Preoperative Thalidomide With Radiation Therapy For Patients With Low-Grade Primary Soft Tissue Sarcoma or Thalidomide With Radiation Therapy and Chemotherapy For Patients With High-Grade or Intermediate-Grade Primary Soft Tissue Sarcoma of the Arm, Leg, or Body Wall

Phase 2

Terminated

Conditions: Recurrent Adult Soft Tissue Sarcoma
Stage I Adult Soft Tissue Sarcoma AJCC v7
Stage II Adult Soft Tissue Sarcoma AJCC v7
Stage III Adult Soft Tissue Sarcoma AJCC v7

Interventions: Other: Laboratory Biomarker Analysis
Drug: Dacarbazine
Radiation: Radiation Therapy
Drug: Doxorubicin Hydrochloride
Biological: Filgrastim
Drug: Ifosfamide
Drug: Thalidomide
Procedure: Therapeutic Conventional Surgery

Registration Number: NCT00089544

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: Thalidomide may stop the growth of soft tissue sarcoma by stopping blood flow to the tumor. Radiation therapy uses high-energy x-rays to damage tumor cells. Drugs used in chemotherapy, such as doxorubicin, ifosfamide, and dacarbazine, work in different ways to stop tumor cells from dividing so they stop growing or die. Giving thalidomide together with radiation therapy and/or chemotherapy before surgery may shrink the tumor so that it can be removed. This phase II trial is studying how well giving preoperative (before surgery) thalidomide together with radiation therapy works in treating patients with low-grade primary soft tissue sarcoma, and how well giving thalidomide together with radiation therapy, doxorubicin, ifosfamide, and dacarbazine works in treating patients with high-grade or intermediate-grade primary soft tissue sarcoma of the arm, leg, chest wall, or abdominal wall.

Detailed Description: OBJECTIVES:

I. Determine the treatment delivery and toxicity of the combination of thalidomide and radiotherapy in patients with low-grade primary soft tissue sarcoma of the extremity or body wall.

II. Determine the treatment delivery and toxicity of the combination of thalidomide and doxorubicin, ifosfamide, dacarbazine, and radiotherapy in patients with high- or intermediate-grade primary soft tissue sarcoma of the extremity or body wall and compare these results with those of patients treated on RTOG-9514.

III. Determine the feasibility of using specific tissue and circulating biomarkers of antiangiogenic response in patients treated with these regimens, in a multi-institutional setting.

IV. Determine the quantitative changes and patient variabilities of these biomarkers before, during, and after therapy with these regimens.

V. Determine the baseline data sets of biomarkers, particularly circulating endothelial cells, in patients treated with these regimens.

VI. Determine the tolerance to long-term post-operative thalidomide in these patients.

VII. Determine the clinical response to pre-operative therapy in these patients.

VIII. Correlate local control and disease-free survival with surrogate biological endpoints in patients treated with these regimens.

OUTLINE: This is a pilot, cohort study. Patients with high- or intermediate-grade tumors \>= 8 cm in diameter are assigned to cohort A and patients with low-grade tumors \> 5 cm in diameter are assigned to cohort B.

Cohort A: Patients receive doxorubicin, ifosfamide, and dacarbazine IV continuously on days 1-3, 22-24, and 43-45. Patients receive filgrastim (G-CSF) subcutaneously beginning on days 4, 25, and 46 and continuing until blood counts recover. Patients undergo radiotherapy once daily on days 7-11, 14-18, 21, 28-32, 35-39, and 42. Patients receive oral thalidomide once daily on days 7-21 and 26-42. Patients undergo surgical resection between days 84 and 98. Beginning 2 weeks after surgery, patients receive oral thalidomide once daily for 12 months in the absence of unacceptable toxicity.

Cohort B: Patients receive oral thalidomide once daily beginning on day 1 and continuing until 1 week before surgery. Patients undergo radiotherapy once daily, 5 days a week, on weeks 1-5. Patients undergo surgical resection between days 77 and 91. Beginning 2 weeks after surgery, patients receive oral thalidomide once daily for 6 months in the absence of unacceptable toxicity.

