Combination Chemotherapy and Peripheral Stem Cell Transplantation in Treating Patients With Sarcoma
Study Details
Study Description
Brief Summary
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 and combining chemotherapy with peripheral stem cell transplantation may allow the doctor to give higher doses of chemotherapy drugs and kill more tumor cells.
PURPOSE: Phase II trial to study the effectiveness of high-dose combination chemotherapy and peripheral stem cell transplantation in treating patients who have advanced or recurrent sarcoma.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Detailed Description
OBJECTIVES: I. Determine the feasibility of sequential high-dose chemotherapy with ifosfamide and doxorubicin followed by melphalan and cisplatin, each followed by autologous peripheral blood stem cell support, in patients with high-risk or advanced sarcomas. II. Determine the toxic effects of this regimen in these patients. III. Determine response rate and disease-free and overall survival in these patients treated with this regimen.
OUTLINE: Beginning at least 4 weeks prior to the start of chemotherapy, patients receive filgrastim (G-CSF) subcutaneously daily until the completion of peripheral blood stem cell (PBSC) harvesting. Beginning 5 days after the start of G-CSF, PBSCs are collected over several days. Patients who do not mobilize sufficient cells undergo bone marrow harvest. Regimen A: Patients receive high-dose ifosfamide IV and doxorubicin IV continuously over 96 hours on days -8 to -4. 12.5% of PBSCs or bone marrow are reinfused on day -2 and 37.5% are reinfused on day 0. Patients receive G-CSF IV beginning on day 0 and continuing until blood counts recover. Regimen B: Beginning at least 4 weeks after day 1 of Regimen A, patients receive high-dose melphalan IV followed immediately by cisplatin IV on days -11 and -4. Patients receive G-CSF IV on days -10 to -6. 12.5% of PBSCs or bone marrow are reinfused on day -3 and the remaining 37.5% are reinfused on day 0. Patients receive G-CSF IV beginning on day 0 and continuing until blood counts recover. Patients are followed monthly for 1 year, every 3 months for 1 year, and then as needed for 3 years.
PROJECTED ACCRUAL: A total of 30 patients will be accrued for this study within 3 years.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Doxorubicin/Ifosfamide + Melphalan/CDDP + PSCT Cycle 1 Day -8 through Day -4 (96h) Doxorubicin 150 mg/m2 (CI) + Ifosfamide 14 g/m2 mixed with mesna (CI) Day -3 Mesna 3.5 g/m2 over 24 h Day -2 12.5% of stem cell reinfused. Cycle2 Day -11 Melphalan 75 mg/m2 + Cisplatin 100 mg/m2 Day -10 thru Day -6 G-CSF 5ug/kg Day -4 Melphalan 75 mg/m2 + Cisplatin 100 mg/m2 Day -3 12.5% if stem cell reinfused Day 0 37.5% of stem cell reinfused |
Biological: filgrastim
5 ug/kg daily following stem cell reinfusion
Drug: cisplatin
Course 2 - 100 mg/m2 at an infusion rate of 25 mg/hr
Drug: doxorubicin hydrochloride
Course 1 - 150 mg/m2 by continuous intravenous infusion for 96 hours.
Drug: ifosfamide
Course 1 - 14 gm/M2 by continuous intravenous infusion for 96 hours.
Drug: melphalan
Course 2 - 75 mg/m2 infused at a rate of 5 mg/minute
Procedure: peripheral blood stem cell transplantation
Administered on Day 0 following high-dose chemotherapy in both courses 1 and 2
|
Outcome Measures
Primary Outcome Measures
- Number of Participants With Grade 3 Bilirubin [2 years after completion of treatment]
Criteria for early termination of this feasibility study: > 2 patients experience grade 4 or 5 hematologic toxicity or more that 3 patients experience grade 3 hematologic toxicity; > 2 patients experience grade 3 hepatic or gastrointestinal toxicity or > 3 patients are unable to receive the second cycle of treatment; > 2 patients experience grade 5 toxicity related to treatment regimen.
