Sarcoma, Soft Tissue
Conditions
Keywords
Sarcoma, Synovial sarcoma, Pazopanib(GW786034), Adipocytic tumors, Leiomyosarcoma, Phase II
Brief summary
The purpose of this study is to evaluate the activity and tolerability of pazopanib in subjects with advanced and/or metastatic soft tissue sarcoma who have relapsed following standard therapies or for whom no standard therapy exists and to characterize the pharmacokinetics of pazopanib in this subject population.
Interventions
DRUGpazopanib
oral tablet
Sponsors
GlaxoSmithKline
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
21 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histological evidence of high or intermediate grade malignant soft tissue sarcoma, or cytological evidence in case of presence of multiple metastases. List of eligible and ineligible tumours are included in the protocol. * Formalin fixed paraffin embedded tumour blocks and representative H/E (haematoxylin/eosin) slides must be available for histological central review. Histological central review is not required before treatment start but is mandatory within 3 months of registration. Local histopathological diagnosis will be accepted for entry into the study. * Presence of measurable disease (according to RECIST criteria). * Relapsed or refractory disease incurable by surgery or radiotherapy. * Evidence of objective progression within the last 6 months (RECIST) documented by measurements of disease, * Patients must either not be eligible for chemotherapy (for instance because of age, or because of a biological condition, or because of patient-refusal) or must have received no more than one combination or two single agents chemotherapy regimen for advanced disease; (neo) adjuvant therapy is not counted towards this requirement. * At least 18 years of age * WHO performance status 0 or 1 * Adequate bone marrow function * Adequate hepatic function * Adequate renal function * PT / PTT less than 1.2 x UNL. * LVEF above the lower limit of normal for the institution, based on ECHO or MUGA * Able to swallow and retain oral medication * Women should not be of childbearing potential and agree to use contraceptive methods (Oral contraceptives are not allowed). * Absence of any serious and/or unstable pre-existing medical, psychiatric or other condition (including lab abnormality) that could interfere with patient safety or obtaining informed consent. * Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be assessed with the patient before registration in the trial. * Written informed consent is given according to ICH/GCP, and national/local regulations before patient registration/randomization.
Exclusion criteria
* history of leptomeningeal or brain metastases * history of malignancies other than sarcoma (except for basal cell or squamous cell carcinoma of the skin, carcinoma in situ of the cervix or breast, or the patient has been free of any other malignancies for greater than 3 years). * Class II, III or IV heart failure (NYHA classification). A patient who has a history of class II heart failure and is asymptomatic on treatment may be considered eligible. * Arterial or venous thrombosis, myocardial infarction, unstable angina, cardiac angioplasty or stenting within the last 3 months * Uncontrolled or poorly controlled hypertension. Initiation or adjustment of BP medications is permitted prior to study entry, provided that patient has 3 consecutive BP readings less than 150 / 90 mm Hg each separated by a minimum of 24 hrs. These readings need to be collected prior to registration in the study. * Women of childbearing potential, who are pregnant (negative serum pregnancy test at entry) or lactating. * Therapeutic dose warfarin. Low molecular weight heparin and prophylactic low dose warfarin are permitted. PT/INR and PPT must meet the above inclusion criteria. * Concurrent therapy with any specifically prohibited medication or requirement for using any of these medications during treatment with pazopanib * Major surgery, hormonal therapy (other than replacement), chemotherapy or radiotherapy, immunotherapy or other investigational agent within the last 28 days and/or not recovered from prior therapy within the last 28 days. Use of erythropoietin is considered supportive care and is permitted. The patient should have recovered from prior surgery and have no open wounds. * History of malabsorption syndrome, disease significantly affecting gastrointestinal function or major resection of the stomach or small bowel that could affect absorption, distribution, metabolism or excretion of study drugs. No unresolved bowel obstruction or diarrhea.