Sarcoma
Conditions
Keywords
adult angiosarcoma, recurrent adult soft tissue sarcoma, stage I adult soft tissue sarcoma, stage II adult soft tissue sarcoma, stage III adult soft tissue sarcoma, stage IV adult soft tissue sarcoma
Brief summary
RATIONALE: Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Bevacizumab may also stop the growth of tumor cells by blocking blood flow to the tumor. PURPOSE: This phase II trial is studying how well bevacizumab works in treating patients with angiosarcoma.
Detailed description
OBJECTIVES: Primary * Determine the median progression-free survival, in terms of stable disease, of patients with newly diagnosed or recurrent/refractory angiosarcoma treated with bevacizumab. Secondary * Evaluate the treatment effect of bevacizumab on the objective response rate as assessed by modified RECIST criteria in patients with angiosarcoma. * Evaluate the duration of response. * Assess the treatment effect of bevacizumab on duration of overall survival. * Explore the objective response by target tumor density changes on CT scan. * Evaluate the safety and tolerability of bevacizumab in patients with angiosarcoma. OUTLINE: This is an open-label, multicenter study. Patients receive bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed every 3 to 4 months for 2 years. PROJECTED ACCRUAL: A total of 31 patients will be accrued for this study.
Interventions
BIOLOGICALBevacizumab
Bevacizumab 15 mg/kg IV infusion given on day 1 every 21 days = (1 cycle).
Sponsors
Genentech, Inc.
Northwestern University
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
DISEASE CHARACTERISTICS: * Histologically confirmed angiosarcoma * Any stage disease * Must be deemed not surgically resectable (complete resection) and/or no other therapeutic modality is known to be curative * No angiosarcoma of a vessel wall * Newly diagnosed or recurrent/refractory disease * No prior tumor-related hemorrhage (any grade) * Measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as ≥ 20 mm with conventional techniques or as ≥ 10 mm with spiral CT scan * No CNS disease, brain metastases, or primary brain tumors PATIENT CHARACTERISTICS: * ECOG performance status of 0 or 1 * Absolute granulocyte count ≥ 1,500/mm\^3 * Platelet count ≥ 100,000/mm\^3 * Hemoglobin ≥ 9 gm/dL (transfusion and epoetin alfa allowed) * Creatinine ≤ 1.5 times upper limit of normal (ULN) * Urine protein:creatinine ratio ≤ 1.0 * Total bilirubin ≤ 1.5 mg/dL * Aspartate aminotransferase \< 5 times ULN * Alkaline phosphatase \< 5 times ULN * PT/INR ≤ 1.5 times ULN * PTT ≤ 1.5 times ULN * Fertile patients must use effective contraception * Ejection fraction \> 49% for patients with prior anthracycline therapy, ischemic cardiac disease, or history of heart failure * No uncontrolled active infection * No uncontrolled high blood pressure (defined as \> 150/100 mm Hg) * No symptomatic congestive heart failure (New York Heart Association class II-IV), unstable angina, cardiac arrhythmia, or myocardial infarction within the past 6 months * No psychiatric illness or social situation that would limit study compliance * No serious, nonhealing wound, ulcer, or bone fracture * No evidence of bleeding diathesis or coagulopathy * No clinically significant peripheral vascular disease * Not pregnant or nursing * No seizures not controlled with standard medical therapy * No embolic or hemorrhagic stroke or prior transient ischemic attack * No history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 6 months * No significant traumatic injury within the past 6 weeks PRIOR CONCURRENT THERAPY: * No prior therapy with bevacizumab or other antiangiogenesis treatment * No major surgical procedure or open biopsy within the past 6 weeks * No more than 2 prior chemotherapy regimens * No fine-needle aspiration or core-needle biopsy or other minor surgical procedure within the past 7 days * No radiotherapy within the past 28 days * No concurrent chronic daily treatment with aspirin \> 325 mg/day or nonsteroidal anti-inflammatory medications * No concurrent warfarin or any other anticoagulant (any dose) * No concurrent radiotherapy * No concurrent major surgery
