Angiosarcoma
Conditions
Brief summary
Open-label phase II trial investigating the efficacy and safety of the investigational combination of pazopanib and paclitaxel.
Detailed description
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).
Interventions
DRUGPazopanib + Paclitaxel
pazopanib in combination with paclitaxel in the treatment of patients with advanced or metastatic angiosarcoma.
Sponsors
Universitätsmedizin Mannheim
Helios Klinikum Berlin-Buch
University Hospital Dresden
Universitätsklinikum Hamburg-Eppendorf
University Hospital, Essen
Hannover Medical School
Klinikum der Universitaet Muenchen, Grosshadern
Medical University of Vienna
Medical University of Graz
Medical University Innsbruck
Novartis Pharmaceuticals
Heidelberg 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
* 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Progression-free Survival | 6 Month | 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. |
| Rate of Progression-free Survival, Subgroup 1 Analysis | 6 months | 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. |
| Rate of Progression-free Survival, Subgroup 2 Analysis | 6 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Response Rate (RR) | 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 | 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 |
| Response Rate (RR), Subgroup1 Analysis | 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 | 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 |
| Overall Survival | from start of treatment until death within study's actual observation time for OS (22 months). | Survival time of patient from start of treatment until death |
| Adverse Events and Serious Adverse Events | 30 days after EOS of last patient or end of overall study observation period (22 months) | Number of patients in which adverse events occur during treatment according to Common Toxicity Criteria for Adverse Effects, Version 4.0 |
| Response Rate (RR), Subgroup 2 Analysis | 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 | 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 |
| Overall Survival, Subgroup 1 Analysis | from start of treatment until death within study's actual observation time for OS (22 months) | Survival time of patients from start of treatment until death, Subgroup 1 categorizing 26 overall participants into 18 cutaneous angiosarcoma versus 8 visceral angiosarcomas |
| Overall Survival, Subgroup 2 Analysis | from start of treatment until death within study's actual observation time for OS (22 months) | 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 |
Countries
Austria, Germany
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Pazopanib + Paclitaxel 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)
Pazopanib + Paclitaxel: pazopanib in combination with paclitaxel in the treatment of patients with advanced or metastatic angiosarcoma. | 26 |
| Total | 26 |
Baseline characteristics
| Characteristic | Pazopanib + Paclitaxel | — |
|---|---|---|
| Age, Continuous | 57.8 years STANDARD_DEVIATION 13.5 | — |
| Race and Ethnicity Not Collected | — | — Participants |
| Sex: Female, Male Female | 23 Participants | — |
| Sex: Female, Male Male | 3 Participants | — |
| Subgroup 1 for Analyses cutaneous angiosarcoma | 18 Participants | — |
| Subgroup 1 for Analyses visceral angiosarcoma | 8 Participants | — |
| Subgroup 2 for Analyses primary angiosarcoma | 13 Participants | — |
| Subgroup 2 for Analyses secondary angiosarcoma | 13 Participants | — |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 26 |
| other Total, other adverse events | 25 / 26 |
| serious Total, serious adverse events | 10 / 26 |
Outcome results
Primary
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.
Time frame: 6 Month
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pazopanib + Paclitaxel | Rate of Progression-free Survival | 12 Participants |
Comparison: Question is, if 6 months progression free survival rate (PFS-R) denoted by pPFS is higher than 35%. Test hypothesis is thus formulated as: H0: pPFS ≤0.35 versus H1: pPFS ≥0.35. This hypothesis is tested at the one-side significance level of 0.05. A 6 months PFS-R of 0.55 of cases or more is considered as clinically relevant success rate. The design is chosen such that rates of 0.55 or higher can be detected with a power of at least 0.8.
Primary
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.
Time frame: 6 months
Population: Subgroup 1 (categorizing total number of 12 participants showing PFR survival after 6 months into cutaneous AS versus visceral AS)
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Pazopanib + Paclitaxel | Rate of Progression-free Survival, Subgroup 1 Analysis | cutaneous angiosarcoma | 11 Participants |
| Pazopanib + Paclitaxel | Rate of Progression-free Survival, Subgroup 1 Analysis | visceral angiosarcoma | 1 Participants |
Primary
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.
Time frame: 6 months
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Pazopanib + Paclitaxel | Rate of Progression-free Survival, Subgroup 2 Analysis | primary angiosarcoma | 6 Participants |
| Pazopanib + Paclitaxel | Rate of Progression-free Survival, Subgroup 2 Analysis | secondary angiosarcoma | 6 Participants |
Secondary
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
Time frame: 30 days after EOS of last patient or end of overall study observation period (22 months)
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Pazopanib + Paclitaxel | Adverse Events and Serious Adverse Events | Patients with AEs | 25 Participants |
| Pazopanib + Paclitaxel | Adverse Events and Serious Adverse Events | Patients with SAEs | 10 Participants |
Secondary
Overall Survival
Survival time of patient from start of treatment until death
Time frame: from start of treatment until death within study's actual observation time for OS (22 months).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pazopanib + Paclitaxel | Overall Survival | 21.6 months |
Comparison: The analysis of secondary endpoints is of descriptive nature and generally consists of summary statistics and interval estimation.~Overall survival (OS) was defined as the time of start of treatment until death (event status=1) or last contact (censoring, event status=0). OS was analyzed using Kaplan-Meier curves. Median survival time is provided alonsgside two-sided 95% confidence interval (CI), if possible.