- Toxicities Counts [2 months after completion of second cycle of treatment.]
Number of patients with grade 3 and 4 toxicities observed during cycles 1 & 2 using the Common Toxicity Criteria Version for Chemotherapy.
Secondary Outcome Measures
- 5-year Progression-free Survival [Until disease progression, up to 5 Years]
Estimated using the product-limit method of Kaplan and Meier. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST), as a 25% increase in the sum of the longest diameter of target lesions, or the appearance of new lesions.
- 5-year Overall Survival [Until death from any cause, up to 5 years]
Estimated using the product-limit method of Kaplan and Meier.
Eligibility Criteria
Criteria
DISEASE CHARACTERISTICS: Histologically confirmed sarcomas in the following categories:
Soft tissue sarcoma (STS) High-grade STS of the extremities Primary extending to fascia or locally recurrent At least 10 cm in greatest dimension or multifocal on surgical pathology Primary site controlled by surgery and/or radiotherapy High-grade truncal or head and neck sarcoma At least 10 cm in greatest dimension or any size with no surgical options for clear margins Primary site controlled by surgery and/or radiotherapy Locally recurrent disease in CR or PR after surgery, chemotherapy, or radiotherapy Metastatic STS in CR or PR after surgery, chemotherapy, or radiotherapy Osteosarcoma (OS) Extremity OS after neoadjuvant chemotherapy and surgical resection provided: Less than 50% necrosis in the surgical specimen LDH or alkaline phosphatase greater than 2 times normal at presentation Axial OS in CR or PR after chemotherapy and/or surgery Primary or recurrent metastatic OS in CR or PR after chemotherapy, surgery, and/or radiotherapy Ewing's sarcoma or primitive neuroectodermal tumor Primary site in CR or PR after chemotherapy, radiotherapy, or surgery Rib, pelvic, or axial skeleton primary Bulky tumor (at least 10 cm in greatest diameter) Primary or recurrent metastatic disease in CR or PR after surgery, chemotherapy, or radiotherapy Rhabdomyosarcoma Gross residual disease after primary treatment with surgery, chemotherapy, and radiotherapy Primary group IV or recurrent metastatic disease in CR or PR after chemotherapy and radiotherapy with or without surgery No brain metastasis No histologically confirmed bone marrow metastasis Prior metastases allowed with clearing of bone marrow at entry No contraindication to collection of mobilized stem cells or, if needed, autologous bone marrow
PATIENT CHARACTERISTICS: Age: 10 to 55 Performance status: Karnofsky 80-100% Hematopoietic:
Absolute neutrophil count greater than 2,000/mm3 Platelet count greater than 150,000/mm3 Hemoglobin greater than 10 g/dL Hepatic: See Disease Characteristics Bilirubin less than 1.5 mg/dL AST and ALT less than 3 times normal Hepatitis B surface antigen negative
Negative hepatitis C antigen test required in patients with hepatitis C antibody Renal:
Creatinine less than 1.4 mg/dL Creatinine clearance greater than 75 mL/min Cardiovascular:
LVEF at least 55% by MUGA or echocardiogram No history of significant cardiac disease Pulmonary: FEV1 greater than 2 liters PaO2 greater than 70 mm Hg on room air PaCO2 less than 42 mm Hg on room air DLCO greater than 60% predicted Other: No hearing loss of greater than 40 decibels HIV negative No organic or psychiatric CNS dysfunction that would preclude study No other medical or psychosocial problems that would place patient at unacceptable risk No history of other malignancy except nonmelanoma skin cancer or carcinoma in situ of the cervix Not pregnant Negative pregnancy test Fertile patients must use effective contraception
PRIOR CONCURRENT THERAPY: More than 2 weeks since treatment to control primary or recurrent tumor Biologic therapy: Not specified Chemotherapy: See Disease Characteristics No more than 2 prior chemotherapy regimens (including adjuvant therapy) Prior cumulative cisplatin dose less than 400 mg/m2 Prior cumulative doxorubicin dose less than 240 mg/m2 Endocrine therapy: Not specified Radiotherapy: See Disease Characteristics No prior radiotherapy to more than 20% of the bone marrow-containing axial skeleton No prior radiotherapy to the left chest wall Surgery: See Disease Characteristics
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Cancer Center and Beckman Research Institute, City of Hope | Duarte | California | United States | 91010-3000 |
Sponsors and Collaborators
- City of Hope Medical Center
- National Cancer Institute (NCI)
Investigators
- Study Chair: George Somlo, MD, City of Hope Comprehensive Cancer Center
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 94072
- P30CA033572
- CHNMC-IRB-94072
- NCI-V94-0545
- CDR0000063845
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Doxorubicin/Ifosfamide + Melphalan/CDDP + PSCT |
|---|---|
| Arm/Group Description | Cycle 1 Day -8 through Day -4 (96h) Doxorubicin 150 mg/m2 (CI) + Ifosfamide 14 g/m2 mixed with mesna (CI) Day -3 Mesna 3.5 g/m2 over 24 h Day -2 12.5% of stem cell reinfused. Cycle2 Day -11 Melphalan 75 mg/m2 + Cisplatin 100 mg/m2 Day -10 thru Day -6 G-CSF 5ug/kg Day -4 Melphalan 75 mg/m2 + Cisplatin 100 mg/m2 Day -3 12.5% if stem cell reinfused Day 0 37.5% of stem cell reinfused |
| Period Title: Overall Study | |
| STARTED | 13 |
| COMPLETED | 13 |
| NOT COMPLETED | 0 |
Baseline Characteristics
| Arm/Group Title | Doxorubicin/Ifosfamide + Melphalan/CDDP + PSCT |
|---|---|
| Arm/Group Description | Cycle 1 Day -8 through Day -4 (96h) Doxorubicin 150 mg/m2 (CI) + Ifosfamide 14 g/m2 mixed with mesna (CI) Day -3 Mesna 3.5 g/m2 over 24 h Day -2 12.5% of stem cell reinfused. Cycle2 Day -11 Melphalan 75 mg/m2 + Cisplatin 100 mg/m2 Day -10 thru Day -6 G-CSF 5ug/kg Day -4 Melphalan 75 mg/m2 + Cisplatin 100 mg/m2 Day -3 12.5% if stem cell reinfused Day 0 37.5% of stem cell reinfused |
| Overall Participants | 13 |
| Age (years) [Median (Full Range) ] | |
| Median (Full Range) [years] |
31
|
| Sex: Female, Male (Count of Participants) | |
| Female |
3
23.1%
|
| Male |
10
76.9%
|
| Region of Enrollment (participants) [Number] | |
| United States |
13