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Median Progression-free Survival of Patients Treated With the Study Drug as Defined by RECIST Criteria. | After cycles 2 and 4, then every 3 cycles thereafter while on treatment (1 cycle = 21 days); every 3-4 months after treatment up to 2 years. | During treatment, tumor assessment was done by MRI scan after the second cycle of study treatment, after the forth cycle of study treatment, and then every 3 cycles of treatment thereafter. After Study drug completion, tumor assessment by MRI was done every 3 to 4 months (for up to 2 years after the last bevacizumab dosage). Responses were categorized according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria version 1.0. Progressive Disease (PD) was defined as having at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started or the appearance of one or more new lesions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate in Patients Treated With Bevacizumab. | After cycles 2 and 4, then every 3 cycles thereafter while on treatment (1 cycle = 21 days); every 3-4 months after treatment up to 2 years. | Objective response rate will be measured per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions. Stable Disease, neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum diameters while on study. Progressive Disease, defined as having at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started or the appearance of one or more new lesions. |
| Duration of Response. | After cycles 2 and 4, then every 3 cycles thereafter while on treatment (1 cycle = 21 days); every 3-4 months after treatment up to 2 years. | During treatment, evaluation of response will be done by MRI scan after the second cycle of study treatment, after the forth cycle of study treatment, and then every 3 cycles of treatment. After Study drug completion, evaluation of response will be assessed by MRI every 3 to 4 months (for 2 years after the last bevacizumab dosage). |
| Assess the Treatment Effect of Bevacizumab on Duration of Overall Survival | After cycles 2 and 4, then every 3 cycles thereafter while on treatment (1 cycle = 21 days); every 3-4 months after treatment up to 2 years | After Study drug completion, assessment of treatment effect of bevacizumab on duration of overall survival will be assessed by MRI every 3 to 4 months (for 2 years after the last bevacizumab dosage). |
| Evaluate the Toxicity of Bevacizumab. | Day 1 of every cycle, on average every 21 days until end of treatment up to 2 years. | Toxicity data for bevacizumab will be collected on day 1 of every cycle (1 cycle = 21 days) during treatment according to the National Cancer Institute's Common Toxicity Criteria for adverse events version 3.0 (CTCAE v3.0). In general adverse events (AEs) will be graded according to the following: Grade 1 Mild AE Grade 2 Moderate AE Grade 3 Severe AE Grade 4 Life-threatening or disabling AE Grade 5 Death related to AE |
Countries
United States
Participant flow
Recruitment details
The study opened for accrual on June 1, 2005 with an accrual goal of up to 31 patients. The study was designed to enroll 12 patients initially and do an interim efficacy assessment. Accrual was suspended on February 28, 2007 for this analysis and reopened on May 15, 2007. Study was closed to accrual permanently on April 19, 2010.
Participants by arm
| Arm | Count |
|---|---|
| Bevacizumab Bevacizumab treatment until disease progression or intolerance
Bevacizumab: Bevacizumab 15 mg/kg IV infusion given on day 1 every 21 days = (1 cycle). | 32 |
| Total | 32 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Bevacizumab Treatment Cycles 1-2 | Physician Decision | 1 |
| Bevacizumab Treatment Cycles 1-2 | Withdrawal by Subject | 1 |
| Continued Bevacizumab Cycle 3+ | Disease progressed | 7 |
| First Response Assessment | Death | 1 |
| First Response Assessment | Physician Decision | 2 |
| First Response Assessment | Withdrawal by Subject | 1 |
| Follow up for Survival x 2 Years | Death | 13 |
| Follow up for Survival x 2 Years | Lost to Follow-up | 4 |
| Follow up for Survival x 2 Years | Other | 9 |
Baseline characteristics
| Characteristic | Bevacizumab |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 16 Participants |
| Age, Categorical Between 18 and 65 years | 16 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 30 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 30 Participants |
| Region of Enrollment United States | 32 Participants |
| Sex: Female, Male Female | 19 Participants |
| Sex: Female, Male Male | 13 Participants |
| Type of Sarcoma angiosarcoma | 24 Participants |
| Type of Sarcoma epitheliod hemangioendothelioma | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 14 / 30 |
| other Total, other adverse events | 30 / 30 |
| serious Total, serious adverse events | 8 / 30 |
Outcome results
Primary
Median Progression-free Survival of Patients Treated With the Study Drug as Defined by RECIST Criteria.