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival at Week 12 | Week 12 | Progression free survival at week 12 is the number of participants who had a complete response (CR, all detectable tumor had disappeared) or a partial response (PR, a \>=30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum) or stable disease (SD, no change) 12 weeks from start of therapy, per response evaluation criteria in solid tumors (RECIST v1.0). Clinical progression is progression of disease without documented radiological evidence. Progressive disease (PD), a \>=20% increase in target lesions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | Start of therapy until death (up to approximately 5 years) | Overall survival is defined as the time from start of therapy until death. Participants who were still alive at the time of analysis were censored. |
| Progression Free Survival | Start of therapy until progression (up to approximately 5 years) | Progression free survival is defined as the interval between the start of treatment and the earliest date of disease progression or death due to any cause. Assessments of progression were made by the investigator. |
| Overall Response | Baseline until either response or progression (up to approximately 5 years) | Overall response is the number of participants who had a best outcome of a complete response (CR, all detectable tumor had disappeared) or a partial response (PR, a \>=30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum) per response evaluation criteria in solid tumors (RECIST v1.0) at some point during the study. Progressive disease (PD), a \>=20% increase in target lesions. Clinical progression is progression of disease without documented radiological evidence. |
Countries
Belgium, France, Hungary, Netherlands, United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Pazopanib 800 mg Pazopanib 800 milligram (mg) (tablets) administered orally once a day | 142 |
| Total | 142 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Deteriorization of General Condition | 1 |
| Overall Study | Disease Progression, Relapse, Death | 120 |
| Overall Study | Intercurrent Death | 2 |
| Overall Study | Intercurrent Illness | 3 |
| Overall Study | Interruption: Cold/Flu-like Symptoms | 1 |
| Overall Study | Patient Refusal: Not Related to Toxicity | 2 |
| Overall Study | Radiotherapy to Destroy Last Lesion | 1 |
| Overall Study | Surgery Performed on Target Lesion | 1 |
| Overall Study | Switch to Commercial Treatment | 1 |
| Overall Study | Toxicity (or Toxic Death) | 10 |
Baseline characteristics
| Characteristic | Pazopanib 800 mg |
|---|---|
| Age, Continuous | 51.0 years |
| Sex: Female, Male Female | 71 Participants |
| Sex: Female, Male Male | 71 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 137 / 142 |
| serious Total, serious adverse events | 39 / 142 |
Outcome results
Primary
Progression Free Survival at Week 12
Progression free survival at week 12 is the number of participants who had a complete response (CR, all detectable tumor had disappeared) or a partial response (PR, a \>=30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum) or stable disease (SD, no change) 12 weeks from start of therapy, per response evaluation criteria in solid tumors (RECIST v1.0). Clinical progression is progression of disease without documented radiological evidence. Progressive disease (PD), a \>=20% increase in target lesions.
Time frame: Week 12