100%
|
Outcome Measures
| Title | Number of Participants With Grade 3 Bilirubin |
|---|---|
| Description | Criteria for early termination of this feasibility study: > 2 patients experience grade 4 or 5 hematologic toxicity or more that 3 patients experience grade 3 hematologic toxicity; > 2 patients experience grade 3 hepatic or gastrointestinal toxicity or > 3 patients are unable to receive the second cycle of treatment; > 2 patients experience grade 5 toxicity related to treatment regimen. |
| Time Frame | 2 years after completion of treatment |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Doxorubicin/Ifosfamide + Melphalan/CDDP + PSCT |
|---|---|
| Arm/Group Description | Cycle 1 Day -8 through Day -4 (96h) Doxorubicin 150 mg/m2 (CI) + Ifosfamide 14 g/m2 mixed with mesna (CI) Day -3 Mesna 3.5 g/m2 over 24 h Day -2 12.5% of stem cell reinfused. Cycle2 Day -11 Melphalan 75 mg/m2 + Cisplatin 100 mg/m2 Day -10 thru Day -6 G-CSF 5ug/kg Day -4 Melphalan 75 mg/m2 + Cisplatin 100 mg/m2 Day -3 12.5% if stem cell reinfused Day 0 37.5% of stem cell reinfused |
| Measure Participants | 13 |
| Number [participants with Grade 3 Bilirubin] |
3
23.1%
|
| Title | Toxicities Counts |
|---|---|
| Description | Number of patients with grade 3 and 4 toxicities observed during cycles 1 & 2 using the Common Toxicity Criteria Version for Chemotherapy. |
| Time Frame | 2 months after completion of second cycle of treatment. |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Cycle 1 | Cycle 2 |
|---|---|---|
| Arm/Group Description | Day -8 through Day -4 (96h) Doxorubicin 150 mg/m2 (CI) + Ifosfamide 14 g/m2 mixed with mesna (CI) Day -3 Mesna 3.5 g/m2 over 24 h Day -2 12.5% of stem cell reinfused. | Day -11 Melphalan 75 mg/m2 + Cisplatin 100 mg/m2 Day -10 thru Day -6 G-CSF 5ug/kg Day -4 Melphalan 75 mg/m2 + Cisplatin 100 mg/m2 Day -3 12.5% if stem cell reinfused Day 0 37.5% of stem cell reinfused |
| Measure Participants | 13 | 13 |
| Anemia |
8
61.5%
|
3
NaN
|
| Leukopenia |
13
100%
|
11
NaN
|
| Neutropenia |
13
100%
|
11
NaN
|
| Febrile neutropenia |
13
100%
|
9
NaN
|
| Thrombocytopenia |
13
100%
|
11
NaN
|
| Mucositis |
13
100%
|
1
NaN
|
| Bacteremia/sepsis |
2
15.4%
|
4
NaN
|
| Hyperglycemia |
5
38.5%
|
1
NaN
|
| Pulmonary function impairment (FEV1) |
1
7.7%
|
0
NaN
|
| Pulmonary infiltrates |
0
0%
|
2
NaN
|
| Diarrhea |
1
7.7%
|
0
NaN
|
| Arrhythmia |
1
7.7%
|
1
NaN
|
| Hematuria |
1
7.7%
|
0
NaN
|
| Mood |
1
7.7%
|
1
NaN
|
| Elevated PTT |
1
7.7%
|
0
NaN
|
| Title | 5-year Progression-free Survival |
|---|---|
| Description | Estimated using the product-limit method of Kaplan and Meier. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST), as a 25% increase in the sum of the longest diameter of target lesions, or the appearance of new lesions. |
| Time Frame | Until disease progression, up to 5 Years |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Doxorubicin/Ifosfamide + Melphalan/CDDP + PSCT |
|---|---|