During treatment, tumor assessment was done by MRI scan after the second cycle of study treatment, after the forth cycle of study treatment, and then every 3 cycles of treatment thereafter. After Study drug completion, tumor assessment by MRI was done every 3 to 4 months (for up to 2 years after the last bevacizumab dosage). Responses were categorized according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria version 1.0. Progressive Disease (PD) was defined as having at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started or the appearance of one or more new lesions.
Time frame: After cycles 2 and 4, then every 3 cycles thereafter while on treatment (1 cycle = 21 days); every 3-4 months after treatment up to 2 years.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bevacizumab | Median Progression-free Survival of Patients Treated With the Study Drug as Defined by RECIST Criteria. | 12.4 Weeks |
Comparison: This is a two stage optimal simon design testing the Null hypothesis: bevacizumab is not effective with P\<=0.220 and the alternative hypothesis: bevacizumab is effective with P \>=0.450 and has a sample size of 16.96 and a probability of early termination of 0.739. p=probability (progression free survival - PFS time\>/=3 months).Kaplan-Meier estimate
Secondary
Assess the Treatment Effect of Bevacizumab on Duration of Overall Survival
After Study drug completion, assessment of treatment effect of bevacizumab on duration of overall survival will be assessed by MRI every 3 to 4 months (for 2 years after the last bevacizumab dosage).
Time frame: After cycles 2 and 4, then every 3 cycles thereafter while on treatment (1 cycle = 21 days); every 3-4 months after treatment up to 2 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bevacizumab | Assess the Treatment Effect of Bevacizumab on Duration of Overall Survival | 107 Weeks |
Secondary
Duration of Response.
During treatment, evaluation of response will be done by MRI scan after the second cycle of study treatment, after the forth cycle of study treatment, and then every 3 cycles of treatment. After Study drug completion, evaluation of response will be assessed by MRI every 3 to 4 months (for 2 years after the last bevacizumab dosage).
Time frame: After cycles 2 and 4, then every 3 cycles thereafter while on treatment (1 cycle = 21 days); every 3-4 months after treatment up to 2 years.
Population: Data for this outcome measure was not collected. By the time the results of the study were being collected, this outcome measure was no longer relevant as Recist 1.0 was in use. As a result, data for this outcome measure was not collected or analysed. Time to progression was a more relevant data point.
Secondary
Evaluate the Toxicity of Bevacizumab.
Toxicity data for bevacizumab will be collected on day 1 of every cycle (1 cycle = 21 days) during treatment according to the National Cancer Institute's Common Toxicity Criteria for adverse events version 3.0 (CTCAE v3.0). In general adverse events (AEs) will be graded according to the following: Grade 1 Mild AE Grade 2 Moderate AE Grade 3 Severe AE Grade 4 Life-threatening or disabling AE Grade 5 Death related to AE
Time frame: Day 1 of every cycle, on average every 21 days until end of treatment up to 2 years.
