
  • NSC #119875
Drug: dexrazoxane hydrochloride
Other Names:
  • ADR-529
  • ZINECARD
  • ICRF-187
  • NSC #169780
Drug: doxorubicin hydrochloride
Other Names:
  • Adriamycin
  • NSC #123127
Drug: etoposide
Other Names:
  • VP-16
  • VePesid
  • NSC #141540
Drug: ifosfamide
Other Names:
  • IFX
  • IFOS
  • NSC #109724
Drug: methotrexate
Other Names:
  • MTX
  • amethopterin
  • NSC #000740
Procedure: conventional surgery

Detailed Description:

OBJECTIVES: I. Compare the efficacy of three intensification regimens (doxorubicin vs doxorubicin plus ifosfamide vs doxorubicin plus ifosfamide and etoposide) in patients with newly diagnosed, previously untreated, nonmetastatic osteosarcoma. II. Determine the effect of postoperative dose intensification on outcome in patients with standard response to preoperative chemotherapy. III. Determine the effect of dexrazoxane cardioprotection during standard induction therapy on histologic response in these patients. IV. Evaluate biological factors that may predict outcome in these patients. V. Determine the safety of dexrazoxane administered with doxorubicin in combination with cisplatin or cisplatin and ifosfamide in these patients. VI. Determine the effect of dexrazoxane on cytotoxicity as measured by tumor necrosis at definitive surgery in these patients. VII. Assess the feasibility of administering doxorubicin with dexrazoxane cardioprotection or high dose ifosfamide with etoposide to standard risk patients who are also receiving methotrexate and cisplatin.

OUTLINE: This is a multicenter study. Patients are enrolled sequentially on 1 of 3 pilot intensification regimens. After surgery to completely remove the primary tumor, patients are assigned to 1 of 2 adjuvant chemotherapy groups based on percent necrosis at limb salvage. Pilot 1: (Closed to accrual as of 6/2/2000) Patients receive dexrazoxane IV followed immediately by doxorubicin IV over 20 minutes plus cisplatin IV over 4 hours on days 1 and 2 of weeks 1 and 6. Methotrexate IV over 4 hours is administered on day 1 of weeks 4, 5, 9, and 10. Patients undergo surgery on week 11. Adjuvant chemotherapy begins on day 1 of week 13. Group 1 (good response to neoadjuvant chemotherapy): Patients receive methotrexate IV over 4 hours every 3 weeks for 6 courses, beginning on week 13. Patients also receive dexrazoxane and doxorubicin every 3 weeks for 4 courses, beginning on week 14. Cisplatin is administered with the first 2 courses of dexrazoxane and doxorubicin. Group 2 (standard response to neoadjuvant chemotherapy): Patients receive methotrexate and cisplatin as in group 1 plus dexrazoxane and doxorubicin for 6 courses. Pilot 2: Patients receive preoperative therapy comprised of dexrazoxane, doxorubicin, and methotrexate as in pilot 1. Ifosfamide IV over 4 hours is also administered on days 1-5 of week 1. Patients undergo surgery on week 11, then begin adjuvant chemotherapy on week 13. Group 1: Patients receive methotrexate, dexrazoxane, and doxorubicin as in pilot 1, group 1. Ifosfamide is also administered on weeks 14 and 20. Cisplatin is administered on weeks 17, 23, and 26. Group 2: Patients receive methotrexate, dexrazoxane, and doxorubicin as in pilot 1, group 2. Ifosfamide is administered on weeks 14, 20, 26, and 31. Cisplatin is administered on weeks 17, 23, and 29. Pilot 3: (Open to accrual as of 6/2/2000) Patients receive preoperative therapy comprised of methotrexate, dexrazoxane, doxorubicin, ifosfamide, and cisplatin as in pilot 2. Patients undergo surgery on week 11, then begin adjuvant chemotherapy on week 13. Group 1: Patients receive methotrexate, dexrazoxane, doxorubicin, ifosfamide, and cisplatin as in pilot 2, group 1. Group 2: Patients receive methotrexate on weeks 13, 19, 29, 32, 35, and 36, high dose ifosfamide and etoposide IV over 4 hours on days 1-5 of weeks 14, 23, and 26, and cisplatin on weeks 20, 30, and 33. Dexrazoxane and doxorubicin are administered on weeks 17, 20, 30, and 33. Patients are followed every 3 months for 1 year, every 6 months for 4 years and then annually thereafter.

PROJECTED ACCRUAL: Approximately 180 patients will be accrued for this study within 2 years.

  Eligibility

Ages Eligible for Study:   up to 30 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

DISEASE CHARACTERISTICS: Histologically proven newly diagnosed moderate or high grade osteosarcoma without metastases No prior treatment, including complete resection No parosteal or periosteal sarcoma No osteosarcoma associated with Paget's disease No nonresectable tumors or tumors that may result in marginal or interlesion resection Must be enrolled on protocol POG-9851

PATIENT CHARACTERISTICS: Age: 30 and under Performance status: ECOG 0-2 Life expectancy: Not specified Hematopoietic: Absolute neutrophil count at least 1,000/mm3 Platelet count at least 100,000/mm3 Hepatic: Bilirubin no greater than 1.5 times normal SGOT no greater than 3 times normal Renal: Creatinine normal Phosphate at least 3.0 mg/dL without supplementation Cardiovascular: Shortening fraction at least 28% by echocardiogram If echocardiogram unsatisfactory, must have ejection fraction at least 50% No history of pericarditis or myocarditis No symptomatic arrhythmia or symptomatic cardiac conduction disturbances

PRIOR CONCURRENT THERAPY: See Disease Characteristics Biologic therapy: Not specified Chemotherapy: No prior chemotherapy Endocrine therapy: Not specified Radiotherapy: No prior radiotherapy Surgery: See Disease Characteristics

  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: NCT00003937

  Show 148 Study Locations
Sponsors and Collaborators
Children's Oncology Group
Investigators
Study Chair: Cindy Schwartz, MD Sidney Kimmel Comprehensive Cancer Center
  More Information

Additional Information:
Publications:
Responsible Party: Children's Oncology Group
ClinicalTrials.gov Identifier: NCT00003937     History of Changes
Other Study ID Numbers: P9754, COG-P9754, POG-P9754, CCG-P9754, CDR0000067129
Study First Received: November 1, 1999
Last Updated: August 4, 2014
Health Authority: United States: Federal Government

Keywords provided by Children's Oncology Group:
localized osteosarcoma
cardiac toxicity

Additional relevant MeSH terms:
Osteosarcoma
Neoplasms
Neoplasms by Histologic Type
Neoplasms, Bone Tissue
Neoplasms, Connective and Soft Tissue
Neoplasms, Connective Tissue
Sarcoma
Cisplatin
Dexrazoxane
Doxorubicin
Etoposide
Etoposide phosphate
Ifosfamide
Isophosphamide mustard
Liposomal doxorubicin
Methotrexate
Razoxane
Abortifacient Agents
Abortifacient Agents, Nonsteroidal
Alkylating Agents
Antibiotics, Antineoplastic
Antimetabolites
Antimetabolites, Antineoplastic
Antimitotic Agents
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Antineoplastic Agents, Phytogenic
Antirheumatic Agents
Cardiotonic Agents
Cardiovascular Agents

ClinicalTrials.gov processed this record on October 29, 2014