Adult Angiosarcoma, Adult Epithelioid Sarcoma, Adult Leiomyosarcoma, Adult Malignant Fibrous Histiocytoma, Adult Neurofibrosarcoma, Adult Synovial Sarcoma, Ovarian Sarcoma, Recurrent Adult Soft Tissue Sarcoma, Recurrent Uterine Sarcoma, Stage III Adult Soft Tissue Sarcoma, Stage III Uterine Sarcoma, Stage IV Adult Soft Tissue Sarcoma, Stage IV Uterine Sarcoma, Uterine Carcinosarcoma, Uterine Leiomyosarcoma
Conditions
Brief summary
This phase II trial is studying how well sorafenib works in treating patients with metastatic, locally advanced, or recurrent sarcoma. Sorafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor.
Detailed description
PRIMARY OBJECTIVES: I. The primary endpoint is the response rate (CR+PR) for each stratum of sarcoma patients treated with sorafenib as defined by RECIST. SECONDARY OBJECTIVES: I. Progression-free survival (defined as CR + PR + SD, assessed at 3 months or 6 months). II. Overall survival. III. Pharmacokinetics of sorafenib in this patient population (all sites will participate). IV. Frequency of B-raf mutations in the patients' sarcomas treated as part of this study and correlation with response or resistance to sorafenib (all sites will participate). V. Ras-raf kinase pathway activation in pre-treatment existing tumor specimens (paraffin section immunohistochemistry; all sites will participate). VI. At MSKCC only: Pre and post treatment specimen changes in downstream events of ras signaling, specifically inhibition of ERK phosphorylation. Only patients with angiosarcoma and MPNST will undergo biopsy (up to 10 patients). VII. At MSKCC only: Circulating Endothelial Cells (CECs), VE-cadherin levels, and soluble protein levels (VEGF, bFGF, endostatin) as a measures of angiogenesis before and after starting sorafenib therapy. OUTLINE: This is an open-label, non-randomized, multicenter study. Patients are stratified according to sarcoma histology (angiosarcoma vs malignant peripheral nerve sheath tumor vs leiomyosarcoma \[closed to accrual as of 11/29/06\] vs high-grade undifferentiated pleomorphic sarcoma \[i.e., malignant fibrous histiocytoma (including myxofibrosarcoma)(closed to accrual as of 11/29/06)\] vs synovial sarcoma (closed to accrual as of 11/29/06) vs all other types of sarcoma). Patients receive oral sorafenib twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study, patients are followed at 4 weeks.
Interventions
DRUGsorafenib tosylate
Given orally
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically or cytologically confirmed sarcoma, including any of the following neoplastic subtypes: * Giant hemangioma * Angiosarcoma (including epithelioid hemangioendothelioma) * Malignant peripheral nerve sheath tumor * Leiomyosarcoma (closed to accrual as of 11/29/06) * High-grade undifferentiated pleomorphic sarcoma (i.e., malignant fibrous histiocytoma \[including myxofibrosarcoma\]) (closed to accrual as of 11/29/06) * Synovial sarcoma (closed to accrual as of 11/29/06) * Carcinosarcoma (closed to accrual as of 11/29/06) * Metastatic, locally advanced, or locally recurrent disease * Measurable disease, defined as ≥ 1 unidimensionally measurable lesion ≥ 20 mm by conventional techniques OR ≥ 10 mm by spiral CT scan * Lesions in a previously irradiated area may be considered measurable provided there is evidence of subsequent disease progression that cannot be attributed to necrosis or bleeding * No gastrointestinal stromal tumor * No known brain metastases * Performance status - ECOG 0-2 * Absolute neutrophil count ≥ 1,500/mm\^3 * Platelet count ≥ 100,000/mm\^3 * No evidence of bleeding diathesis * Bilirubin ≤ 1.5 mg/dL * INR ≤ 1.5 * AST and ALT ≤ 2.5 times upper limit of normal * Creatinine ≤ 1.5 mg/dL * No symptomatic congestive heart failure * No unstable angina pectoris * No cardiac arrhythmia * No uncontrolled hypertension * No history of allergic reaction to compounds of similar chemical or biologic composition to sorafenib * No known HIV positivity * No active or ongoing infection * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception * No psychiatric illness or social situation that would preclude study compliance * No swallowing dysfunction that would preclude the swallowing of tablets * Other malignancies allowed provided sarcoma is the primary disease requiring treatment * No other uncontrolled illness * No more than 1 prior chemotherapy regimen for recurrent or metastatic disease (≤ 3 regimens for angiosarcoma or malignant peripheral nerve sheath tumor) * Adjuvant chemotherapy completed \> 1 year prior to study entry is not considered a line of prior treatment * More than 3 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin) * At least 3 weeks since prior radiotherapy * Recovered from prior antitumor therapy * Alopecia allowed * No prior sorafenib * No prior small molecule inhibitors of MAPK signaling intermediates * No concurrent therapeutic anticoagulation * Prophylactic anticoagulation (i.e., low-dose warfarin) of venous or arterial devices allowed provided requirements for PT, INR, or PTT requirements are met * No other concurrent investigational agents * No concurrent cytochrome P450 enzyme-inducing antiepileptic drugs (e.g., phenytoin, carbamazepine, or phenobarbital) * No concurrent rifampin or Hypericum perforatum (St. John's wort)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate Measured by Complete Response (CR) Rate and Partial Response (PR) Rate as Determined by RECIST | Up to 4 weeks | A 5% response rate is considered not promising, a 20% response rate is considered promising. For each stratum, the response rate will be estimated and a confidence interval will be constructed. |