| Arm/Group Description | Cycle 1 Day -8 through Day -4 (96h) Doxorubicin 150 mg/m2 (CI) + Ifosfamide 14 g/m2 mixed with mesna (CI) Day -3 Mesna 3.5 g/m2 over 24 h Day -2 12.5% of stem cell reinfused. Cycle2 Day -11 Melphalan 75 mg/m2 + Cisplatin 100 mg/m2 Day -10 thru Day -6 G-CSF 5ug/kg Day -4 Melphalan 75 mg/m2 + Cisplatin 100 mg/m2 Day -3 12.5% if stem cell reinfused Day 0 37.5% of stem cell reinfused |
| Measure Participants | 13 |
| Number (95% Confidence Interval) [percentage of participants] |
23
176.9%
|
| Title | 5-year Overall Survival |
|---|---|
| Description | Estimated using the product-limit method of Kaplan and Meier. |
| Time Frame | Until death from any cause, up to 5 years |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Doxorubicin/Ifosfamide + Melphalan/CDDP + PSCT |
|---|---|
| Arm/Group Description | Cycle 1 Day -8 through Day -4 (96h) Doxorubicin 150 mg/m2 (CI) + Ifosfamide 14 g/m2 mixed with mesna (CI) Day -3 Mesna 3.5 g/m2 over 24 h Day -2 12.5% of stem cell reinfused. Cycle2 Day -11 Melphalan 75 mg/m2 + Cisplatin 100 mg/m2 Day -10 thru Day -6 G-CSF 5ug/kg Day -4 Melphalan 75 mg/m2 + Cisplatin 100 mg/m2 Day -3 12.5% if stem cell reinfused Day 0 37.5% of stem cell reinfused |
| Measure Participants | 13 |
| Number (95% Confidence Interval) [percentage of participants] |
31
238.5%
|
Adverse Events
| Time Frame | Adverse events collected over a period of 45 months | |
|---|---|---|
| Adverse Event Reporting Description | "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment. | |
| Arm/Group Title | Doxorubicin/Ifosfamide + Melphalan/CDDP + PSCT | |
| Arm/Group Description | Cycle 1 Day -8 through Day -4 (96h) Doxorubicin 150 mg/m2 (CI) + Ifosfamide 14 g/m2 mixed with mesna (CI) Day -3 Mesna 3.5 g/m2 over 24 h Day -2 12.5% of stem cell reinfused. Cycle2 Day -11 Melphalan 75 mg/m2 + Cisplatin 100 mg/m2 Day -10 thru Day -6 G-CSF 5ug/kg Day -4 Melphalan 75 mg/m2 + Cisplatin 100 mg/m2 Day -3 12.5% if stem cell reinfused Day 0 37.5% of stem cell reinfused | |
All Cause Mortality |
||
| Doxorubicin/Ifosfamide + Melphalan/CDDP + PSCT | ||
| Affected / at Risk (%) | # Events | |
| Total | / (NaN) | |
Serious Adverse Events |
||
| Doxorubicin/Ifosfamide + Melphalan/CDDP + PSCT | ||
| Affected / at Risk (%) | # Events | |
| Total | 3/13 (23.1%) | |
| Cardiac disorders | ||
| Dysrhythmias | 1/13 (7.7%) | 1 |
| Investigations | ||
| Partial Thromboplastin Time | 1/13 (7.7%) | 1 |
| Respiratory, thoracic and mediastinal disorders | ||
| Pulmonary | 1/13 (7.7%) | 1 |
Other (Not Including Serious) Adverse Events |
||
| Doxorubicin/Ifosfamide + Melphalan/CDDP + PSCT | ||
| Affected / at Risk (%) | # Events | |
| Total | 13/13 (100%) | |
| Blood and lymphatic system disorders | ||
| Clinical Coagulation | 9/13 (69.2%) | 13 |
| Febrile neutropenia | 1/13 (7.7%) | 2 |
| Cardiac disorders | ||
| Dysrhythmias | 6/13 (46.2%) | 8 |
| Pericardial | 7/13 (53.8%) | 10 |
| EF/CHF | 6/13 (46.2%) | 9 |
| Ear and labyrinth disorders | ||
| Ear disorder | 1/13 (7.7%) | 1 |
| Hearing | 9/13 (69.2%) | 16 |
| Eye disorders | ||
| Eye disorder | 1/13 (7.7%) | 1 |
| Vision | 9/13 (69.2%) | 16 |
| Gastrointestinal disorders | ||
