Combination Chemotherapy and Dexrazoxane Followed by Surgery and Radiation Therapy in Treating Patients With Advanced Soft Tissue Sarcoma or Recurrent Bone Sarcoma

• Sponsor: City of Hope Medical Center (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00544778
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 7
• Arm: 1

Study Details

Study Description

Brief Summary

RATIONALE: Drugs used in chemotherapy, such as doxorubicin, ifosfamide, and irinotecan, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Chemoprotective drugs, such as dexrazoxane, may protect normal cells from the side effects of chemotherapy. Giving combination chemotherapy together with dexrazoxane before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving radiation therapy after surgery may kill any tumor cells that remain after surgery.

PURPOSE: This phase II trial is studying how well giving combination chemotherapy together with dexrazoxane followed by surgery and radiation therapy works in treating patients with advanced soft tissue sarcoma or recurrent bone sarcoma.

Condition or Disease	Intervention/Treatment	Phase
Sarcoma	Biological: filgrastim; Drug: dexrazoxane hydrochloride; Drug: doxorubicin hydrochloride; Drug: ifosfamide; Drug: irinotecan hydrochloride; Genetic: protein expression analysis; Other: immunoenzyme technique; Procedure: adjuvant therapy; Procedure: conventional surgery; Procedure: neoadjuvant therapy; Radiation: radiation therapy	Phase 2

Detailed Description

OBJECTIVES:

• To evaluate the effectiveness of neoadjuvant dose-dense chemotherapy comprising doxorubicin hydrochloride, ifosfamide, and irinotecan hydrochloride in combination with dexrazoxane hydrochloride followed by surgery and radiotherapy in patients with advanced soft tissue sarcoma or recurrent bone sarcoma.

• To evaluate the toxicities of this regimen in these patients.

• To compare the duration of disease-free and overall survival of patients with advanced soft tissue sarcoma who receive this therapy on a neoadjuvant basis with historical controls.

• To evaluate laboratory correlates of chemotherapy resistance for the cytotoxic agents used in this study.

OUTLINE: Patients are stratified by type of sarcoma (soft tissue vs bone), prior treatment (untreated vs treated), and presence of metastases (yes vs no).

• Courses 1 and 2: Patients receive doxorubicin hydrochloride and dexrazoxane hydrochloride IV continuously over 96 hours. Treatment repeats every 3 weeks for 2 courses.

• Courses 3 and 4: Patients receive ifosfamide IV over 2 hours twice a day (every 12 hours) on days 1-3. Treatment repeats every 3 weeks for 2 courses.

• Courses 5 and 6: Patients receive irinotecan hydrochloride IV over 1 hour once a day on days 1-5 and 8-12. Treatment repeats every 3 weeks for 2 courses.

Patients also receive filgrastim (G-CSF) subcutaneously once a day beginning 3 days after completion of chemotherapy and continuing until blood counts recover.

Patients then undergo standard surgery and radiotherapy.

Patients undergo blood sample collection periodically for correlative studies. Samples are analyzed for MDR (multidrug resistance gene) protein expression via immunoperoxidase staining.

After completion of study treatment, patients are followed every 3 months for 2 years, every 6 months for 2 years, and then once a year thereafter.

Study Design

• Study Type: Interventional
• Actual Enrollment: 7 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Trial of Neoadjuvant Dose-Dense Doxorubicin, Ifosfamide, and Irinotecan (CPT-11) for Advanced Soft Tissue and Recurrent Bone Sarcomas
• Study Start Date: Aug 1, 2001
• Actual Primary Completion Date: Nov 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm 1 High-dose chemotherapy with doxorubicin at 120 mg/m2 and ifosfamide at 2 g/m2 followed by a prolonged schedule of CPT-11 at 20 mg/m2.	Biological: filgrastim; Drug: dexrazoxane hydrochloride; Drug: doxorubicin hydrochloride; Drug: ifosfamide; Drug: irinotecan hydrochloride; Genetic: protein expression analysis; Other: immunoenzyme technique; Procedure: adjuvant therapy; Procedure: conventional surgery; Procedure: neoadjuvant therapy; Radiation: radiation therapy

Outcome Measures

Primary Outcome Measures

1. Response Rate [First disease evaluation one month after the start of treatment and every 3 months there after, up to 2 years.]