Patients are followed every 3 months for 2 years and then every 6 months for 4 years.

PROJECTED ACCRUAL: A total of 44 patients (22 per cohort) will be accrued for this study within 17 months.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 23

Inclusion Criteria

Diagnosis of primary soft tissue sarcoma
- T2a or T2b disease
- Superficial or deep tumor
- Grade 1, 2, 3, or 4
- Tumor located on the upper extremity (including shoulder), lower extremity (including hip), or trunk
Meets 1 of the following criteria:
- Tumor ? 8 cm in maximal diameter and grade 3 or 4 (intermediate or high grade) (cohort A)
- Tumor > 5 cm in maximal diameter and grade 1 or 2 (low grade) (cohort B)
Locally recurrent disease allowed provided there has been no prior radiotherapy to the primary tumor
No histologically confirmed rhabdomyosarcoma, extraosseous Ewing's primitive neuroectodermal tumors, osteosarcoma or chondrosarcoma, Kaposi's sarcoma, angiosarcoma, desmoid tumors, or dermatofibrosarcoma protuberans
No overt evidence of lung metastases (CT scan evidence of small incidental lesions without histologic diagnosis allowed)
No evidence of other metastases
No sarcoma of the head, neck, intra-abdominal, or retroperitoneal region
Performance status - Zubrod 0-1
At least 2 years
Absolute neutrophil count ? 1,500/mm^3
Platelet count ? 120,000/mm^3
Hemoglobin ? 8.0 g/dL (cohort A)
No known hypercoagulable disorders, such as the following:
- APC resistance (factor V Leiden)
- Protein S deficiency
- Protein C deficiency
- Antithrombin III deficiency
- Hyperhomocystinemia
- Dysplasminogenemia
- High plasminogen activator inhibitor
- Dysfibrinogenemia
- Antiphospholipid syndrome
- Thrombocythemia
- Dysproteinemia
Fibrin split products < 2 times upper limit of normal (ULN)
Fibrinogen > 200 mg/dL
Bilirubin ? 1.5 mg/dL (1.0 mg/dL for patients with Gilbert's syndrome)
AST and ALT ? 2.0 times ULN
PT and PTT < 1.25 times ULN (except in patients treated with anticoagulants for unrelated medical conditions [e.g., atrial fibrillation])
No history of hepatic cirrhosis
Creatinine ? 1.5 mg/dL
Creatinine clearance > 60 mL/min
No atherosclerotic coronary artery disease that required bypass surgery within the past year
No uncompensated coronary artery disease by ECG or physical examination
No myocardial infarction within the past 6 months
No severe or unstable angina within the past 6 months
No uncompensated congestive heart failure
No New York Heart Association class II-IV heart disease
No symptomatic peripheral vascular disease
No history of deep vein thrombosis
Cohort A only:
- EF ? 50% within the past 6 months
- LVEF > 50%
No pulmonary embolus except if caused directly by foreign body implants (e.g., central venous catheters or portacaths)
No global neurocognitive symptomatology
No fatigue ? grade 2
No history of uncontrolled seizures or uncontrolled seizure disorder
No sensory neuropathy ? grade 2 except for localized neuropathy due to mechanical cause or trauma
No other malignancies within the past 3 years except non-invasive malignancies (e.g., carcinoma in situ of the cervix, breast, or oral cavity) or squamous or basal cell skin cancer
No history of uncontrolled myxedema
No hypothyroidism ? grade 3
No active uncontrolled bacterial, viral, or fungal infection
No other significant illness that would preclude surgery
No other major illness or psychiatric impairment that would preclude study therapy
No known AIDS
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use 2 effective barrier methods of contraception for 4 weeks before, during, and for at least 4 weeks after study treatment
No prior thalidomide
No prior biologic therapy for this tumor
No prior chemotherapy for this tumor
See Disease Characteristics
No prior radiotherapy for this tumor
See Cardiovascular
No other concurrent investigational drugs
No concurrent sedating drugs
No concurrent illegal sedating "recreational" drugs
No concurrent alcohol intake of more than 1 drink per day