Population: Intent-to-Treat (ITT) Population: All eligible participants entered into the study and who had taken \>=1 dose of investigational product. Four participants were considered not evaluable for efficacy by the study coordinator for one of the following reasons: absence of target lesions, documented progression at trial entry, or ineligible histology.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pazopanib 800 mg - Adipocytic Tumors | Progression Free Survival at Week 12 | Unknown | 0 participants |
| Pazopanib 800 mg - Adipocytic Tumors | Progression Free Survival at Week 12 | Stable Disease | 5 participants |
| Pazopanib 800 mg - Adipocytic Tumors | Progression Free Survival at Week 12 | CR+PR+SD | 5 participants |
| Pazopanib 800 mg - Adipocytic Tumors | Progression Free Survival at Week 12 | Progressive Disease | 13 participants |
| Pazopanib 800 mg - Adipocytic Tumors | Progression Free Survival at Week 12 | Missing | 1 participants |
| Pazopanib 800 mg - Adipocytic Tumors | Progression Free Survival at Week 12 | Complete Response | 0 participants |
| Pazopanib 800 mg - Adipocytic Tumors | Progression Free Survival at Week 12 | Partial Response | 0 participants |
| Pazopanib 800 mg - Leiomyosarcoma | Progression Free Survival at Week 12 | Missing | 3 participants |
| Pazopanib 800 mg - Leiomyosarcoma | Progression Free Survival at Week 12 | CR+PR+SD | 17 participants |
| Pazopanib 800 mg - Leiomyosarcoma | Progression Free Survival at Week 12 | Partial Response | 1 participants |
| Pazopanib 800 mg - Leiomyosarcoma | Progression Free Survival at Week 12 | Stable Disease | 16 participants |
| Pazopanib 800 mg - Leiomyosarcoma | Progression Free Survival at Week 12 | Complete Response | 0 participants |
| Pazopanib 800 mg - Leiomyosarcoma | Progression Free Survival at Week 12 | Progressive Disease | 19 participants |
| Pazopanib 800 mg - Leiomyosarcoma | Progression Free Survival at Week 12 | Unknown | 2 participants |
| Pazopanib 800 mg - Synovial Sarcoma | Progression Free Survival at Week 12 | Progressive Disease | 15 participants |
| Pazopanib 800 mg - Synovial Sarcoma | Progression Free Survival at Week 12 | Complete Response | 0 participants |
| Pazopanib 800 mg - Synovial Sarcoma | Progression Free Survival at Week 12 | Partial Response | 4 participants |
| Pazopanib 800 mg - Synovial Sarcoma | Progression Free Survival at Week 12 | Missing | 4 participants |
| Pazopanib 800 mg - Synovial Sarcoma | Progression Free Survival at Week 12 | Unknown | 0 participants |
| Pazopanib 800 mg - Synovial Sarcoma | Progression Free Survival at Week 12 | Stable Disease | 14 participants |
| Pazopanib 800 mg - Synovial Sarcoma | Progression Free Survival at Week 12 | CR+PR+SD | 18 participants |
| Pazopanib 800mg - Other Soft Tissue Sarcoma (STS) | Progression Free Survival at Week 12 | CR+PR+SD | 17 participants |
| Pazopanib 800mg - Other Soft Tissue Sarcoma (STS) | Progression Free Survival at Week 12 | Complete Response | 0 participants |
| Pazopanib 800mg - Other Soft Tissue Sarcoma (STS) | Progression Free Survival at Week 12 | Stable Disease | 16 participants |
| Pazopanib 800mg - Other Soft Tissue Sarcoma (STS) | Progression Free Survival at Week 12 | Progressive Disease | 21 participants |
| Pazopanib 800mg - Other Soft Tissue Sarcoma (STS) | Progression Free Survival at Week 12 | Unknown | 1 participants |
| Pazopanib 800mg - Other Soft Tissue Sarcoma (STS) | Progression Free Survival at Week 12 | Missing | 2 participants |
| Pazopanib 800mg - Other Soft Tissue Sarcoma (STS) | Progression Free Survival at Week 12 | Partial Response | 1 participants |
p-value: 0.65390% CI: [11, 47.6]binomial exact method
p-value: 0.00390% CI: [28.4, 55.5]binomial exact method
p-value: <0.00190% CI: [34.3, 63.2]binomial exact method
p-value: 0.00390% CI: [28.4, 55.5]binomial exact method
Secondary
Overall Response
Overall response is the number of participants who had a best outcome of a complete response (CR, all detectable tumor had disappeared) or a partial response (PR, a \>=30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum) per response evaluation criteria in solid tumors (RECIST v1.0) at some point during the study. Progressive disease (PD), a \>=20% increase in target lesions. Clinical progression is progression of disease without documented radiological evidence.
