Evaluation of Votrient in Angiosarcoma

Study Overview
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Brief Summary
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Open-label phase II trial investigating the efficacy and safety of the investigational combination of pazopanib and paclitaxel.

Detailed Description
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Open-label phase II trial investigating the efficacy and safety of the investigational combination of pazopanib and paclitaxel.This multi-center, open-label, prospective, single arm phase II study was designed to evaluate the clinical efficacy and safety of the experimental combination of pazopanib with paclitaxel in the treatment of patients with advanced or metastatic angiosarcoma.The safety evaluations (physical examination, laboratory checks as defined in protocol, toxicity/adverse event assessment according Eastern Cooperative Oncology Group version 4.0) are scheduled every cycle at day 1, 8, 15 and 29 (= day 1 of the next cycle).

Official Title
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Single-arm, Multicenter, Open Label Phase II Trial to Evaluate the Efficacy of Pazopanib in Combination With Paclitaxel in Advanced and Relapsed Angiosarcoma

Conditions
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Angiosarcoma

Intervention / Treatment
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* Drug: Pazopanib + Paclitaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must provide written informed consent prior to performance of study-specific procedures or assessments and must be willing to comply with treatment and follow-up. Note: Procedures conducted as part of the subject's routine clinical management (e.g., blood count, imaging studies) and obtained prior to signing informed consent may be utilized for screening or baseline purposes provided these procedures are conducted as specified in the protocol. Age ≥ 18 years Life expectancy > 3 months Ability to swallow tablets Histological confirmed angiosarcoma, primary and secondary angiosarcoma (e.g. radiation-induced or angiosarcoma in chronical lymphedema) are eligible. Tumor must be locally advanced (unresectable) or metastatic. A progression must be documented within a 6-month period prior to screening. Eastern Cooperative Oncology Group performance status ≤ 2 At least one measurable skin lesion or one measurable radiological (CT or MRI) target lesion (RECIST 1.1) Adequate organ system function as described in protocol A female is eligible to enter and participate in this study if she is either of non childbearing potential (defined in protocol) or childbearing potential with negative pregnancy test within 2 weeks prior to the first dose of study drug and agrees to use adequate contraception (as defined in protocol) during the study and for 30 days after the last dose of study drug. All sexually active male patients must agree to use adequate methods of birth control (see protocol) throughout the study and for 30 days after the last dose of study drug. Exclusion Criteria: Patients who need an active treatment for another malignant disease other than angiosarcoma Prior treatment with taxane within the last 12 months before study entry History or clinical evidence of central nervous system (CNS) metastases or leptomeningeal sarcomatosis.(see protocol) Clinically significant gastrointestinal abnormalities that may increase the risk for gastrointestinal bleeding (see protocol) Clinically significant gastrointestinal abnormalities that may affect absorption of investigational product (see protocol) Presence of uncontrolled infection QT prolongation interval (QTc) > 480 msec. Clinically significant cardiovascular disorders within the past 6 months Major surgery or trauma within 28 days prior to first dose of investigational product and/or presence of any non-healing wound, fracture, or ulcer Poorly controlled hypertension (see protocol) Evidence of active bleeding or bleeding diathesis Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels Uncontrolled seizures, disorders of the CNS or psychiatric disorders which may put patient safety at risk, prevent giving informed consent or impact the patient's compliance with the use of study medication Women who are pregnant or breast feeding Patients who are not able or not willing to interrupt the intake of medications that are not allowed according to study protocol for at least 14 days before start of study medication and for the whole study period Chemotherapy or radiotherapy within 14 days before start of study medication Any ongoing toxicity from prior anti-cancer therapy that is > grade 1 and/or that is progressing in severity, except alopecia