Secondary
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
Time frame: from start of treatment until death within study's actual observation time for OS (22 months)
Population: Overall number of participants analyzed is 26. Thereof, 18 show cutaneous angiosarcoma, and 8 show cutaneos angiosarcoma.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Pazopanib + Paclitaxel | Overall Survival, Subgroup 1 Analysis | cutaneous angiosarcoma | 21.6 months |
| Pazopanib + Paclitaxel | Overall Survival, Subgroup 1 Analysis | visceral angiosaroma | 20.5 months |
Comparison: The analysis of secondary endpoints is of descriptive nature and generally consists of summary statistics and interval estimation.~Overall survival (OS) for subgroup 1 was defined as the time of start of treatment until death (event status=1) or last contact (censoring, event status=0). OS was analyzed using Kaplan-Meier curves. Median survival time is provided alonsgside two-sided 95% confidence interval (CI), if possible.p-value: 0.752Log Rank
Secondary
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
Time frame: from start of treatment until death within study's actual observation time for OS (22 months)
Population: Overall number of participants analyzed is 26. Thereof, 13 show cutaneous angiosarcoma, and 13 show cutaneos angiosarcoma
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Pazopanib + Paclitaxel | Overall Survival, Subgroup 2 Analysis | secondary angiosarcoma | 21.6 months |
| Pazopanib + Paclitaxel | Overall Survival, Subgroup 2 Analysis | primary angiosarcoma | 20.5 months |
Comparison: The analysis of secondary endpoints is of descriptive nature and generally consists of summary statistics and interval estimation.~Overall survival (OS) for subgroup 2 was defined as the time of start of treatment until death (event status=1) or last contact (censoring, event status=0). OS was analyzed using Kaplan-Meier curves. Median survival time is provided alonsgside two-sided 95% confidence interval (CI), if possible.p-value: 0.621Log Rank
Secondary
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
Time frame: 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
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Pazopanib + Paclitaxel | Response Rate (RR) | CR | 2 Participants |
| Pazopanib + Paclitaxel | Response Rate (RR) | PR | 7 Participants |
| Pazopanib + Paclitaxel | Response Rate (RR) | SD | 6 Participants |
| Pazopanib + Paclitaxel | Response Rate (RR) | PD | 10 Participants |
| Pazopanib + Paclitaxel | Response Rate (RR) | NE | 1 Participants |
Secondary
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
Time frame: 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
Population: Total number of participants analyzed is 26. Thereof, 18 show cutaneous AS, and 8 show visceral angiosarcoma
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Pazopanib + Paclitaxel | Response Rate (RR), Subgroup1 Analysis | cutaneous angiosarcoma | PR | 6 Participants |
| Pazopanib + Paclitaxel | Response Rate (RR), Subgroup1 Analysis | cutaneous angiosarcoma | SD | 4 Participants |
| Pazopanib + Paclitaxel | Response Rate (RR), Subgroup1 Analysis | visceral angiosarcoma | SD | 2 Participants |
| Pazopanib + Paclitaxel | Response Rate (RR), Subgroup1 Analysis | visceral angiosarcoma | PD | 4 Participants |
| Pazopanib + Paclitaxel | Response Rate (RR), Subgroup1 Analysis | visceral angiosarcoma | NE | 1 Participants |
| Pazopanib + Paclitaxel | Response Rate (RR), Subgroup1 Analysis | cutaneous angiosarcoma | CR | 2 Participants |
| Pazopanib + Paclitaxel | Response Rate (RR), Subgroup1 Analysis | cutaneous angiosarcoma | PD | 6 Participants |
| Pazopanib + Paclitaxel | Response Rate (RR), Subgroup1 Analysis | cutaneous angiosarcoma | NE | 0 Participants |
| Pazopanib + Paclitaxel | Response Rate (RR), Subgroup1 Analysis | visceral angiosarcoma | CR | 0 Participants |
| Pazopanib + Paclitaxel | Response Rate (RR), Subgroup1 Analysis | visceral angiosarcoma | PR | 1 Participants |
Comparison: Response Rate (RR) is given as Best Overall Response (BOR) and given be absolute and relative frequencies. Categories of BOR are CR, PR, SD, PD and NE)p-value: 0.349Chi squared test, exact
Secondary
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
Time frame: 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
Population: Total number of participants analyzed is 26. Thereof, 13 show primary angiosarcoma, and 13 show secondary angiosarcoma
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Pazopanib + Paclitaxel | Response Rate (RR), Subgroup 2 Analysis | primary angiosarcoma | CR | 0 Participants |
| Pazopanib + Paclitaxel | Response Rate (RR), Subgroup 2 Analysis | secondary angiosarcoma | CR | 2 Participants |
| Pazopanib + Paclitaxel | Response Rate (RR), Subgroup 2 Analysis | primary angiosarcoma | PR | 5 Participants |
| Pazopanib + Paclitaxel | Response Rate (RR), Subgroup 2 Analysis | primary angiosarcoma | SD | 3 Participants |
| Pazopanib + Paclitaxel | Response Rate (RR), Subgroup 2 Analysis | primary angiosarcoma | PD | 5 Participants |
| Pazopanib + Paclitaxel | Response Rate (RR), Subgroup 2 Analysis | primary angiosarcoma | NE | 0 Participants |
| Pazopanib + Paclitaxel | Response Rate (RR), Subgroup 2 Analysis | secondary angiosarcoma | PR | 2 Participants |
| Pazopanib + Paclitaxel | Response Rate (RR), Subgroup 2 Analysis | secondary angiosarcoma | SD | 3 Participants |
| Pazopanib + Paclitaxel | Response Rate (RR), Subgroup 2 Analysis | secondary angiosarcoma | PD | 5 Participants |
| Pazopanib + Paclitaxel | Response Rate (RR), Subgroup 2 Analysis | secondary angiosarcoma | NE | 1 Participants |
p-value: 0.385Chi squared test, exact