   Response rate defined as the proportion of subjects with confirmed partial or complete response as defined by the RECIST criteria.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

DISEASE CHARACTERISTICS:

• Diagnosis of 1 of the following:

• Primary soft tissue sarcoma at high-risk* for recurrence, meeting any of the following criteria:

• Previously untreated locally advanced, nonmetastatic disease

• Advanced (metastatic) disease not amenable to standard or higher priority investigational neoadjuvant therapies

• Recurrent bone sarcoma (e.g., osteogenic sarcoma, Ewing sarcoma, or peripheral neuroectodermal tumor)

• Must have advanced locally recurrent or metastatic disease NOTE: *High-risk is defined as high-grade, deep to fascia, and > 5 cm in greatest dimension

• Measurable or nonmeasurable disease is not required

• Pre-chemotherapy consultation with surgery and radiation oncology is required for formulation of loco-regional therapy

• No gastrointestinal stromal cell sarcoma

• No alveolar soft part sarcoma

• No symptomatic brain metastases

• No requirement for anticonvulsant or corticosteroid therapy

PATIENT CHARACTERISTICS:

• Karnofsky performance status 70-100%

• Life expectancy ≥ 2 months

• Absolute neutrophil count ≥ 2,000/mm^3

• Platelet count > 120,000/mm^3

• Creatinine clearance > 50 mL/min

• Serum bilirubin ≤ 1.5 mg/dL

• SGOT or SGPT ≤ 2.5 times upper limit of normal

• Serum albumin ≥ 2.5 mg/dL

• LVEF ≥ 50% by MUGA scan

• Not pregnant or nursing

• Fertile patients must use effective contraception

• No concurrent nonmalignant illness (e.g., cardiovascular, pulmonary, or CNS disease) that is poorly controlled with currently available treatment or is of such severity that the investigators deem it unwise for the patient to enter the study

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics

• No prior chemotherapy for recurrent (local or metastatic) soft tissue sarcoma

• Prior chemotherapy for recurrent bone sarcoma allowed provided the total dose of doxorubicin hydrochloride is ≤ 300 mg/m^2

• No prior radiotherapy to > 25% of bone marrow

• At least 3 weeks since prior radiotherapy or chemotherapy

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• City of Hope Medical Center
• National Cancer Institute (NCI)

Investigators

• Study Chair: Warren A. Chow, MD, City of Hope Comprehensive Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: City of Hope Medical Center
• ClinicalTrials.gov Identifier: NCT00544778
• Other Study ID Numbers: 00050; P30CA033572; CHNMC-00050; CDR0000566381
• First Posted: Oct 16, 2007
• Last Update Posted: Aug 28, 2014
• Last Verified: Aug 1, 2014

• Keywords provided by City of Hope Medical Center: recurrent adult soft tissue sarcoma; stage III adult soft tissue sarcoma; stage IV adult soft tissue sarcoma; metastatic osteosarcoma; recurrent osteosarcoma; metastatic Ewing sarcoma/peripheral primitive neuroectodermal tumor; recurrent Ewing sarcoma/peripheral primitive neuroectodermal tumor; Ewing sarcoma of bone
• Additional relevant MeSH terms: Sarcoma; Osteosarcoma; Doxorubicin; Liposomal doxorubicin; Dexrazoxane; Irinotecan; Ifosfamide; Razoxane

Study Results

Participant Flow

Arm/Group Title	Arm 1
Arm/Group Description	High-dose chemotherapy with doxorubicin at 120 mg/m2 and ifosfamide at 2 g/m2 followed by a prolonged schedule of CPT-11 at 20 mg/m2.
Period Title: Overall Study
STARTED	7
COMPLETED	7
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Arm 1
Arm/Group Description	High-dose chemotherapy with doxorubicin at 120 mg/m2 and ifosfamide at 2 g/m2 followed by a prolonged schedule of CPT-11 at 20 mg/m2.
Overall Participants	7
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	39
Sex: Female, Male (Count of Participants)
Female	2 28.6%
Male	5 71.4%
Region of Enrollment (participants) [Number]
United States	7 100%

Outcome Measures

1. Primary Outcome

Title	Response Rate
Description	Response rate defined as the proportion of subjects with confirmed partial or complete response as defined by the RECIST criteria.
Time Frame	First disease evaluation one month after the start of treatment and every 3 months there after, up to 2 years.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm 1
Arm/Group Description	High-dose chemotherapy with doxorubicin at 120 mg/m2 and ifosfamide at 2 g/m2 followed by a prolonged schedule of CPT-11 at 20 mg/m2.
Measure Participants	7
Number [percentage of patients responding]	0