Population: Number of participants with either grade 1 (mild), 2 (moderate),3 (severe), 4 (life-threatening) adverse event related to treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Bevacizumab | Evaluate the Toxicity of Bevacizumab. | Hypertension | 7 participants |
| Bevacizumab | Evaluate the Toxicity of Bevacizumab. | Plural effusion | 1 participants |
| Bevacizumab | Evaluate the Toxicity of Bevacizumab. | Liver-clinical | 1 participants |
| Bevacizumab | Evaluate the Toxicity of Bevacizumab. | Anorexia | 2 participants |
| Bevacizumab | Evaluate the Toxicity of Bevacizumab. | Fatigue | 9 participants |
| Bevacizumab | Evaluate the Toxicity of Bevacizumab. | Alopecia | 3 participants |
| Bevacizumab | Evaluate the Toxicity of Bevacizumab. | Dizziness | 2 participants |
| Bevacizumab | Evaluate the Toxicity of Bevacizumab. | Edema | 2 participants |
| Bevacizumab | Evaluate the Toxicity of Bevacizumab. | Dementia | 1 participants |
| Bevacizumab | Evaluate the Toxicity of Bevacizumab. | Hemorrhage (epitasis) | 1 participants |
| Bevacizumab | Evaluate the Toxicity of Bevacizumab. | Participants with one bevacizumab related event | 26 participants |
| Bevacizumab | Evaluate the Toxicity of Bevacizumab. | Thromboyctopenia | 4 participants |
| Bevacizumab | Evaluate the Toxicity of Bevacizumab. | Shortness of breath | 5 participants |
| Bevacizumab | Evaluate the Toxicity of Bevacizumab. | Pain | 3 participants |
| Bevacizumab | Evaluate the Toxicity of Bevacizumab. | Nausea | 5 participants |
| Bevacizumab | Evaluate the Toxicity of Bevacizumab. | Infection | 2 participants |
| Bevacizumab | Evaluate the Toxicity of Bevacizumab. | Headache | 4 participants |
| Bevacizumab | Evaluate the Toxicity of Bevacizumab. | Anemia | 6 participants |
| Bevacizumab | Evaluate the Toxicity of Bevacizumab. | Decline in FEV1 | 1 participants |
| Bevacizumab | Evaluate the Toxicity of Bevacizumab. | Hyperglycemia | 1 participants |
| Bevacizumab | Evaluate the Toxicity of Bevacizumab. | Transient ischemic attack | 1 participants |
| Bevacizumab | Evaluate the Toxicity of Bevacizumab. | Neuromotor function | 2 participants |
| Bevacizumab | Evaluate the Toxicity of Bevacizumab. | Cardiac (congestive heart failure) | 1 participants |
Secondary
Objective Response Rate in Patients Treated With Bevacizumab.
Objective response rate will be measured per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions. Stable Disease, neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum diameters while on study. Progressive Disease, defined as having at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started or the appearance of one or more new lesions.
Time frame: After cycles 2 and 4, then every 3 cycles thereafter while on treatment (1 cycle = 21 days); every 3-4 months after treatment up to 2 years.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Bevacizumab | Objective Response Rate in Patients Treated With Bevacizumab. | Partial response | 4 Participants |
| Bevacizumab | Objective Response Rate in Patients Treated With Bevacizumab. | Stable disease | 15 Participants |
| Bevacizumab | Objective Response Rate in Patients Treated With Bevacizumab. | Progressive disease | 11 Participants |
Post Hoc
Time to Progression
During treatment, tumor assessment was done by MRI scan after the second cycle of study treatment, after the forth cycle of study treatment , and then every 3 cycles of treatment thereafter. After Study drug completion, tumor assessment by MRI was done every 3 to 4 months (for up to 2 years after the last bevacizumab dosage) Responses were categorized according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria version 1.0. Progressive Disease (PD) was defined as having at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started or the appearance of one or more new lesions.
Time frame: After cycles 2 and 4, then every 3 cycles thereafter while on treatment (1 cycle = 21 days); ever 3-4 months after treatment up to 2 years
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Bevacizumab | Time to Progression | 26 Weeks | Standard Deviation 53 |