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Cohort A (chemotherapy, radiation, thalidomide, surgery)	Filgrastim	Patients receive doxorubicin, ifosfamide, and dacarbazine IV continuously on days 1-3, 22-24, and 43-45. Patients receive G-CSF subcutaneously beginning on days 4, 25, and 46 and continuing until blood counts recover. Patients undergo radiotherapy once daily on days 7-11, 14-18, 21, 28-32, 35-39, and 42. Patients receive oral thalidomide once daily on days 7-21 and 26-42. Patients undergo surgical resection between days 84 and 98. Beginning 2 weeks after surgery, patients receive oral thalidomide once daily for 12 months in the absence of unacceptable toxicity.
Cohort B (thalidomide, radiation, surgery)	Laboratory Biomarker Analysis	Patients receive oral thalidomide once daily beginning on day 1 and continuing until 1 week before surgery. Patients undergo radiotherapy once daily, 5 days a week, on weeks 1-5. Patients undergo surgical resection between days 77 and 91. Beginning 2 weeks after surgery, patients receive oral thalidomide once daily for 6 months in the absence of unacceptable toxicity.
Cohort A (chemotherapy, radiation, thalidomide, surgery)	Laboratory Biomarker Analysis	Patients receive doxorubicin, ifosfamide, and dacarbazine IV continuously on days 1-3, 22-24, and 43-45. Patients receive G-CSF subcutaneously beginning on days 4, 25, and 46 and continuing until blood counts recover. Patients undergo radiotherapy once daily on days 7-11, 14-18, 21, 28-32, 35-39, and 42. Patients receive oral thalidomide once daily on days 7-21 and 26-42. Patients undergo surgical resection between days 84 and 98. Beginning 2 weeks after surgery, patients receive oral thalidomide once daily for 12 months in the absence of unacceptable toxicity.
Cohort B (thalidomide, radiation, surgery)	Radiation Therapy	Patients receive oral thalidomide once daily beginning on day 1 and continuing until 1 week before surgery. Patients undergo radiotherapy once daily, 5 days a week, on weeks 1-5. Patients undergo surgical resection between days 77 and 91. Beginning 2 weeks after surgery, patients receive oral thalidomide once daily for 6 months in the absence of unacceptable toxicity.
Cohort A (chemotherapy, radiation, thalidomide, surgery)	Radiation Therapy	Patients receive doxorubicin, ifosfamide, and dacarbazine IV continuously on days 1-3, 22-24, and 43-45. Patients receive G-CSF subcutaneously beginning on days 4, 25, and 46 and continuing until blood counts recover. Patients undergo radiotherapy once daily on days 7-11, 14-18, 21, 28-32, 35-39, and 42. Patients receive oral thalidomide once daily on days 7-21 and 26-42. Patients undergo surgical resection between days 84 and 98. Beginning 2 weeks after surgery, patients receive oral thalidomide once daily for 12 months in the absence of unacceptable toxicity.
Cohort A (chemotherapy, radiation, thalidomide, surgery)	Therapeutic Conventional Surgery	Patients receive doxorubicin, ifosfamide, and dacarbazine IV continuously on days 1-3, 22-24, and 43-45. Patients receive G-CSF subcutaneously beginning on days 4, 25, and 46 and continuing until blood counts recover. Patients undergo radiotherapy once daily on days 7-11, 14-18, 21, 28-32, 35-39, and 42. Patients receive oral thalidomide once daily on days 7-21 and 26-42. Patients undergo surgical resection between days 84 and 98. Beginning 2 weeks after surgery, patients receive oral thalidomide once daily for 12 months in the absence of unacceptable toxicity.
Cohort B (thalidomide, radiation, surgery)	Therapeutic Conventional Surgery	Patients receive oral thalidomide once daily beginning on day 1 and continuing until 1 week before surgery. Patients undergo radiotherapy once daily, 5 days a week, on weeks 1-5. Patients undergo surgical resection between days 77 and 91. Beginning 2 weeks after surgery, patients receive oral thalidomide once daily for 6 months in the absence of unacceptable toxicity.