Time frame: Baseline until either response or progression (up to approximately 5 years)
Population: Intent-to-Treat (ITT) Population: all eligible participants who had started therapy. Four participants were considered not evaluable for efficacy by the study coordinator for one of the following reasons: absence of target lesions, documented progression at trial entry, or ineligible histology.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pazopanib 800 mg - Adipocytic Tumors | Overall Response | Complete Response | 0 participants |
| Pazopanib 800 mg - Adipocytic Tumors | Overall Response | Partial Response | 0 participants |
| Pazopanib 800 mg - Adipocytic Tumors | Overall Response | Stable Disease | 5 participants |
| Pazopanib 800 mg - Adipocytic Tumors | Overall Response | Progressive Disease | 13 participants |
| Pazopanib 800 mg - Adipocytic Tumors | Overall Response | Unknown | 1 participants |
| Pazopanib 800 mg - Adipocytic Tumors | Overall Response | Missing | 0 participants |
| Pazopanib 800 mg - Leiomyosarcoma | Overall Response | Missing | 0 participants |
| Pazopanib 800 mg - Leiomyosarcoma | Overall Response | Progressive Disease | 19 participants |
| Pazopanib 800 mg - Leiomyosarcoma | Overall Response | Complete Response | 0 participants |
| Pazopanib 800 mg - Leiomyosarcoma | Overall Response | Stable Disease | 17 participants |
| Pazopanib 800 mg - Leiomyosarcoma | Overall Response | Partial Response | 1 participants |
| Pazopanib 800 mg - Leiomyosarcoma | Overall Response | Unknown | 4 participants |
| Pazopanib 800 mg - Synovial Sarcoma | Overall Response | Partial Response | 4 participants |
| Pazopanib 800 mg - Synovial Sarcoma | Overall Response | Stable Disease | 14 participants |
| Pazopanib 800 mg - Synovial Sarcoma | Overall Response | Progressive Disease | 13 participants |
| Pazopanib 800 mg - Synovial Sarcoma | Overall Response | Missing | 0 participants |
| Pazopanib 800 mg - Synovial Sarcoma | Overall Response | Unknown | 6 participants |
| Pazopanib 800 mg - Synovial Sarcoma | Overall Response | Complete Response | 0 participants |
| Pazopanib 800mg - Other Soft Tissue Sarcoma (STS) | Overall Response | Unknown | 3 participants |
| Pazopanib 800mg - Other Soft Tissue Sarcoma (STS) | Overall Response | Missing | 0 participants |
| Pazopanib 800mg - Other Soft Tissue Sarcoma (STS) | Overall Response | Partial Response | 3 participants |
| Pazopanib 800mg - Other Soft Tissue Sarcoma (STS) | Overall Response | Progressive Disease | 21 participants |
| Pazopanib 800mg - Other Soft Tissue Sarcoma (STS) | Overall Response | Complete Response | 0 participants |
| Pazopanib 800mg - Other Soft Tissue Sarcoma (STS) | Overall Response | Stable Disease | 14 participants |
Secondary
Overall Survival
Overall survival is defined as the time from start of therapy until death. Participants who were still alive at the time of analysis were censored.
Time frame: Start of therapy until death (up to approximately 5 years)
Population: ITT Population. Four participants were considered not evaluable for efficacy by the study coordinator for one of the following reasons: absence of target lesions, documented progression at trial entry, or ineligible histology.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pazopanib 800 mg - Adipocytic Tumors | Overall Survival | 28.1 years |
| Pazopanib 800 mg - Leiomyosarcoma | Overall Survival | 50.9 years |
| Pazopanib 800 mg - Synovial Sarcoma | Overall Survival | 44.6 years |
| Pazopanib 800mg - Other Soft Tissue Sarcoma (STS) | Overall Survival | 42.6 years |
Secondary
Progression Free Survival
Progression free survival is defined as the interval between the start of treatment and the earliest date of disease progression or death due to any cause. Assessments of progression were made by the investigator.
Time frame: Start of therapy until progression (up to approximately 5 years)
Population: Intent-to-Treat (ITT) Population: all eligible participants who had started therapy. Four participants were considered not evaluable for efficacy by the study coordinator for one of the following reasons: absence of target lesions, documented progression at trial entry, or ineligible histology.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pazopanib 800 mg - Adipocytic Tumors | Progression Free Survival | 11.1 years |
| Pazopanib 800 mg - Leiomyosarcoma | Progression Free Survival | 17.2 years |
| Pazopanib 800 mg - Synovial Sarcoma | Progression Free Survival | 23.4 years |
| Pazopanib 800mg - Other Soft Tissue Sarcoma (STS) | Progression Free Survival | 14.0 years |