Countries
United States
Participant flow
Recruitment details
Protocol Open to Accrual 09/09/2005 Protocol Closed to Accrual 07/22/2008 Primary Completion Date 03/22/2011 Recruitment Location is the medical clinic
Participants by arm
| Arm | Count |
|---|---|
| Angiosarcoma Sorafenib 400 mg PO BID | 44 |
| MPNST Sorafenib 400 mg PO BID | 16 |
| Leiomyosarcoma Sorafenib 400 mg PO BID | 46 |
| Undifferentiated Pleomorphic Sarcoma Sorafenib 400 mg PO BID | 13 |
| Fibrosarcoma Sorafenib 400 mg PO BID | 5 |
| Other Histology Sorafenib 400 mg PO BID | 23 |
| Total | 147 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 4 | 2 | 5 | 1 | 0 | 2 |
| Overall Study | Clinical progression | 1 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Death | 0 | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Decline in performance | 0 | 2 | 0 | 1 | 0 | 2 |
| Overall Study | Not Treated | 1 | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Participant needed surgery | 0 | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Protocol Violation | 1 | 0 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Angiosarcoma | MPNST | Leiomyosarcoma | Undifferentiated Pleomorphic Sarcoma | Fibrosarcoma | Other Histology | Total |
|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 24 Participants | 2 Participants | 11 Participants | 6 Participants | 0 Participants | 1 Participants | 44 Participants |
| Age, Categorical Between 18 and 65 years | 20 Participants | 14 Participants | 35 Participants | 7 Participants | 5 Participants | 22 Participants | 103 Participants |
| Age, Continuous | 54 years STANDARD_DEVIATION 50.91168825 | 47.5 years STANDARD_DEVIATION 34.64823228 | 56 years STANDARD_DEVIATION 33.9411255 | 62.5 years STANDARD_DEVIATION 31.81980515 | 43.5 years STANDARD_DEVIATION 10.60660172 | 44 years STANDARD_DEVIATION 31.11269837 | 54 years STANDARD_DEVIATION 50.91168825 |
| Region of Enrollment Italy | 0 participants | 1 participants | 0 participants | 0 participants | 0 participants | 0 participants | 1 participants |
| Region of Enrollment United States | 44 participants | 15 participants | 46 participants | 13 participants | 5 participants | 23 participants | 146 participants |
| Sex: Female, Male Female | 25 Participants | 9 Participants | 37 Participants | 8 Participants | 4 Participants | 11 Participants | 94 Participants |
| Sex: Female, Male Male | 19 Participants | 7 Participants | 9 Participants | 5 Participants | 1 Participants | 12 Participants | 53 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 36 / 44 | 12 / 16 | 40 / 46 | 10 / 13 | 4 / 5 | 21 / 23 |
| serious Total, serious adverse events | 13 / 44 | 7 / 16 | 7 / 46 | 9 / 13 | 0 / 5 | 5 / 23 |
Outcome results
Primary
Overall Response Rate Measured by Complete Response (CR) Rate and Partial Response (PR) Rate as Determined by RECIST
A 5% response rate is considered not promising, a 20% response rate is considered promising. For each stratum, the response rate will be estimated and a confidence interval will be constructed.
Time frame: Up to 4 weeks
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Angiosarcoma | Overall Response Rate Measured by Complete Response (CR) Rate and Partial Response (PR) Rate as Determined by RECIST | Complete Response | 1 participants |
| Angiosarcoma | Overall Response Rate Measured by Complete Response (CR) Rate and Partial Response (PR) Rate as Determined by RECIST | Partial Response | 4 participants |
| MPNST | Overall Response Rate Measured by Complete Response (CR) Rate and Partial Response (PR) Rate as Determined by RECIST | Complete Response | 0 participants |
| MPNST | Overall Response Rate Measured by Complete Response (CR) Rate and Partial Response (PR) Rate as Determined by RECIST | Partial Response | 0 participants |
| Leiomyosarcoma | Overall Response Rate Measured by Complete Response (CR) Rate and Partial Response (PR) Rate as Determined by RECIST | Complete Response | 0 participants |
| Leiomyosarcoma | Overall Response Rate Measured by Complete Response (CR) Rate and Partial Response (PR) Rate as Determined by RECIST | Partial Response | 1 participants |
| Undifferentiated Pleomorphic Sarcoma | Overall Response Rate Measured by Complete Response (CR) Rate and Partial Response (PR) Rate as Determined by RECIST | Complete Response | 0 participants |
| Undifferentiated Pleomorphic Sarcoma | Overall Response Rate Measured by Complete Response (CR) Rate and Partial Response (PR) Rate as Determined by RECIST | Partial Response | 0 participants |
| Fibrosarcoma | Overall Response Rate Measured by Complete Response (CR) Rate and Partial Response (PR) Rate as Determined by RECIST | Complete Response | 0 participants |
| Fibrosarcoma | Overall Response Rate Measured by Complete Response (CR) Rate and Partial Response (PR) Rate as Determined by RECIST | Partial Response | 0 participants |
| Other Histology | Overall Response Rate Measured by Complete Response (CR) Rate and Partial Response (PR) Rate as Determined by RECIST | Complete Response | 0 participants |
| Other Histology | Overall Response Rate Measured by Complete Response (CR) Rate and Partial Response (PR) Rate as Determined by RECIST | Partial Response | 0 participants |