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pazopanib + Paclitaxel<br>Paclitaxel administered every 28 days at day 1, day 8 and day 15 as a 2h intravenous infusion in a dose of 70mg/m2 in combination with pazopanib in a daily oral dose of 800mg (2x400mg) | Drug: Pazopanib + Paclitaxel<br>* pazopanib in combination with paclitaxel in the treatment of patients with advanced or metastatic angiosarcoma.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Progression-free Survival | The diagnosis of progession is based on tumor measurements assessed 182 days +/- 32 days after start of treatment (with imaging date as reference date) and according to the RECIST Version 1.1 criteria based on a predefined set of target lesions and non-target lesions. | 6 Month | 
| Rate of Progression-free Survival, Subgroup 1 Analysis | Rate of progression-free survival for Subgroup 1 categorizing the 12 participants who showed PFS after 6 months into cutaneous angiosarcoma versus visceral angiosarcoma The diagnosis of progession is based on tumor measurements assessed 182 days +/- 32 days after start of treatment (with imaging date as reference date) and according to the RECIST Version 1.1 criteria based on a predefined set of target lesions and non-target lesions. | 6 months | 
| Rate of Progression-free Survival, Subgroup 2 Analysis | Rate of progression-free survival for Subgroup 1 categorizing the 12 participants who showed PFS after 6 months into primary angiosarcoma versus secondary angiosarcoma. The diagnosis of progession is based on tumor measurements assessed 182 days +/- 32 days after start of treatment (with imaging date as reference date) and according to the RECIST Version 1.1 criteria based on a predefined set of target lesions and non-target lesions. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Survival time of patient from start of treatment until death | from start of treatment until death within study's actual observation time for OS (22 months). | 
| Overall Survival, Subgroup 1 Analysis | Survival time of patients from start of treatment until death, Subgroup 1 categorizing 26 overall participants into 18 cutaneous angiosarcoma versus 8 visceral angiosarcomas | from start of treatment until death within study's actual observation time for OS (22 months) | 
| Overall Survival, Subgroup 2 Analysis | Survival time of patients from start of treatment until death, Subgroup 2 categorizing 26 overall participants into 13 primary cutaneous angiosarcoma versus 13 secondary angiosarcomas | from start of treatment until death within study's actual observation time for OS (22 months) | 
| Response Rate (RR) | Measurable skin lesions will be evaluated clinically and documented photographically, all other target lesions will be evaluated radiologically by CT or MRI according to RECIST Version 1.1. RR is given as 'Best overall response BOR defined as CR (complete remission), PR (partial) remission), SD (stable diesease) and PD (progressive disease) or NE (not evaluated) and provided by absolute and relative frequencies | determined every 8 weeks during first 6 month then every 12 weeks in follow-up period until progression or death or end of overall study observation period (22 months), then evaluated as BOR | 
| Response Rate (RR), Subgroup1 Analysis | Measurable skin lesions will be evaluated clinically and documented photographically, all other target lesions will be evaluated radiologically by CT or MRI according to RECIST Version 1.1. RR is given as 'Best overall response BOR defined as CR (complete remission), PR (partial) remission), SD (stable diesease) and PD (progressive disease) or NE (not evaluated) and provided by absolute and relative frequencies for Subgroup 1 which is the analysis of cutaneous angiosarcoma versus visceral angiosarcoma | determined every 8 weeks during first 6 month then every 12 weeks in follow-up period until progression or death or end of overall study observation period (22 months), then evaluated as BOR | 
| Response Rate (RR), Subgroup 2 Analysis | Measurable skin lesions will be evaluated clinically and documented photographically, all other target lesions will be evaluated radiologically by CT or MRI according to RECIST Version 1.1. RR is given as 'Best overall response BOR defined as CR (complete remission), PR (partial) remission), SD (stable diesease) and PD (progressive disease) or NE (not evaluated) and provided by absolute and relative frequencies for Subgroup 2 which is the analysis of primary angiosarcoma versus secondary angiosarcoma | determined every 8 weeks during first 6 month then every 12 weeks in follow-up period until progression or death or end of overall study observation period (22 months), then evaluated as BOR | 
| Adverse Events and Serious Adverse Events | Number of patients in which adverse events occur during treatment according to Common Toxicity Criteria for Adverse Effects, Version 4.0 | 30 days after EOS of last patient or end of overall study observation period (22 months) |