Cohort A (chemotherapy, radiation, thalidomide, surgery)	Dacarbazine	Patients receive doxorubicin, ifosfamide, and dacarbazine IV continuously on days 1-3, 22-24, and 43-45. Patients receive G-CSF subcutaneously beginning on days 4, 25, and 46 and continuing until blood counts recover. Patients undergo radiotherapy once daily on days 7-11, 14-18, 21, 28-32, 35-39, and 42. Patients receive oral thalidomide once daily on days 7-21 and 26-42. Patients undergo surgical resection between days 84 and 98. Beginning 2 weeks after surgery, patients receive oral thalidomide once daily for 12 months in the absence of unacceptable toxicity.
Cohort A (chemotherapy, radiation, thalidomide, surgery)	Doxorubicin Hydrochloride	Patients receive doxorubicin, ifosfamide, and dacarbazine IV continuously on days 1-3, 22-24, and 43-45. Patients receive G-CSF subcutaneously beginning on days 4, 25, and 46 and continuing until blood counts recover. Patients undergo radiotherapy once daily on days 7-11, 14-18, 21, 28-32, 35-39, and 42. Patients receive oral thalidomide once daily on days 7-21 and 26-42. Patients undergo surgical resection between days 84 and 98. Beginning 2 weeks after surgery, patients receive oral thalidomide once daily for 12 months in the absence of unacceptable toxicity.
Cohort A (chemotherapy, radiation, thalidomide, surgery)	Ifosfamide	Patients receive doxorubicin, ifosfamide, and dacarbazine IV continuously on days 1-3, 22-24, and 43-45. Patients receive G-CSF subcutaneously beginning on days 4, 25, and 46 and continuing until blood counts recover. Patients undergo radiotherapy once daily on days 7-11, 14-18, 21, 28-32, 35-39, and 42. Patients receive oral thalidomide once daily on days 7-21 and 26-42. Patients undergo surgical resection between days 84 and 98. Beginning 2 weeks after surgery, patients receive oral thalidomide once daily for 12 months in the absence of unacceptable toxicity.
Cohort A (chemotherapy, radiation, thalidomide, surgery)	Thalidomide	Patients receive doxorubicin, ifosfamide, and dacarbazine IV continuously on days 1-3, 22-24, and 43-45. Patients receive G-CSF subcutaneously beginning on days 4, 25, and 46 and continuing until blood counts recover. Patients undergo radiotherapy once daily on days 7-11, 14-18, 21, 28-32, 35-39, and 42. Patients receive oral thalidomide once daily on days 7-21 and 26-42. Patients undergo surgical resection between days 84 and 98. Beginning 2 weeks after surgery, patients receive oral thalidomide once daily for 12 months in the absence of unacceptable toxicity.
Cohort B (thalidomide, radiation, surgery)	Thalidomide	Patients receive oral thalidomide once daily beginning on day 1 and continuing until 1 week before surgery. Patients undergo radiotherapy once daily, 5 days a week, on weeks 1-5. Patients undergo surgical resection between days 77 and 91. Beginning 2 weeks after surgery, patients receive oral thalidomide once daily for 6 months in the absence of unacceptable toxicity.

Primary Outcome Measures

Name	Time	Method
Treatment Delivery With Compliance Defined as Receiving at Least 95% of the Pre-operative Protocol Dose of RT, All 3 Cycles of MAID (if Applicable), and Receive Thalidomide on 75% of the Days During Radiation	Duration of treatment (which can continue up to approximately 15 months).	Was to be estimated using a binomial distribution and accompanied by the associated 95% confidence interval. Due to early study closure, this endpoint could not be fully evaluated per the protocol plan.

Secondary Outcome Measures

Name	Time	Method
Wound Complication (Grades 2, 3, 4, and 5) as Measured by CTCAE v3.0	From start of treatment to time of surgery	Will be estimated using a binomial distribution and accompanied by the associated 95% confidence interval.
Response to Pre-operative Therapy Assessed Using RECIST Criteria	From start of treatment to time of surgery.