| Constipation | 12/13 (92.3%) | 21 |
| Diarrhea | 13/13 (100%) | 22 |
| Mucositis oral | 1/13 (7.7%) | 1 |
| Nausea | 13/13 (100%) | 23 |
| Vomiting | 13/13 (100%) | 22 |
| General disorders | ||
| Clinical (Physical Exam) | 9/13 (69.2%) | 12 |
| Hemorrhage | 12/13 (92.3%) | 21 |
| Other Misc | 9/13 (69.2%) | 31 |
| Stomatitis | 12/13 (92.3%) | 22 |
| Chills | 1/13 (7.7%) | 1 |
| Fatigue | 6/13 (46.2%) | 10 |
| Fever (no infection) | 11/13 (84.6%) | 18 |
| Immune system disorders | ||
| Allergy | 12/13 (92.3%) | 21 |
| Infections and infestations | ||
| Infection | 12/13 (92.3%) | 21 |
| Investigations | ||
| AGC | 12/13 (92.3%) | 22 |
| Alanine aminotransferase increased | 1/13 (7.7%) | 2 |
| Alkaline Phosphatase | 9/13 (69.2%) | 12 |
| Amylase | 4/13 (30.8%) | 6 |
| Aspartate aminotransferase increased | 1/13 (7.7%) | 2 |
| Bilirubin | 9/13 (69.2%) | 12 |
| Creatinine | 7/13 (53.8%) | 8 |
| Creatinine increased | 1/13 (7.7%) | 1 |
| Fibrinogen | 2/13 (15.4%) | 3 |
| Hyperbilirubinemia | 1/13 (7.7%) | 1 |
| Neutrophil count decreased | 1/13 (7.7%) | 2 |
| Partial Thromboplastin Time | 7/13 (53.8%) | 11 |
| Platelet count decreased | 1/13 (7.7%) | 2 |
| Platelets | 12/13 (92.3%) | 22 |
| Prothrombin Time | 9/13 (69.2%) | 13 |
| SGOT/SGT | 9/13 (69.2%) | 12 |
| WBC | 1/13 (7.7%) | 2 |
| Metabolism and nutrition disorders | ||
| Weight (Food Intake) | 8/13 (61.5%) | 12 |
| Anorexia | 1/13 (7.7%) | 2 |
| Hypercalcemia | 12/13 (92.3%) | 21 |
| Hyperglycemia | 13/13 (100%) | 23 |
| Hypocalcemia | 13/13 (100%) | 23 |
| Hypoglycemia | 12/13 (92.3%) | 21 |
| Hypomagnesemia | 13/13 (100%) | 23 |
| Nervous system disorders | ||
| Cerebellar | 9/13 (69.2%) | 16 |
| Cortical/State of Consciousness | 9/13 (69.2%) | 16 |
| Dizziness | 1/13 (7.7%) | 2 |
| Headache | 10/13 (76.9%) | 18 |
| Motor Activity | 9/13 (69.2%) | 16 |
| Peripheral Nervous System Sensory | 9/13 (69.2%) | 16 |
| Peripheral motor neuropathy | 1/13 (7.7%) | 1 |
| Peripheral sensory neuropathy | 1/13 (7.7%) | 1 |
| Taste alteration | 1/13 (7.7%) | 1 |
| Psychiatric disorders | ||
| Depression | 1/13 (7.7%) | 1 |
| Ideation | 7/13 (53.8%) | 12 |
| Insomnia | 1/13 (7.7%) | 1 |
| Mood | 9/13 (69.2%) | 16 |
| Renal and urinary disorders | ||
| Fluid Retention | 12/13 (92.3%) | 20 |
| Hematuria | 7/13 (53.8%) | 8 |
| Proteinuria | 7/13 (53.8%) | 8 |
| Respiratory, thoracic and mediastinal disorders | ||
| Pulmonary | 11/13 (84.6%) | 18 |
| Hiccough | 1/13 (7.7%) | 1 |
| Skin and subcutaneous tissue disorders | ||
| Alopecia | 5/13 (38.5%) | 8 |
| Extensive Skin Rash | 8/13 (61.5%) | 11 |
| Local Skin Rash | 8/13 (61.5%) | 11 |
| Vascular disorders | ||
| Ischemia | 7/13 (53.8%) | 10 |
| Hypertension | 2/13 (15.4%) | 3 |
| Hypotension | 2/13 (15.4%) | 3 |
Limitations/Caveats
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.
Results Point of Contact
| Name/Title | Paul Frankel, Ph.D. |
|---|---|
| Organization | City of Hope |
| Phone | (626)256-4673 ext 65265 |
| pfrankel@och.org |
- 94072
- P30CA033572
- CHNMC-IRB-94072
- NCI-V94-0545
- CDR0000063845