Adverse Events

Time Frame	Adverse events were collected over a period of 11 months.
Adverse Event Reporting Description	"Other" adverse events are all grades and attributions to treatment not included in "Serious" adverse events.
Arm/Group Title	Arm 1
Arm/Group Description	High-dose chemotherapy with doxorubicin at 120 mg/m2 and ifosfamide at 2 g/m2 followed by a prolonged schedule of CPT-11 at 20 mg/m2.
All Cause Mortality
	Arm 1
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Arm 1
	Affected / at Risk (%)	# Events
Total	0/7 (0%)
Other (Not Including Serious) Adverse Events
	Arm 1
	Affected / at Risk (%)	# Events
Total	6/7 (85.7%)
Blood and lymphatic system disorders
Febrile neutropenia	4/7 (57.1%)	5
Hemoglobin decreased	6/7 (85.7%)	21
Packed red blood cell transfusion	3/7 (42.9%)	5
Cardiac disorders
Sinus tachycardia	3/7 (42.9%)	5
Eye disorders
Vision blurred	1/7 (14.3%)	1
Gastrointestinal disorders
Abdominal pain	4/7 (57.1%)	4
Constipation	4/7 (57.1%)	6
Diarrhea	3/7 (42.9%)	4
Dyspepsia	4/7 (57.1%)	5
Esophagitis	1/7 (14.3%)	1
Gastrointestinal disorder	1/7 (14.3%)	1
Haematochezia	1/7 (14.3%)	1
Incontinence NOS	2/7 (28.6%)	2
Melaena	1/7 (14.3%)	1
Mucositis oral	2/7 (28.6%)	2
Nausea	6/7 (85.7%)	17
Vomiting	6/7 (85.7%)	11
General disorders
Chest pain	2/7 (28.6%)	2
Chills	2/7 (28.6%)	2
Fatigue	6/7 (85.7%)	22
Fever	1/7 (14.3%)	1
Oedema NOS	2/7 (28.6%)	2
Pain	4/7 (57.1%)	8
Infections and infestations
Catheter related infection	1/7 (14.3%)	1
Infection NOS	1/7 (14.3%)	1
Investigations
Alanine aminotransferase increased	3/7 (42.9%)	4
Alkaline phosphatase increased	4/7 (57.1%)	9
Aspartate aminotransferase increased	5/7 (71.4%)	12
Creatinine increased	2/7 (28.6%)	2
Hyperbilirubinemia	2/7 (28.6%)	2
INR increased	1/7 (14.3%)	1
Leukopenia	2/7 (28.6%)	4
Lymphopenia	3/7 (42.9%)	8
Neutrophil count decreased	2/7 (28.6%)	3
Platelet count decreased	2/7 (28.6%)	3
Weight loss	1/7 (14.3%)	1
Metabolism and nutrition disorders
Anorexia	4/7 (57.1%)	6
Hypercalcemia	1/7 (14.3%)	1
Hyperglycemia	6/7 (85.7%)	11
Hypermagnesemia	1/7 (14.3%)	1
Hypoalbuminemia	6/7 (85.7%)	18
Hypocalcemia	4/7 (57.1%)	9
Hypokalemia	5/7 (71.4%)	10
Hypomagnesemia	2/7 (28.6%)	3
Hyponatremia	6/7 (85.7%)	9
Hypophosphatemia	2/7 (28.6%)	5
Musculoskeletal and connective tissue disorders
Myalgia	2/7 (28.6%)	4
Nervous system disorders
Depressed level of consciousness	1/7 (14.3%)	2
Dizziness	1/7 (14.3%)	1
Extrapyramidal disorder	2/7 (28.6%)	2
Headache	3/7 (42.9%)	3
Peripheral motor neuropathy	6/7 (85.7%)	12
Peripheral sensory neuropathy	1/7 (14.3%)	6
Psychiatric disorders
Anxiety	2/7 (28.6%)	3
Confusion	3/7 (42.9%)	5
Depression	2/7 (28.6%)	2
Hallucination NOS	2/7 (28.6%)	3
Insomnia	2/7 (28.6%)	2
Renal and urinary disorders
Bladder pain	1/7 (14.3%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnea	2/7 (28.6%)	3
Haemoptysis	1/7 (14.3%)	1
Hemorrhage nasal	2/7 (28.6%)	2
Hiccough	1/7 (14.3%)	2
Pneumonitis	1/7 (14.3%)	1
Respiratory disorder	1/7 (14.3%)	1
Skin and subcutaneous tissue disorders
Rash desquamating	1/7 (14.3%)	2
Skin disorder	1/7 (14.3%)	1
Sweating	1/7 (14.3%)	1
Vascular disorders
Hypotension	3/7 (42.9%)	5

Limitations/Caveats

The study was terminated…protocol objectives not met. It was closed prematurely due to withdrawal of support by the sponsor. Subjects have been followed, but there is not enough data generated to continue following the subjects."

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.