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Activity and Tolerability of Pazopanib in Advanced and/or Metastatic Liposarcoma. A Phase II Clinical Trial

Descriptive Information
Brief Title † Activity and Tolerability of Pazopanib in Advanced and/or Metastatic Liposarcoma. A Phase II Clinical Trial
Official Title † Phase II Clinical Trial of Pazopanib to Evaluate the Activity and Tolerability in Patients With Advanced and/or Metastatic Liposarcoma Who Have Relapsed Following Standard Therapies or for Whom no Standard Therapy Exists
Brief Summary Soft tissue and bone sarcomas are rare malignant tumors, which encompasses a large family of more than 50 histologically distinct tumor subtypes, all of which share a putative mesenchymal origin. In the case of soft tissue sarcomas (STS) surgical excision is the mainstay of treatment, but despite curative surgery, around half of patients develop distant metastases and die from disease. Few therapeutic approaches are currently available to patients with unresectable, locally advanced, or metastatic STS and only anthracyclines, ifosfamide and trabectedin have shown activity, with response rates of 20-40% in previously untreated patients. Recent and ongoing trials have investigated a variety of combination chemotherapeutic regimens (variously employing ifosfamide, doxorubicin, gemcitabine, temozolomide, vincristine, cisplatin, and dacarbazine, among others) as well as targeted therapies, which in some cases have yielded improvements in response rate but which have had little impact on survival. No other medical option is currently available, and the median survival of patients with soft-tissue sarcoma with non-resectable metastases is around 12-15 months, and approximately 8 months after second line chemotherapy. Liposarcomas are STS which account for at least 20% of all STS in adults. They can be further classified into 3 histologically and biologically different subtypes: well-differentiated liposarcoma/dedifferentiated liposarcoma (ALT-WD), myxoid or round cell liposarcoma and pleomorphic liposarcoma. ALT-WD liposarcomas are locally aggressive rarely metastasizing tumors characterized by ring or giant marker chromosomes on the cytogenetic analysis and by amplification of the 12q13-21 region on FISH (MDM2, CDK4 and HMGIC). They account for about 40% iv of liposarcomas with a 5 year OS around 80%. In a series of WD/DD treated with several regimens response rate was 12.5% OS 15 months and median PFS 3.6 months(95 CI: 3.3-5.9) Mixoid /round cell liposarcoma accounts for 45-50% of all liposarcomas. They tend to metastasize to unusual soft tissue and bone locations. High histologic grade with more than 5% of round cell component is associated with a 5-year OS of 50% approximately. They are characterized by t(23;16)(q13-14;p11) which leads to the fusion of CHOP and TLS genes Pleomorphic liposarcoma accounts for approximately 5-10% of all liposarcomas, characterized by high grade features with frequent and early lung metastasis and cytogenetically by high chromosome counts and complex structural rearrangements. VEGF is expressed in many STS in which increased expression is associated with higher grade and worse prognosis. Pazopanib is an oral angiogenesis inhibitor that targets mainly VEGFR, PDGFR and c-kit. Recently the results of a phase II trial of pazopanib in STS have been published. It was a four-cohort 2-stages study. The liposarcoma stratum was closed after the first stage because of a PFS at 12 weeks of 17% (3 out of 17 patients did not progressed after 12 weeks). After central pathologic review, 2 other patients initially classified as other STS were found to have liposarcoma with stable disease at 12 weeks (5/19: 26% PFS12w), thus fulfilling criteria for cohort expansion. Phase II study had been completed and in phase III study patients with liposarcomas were excluded so therefore data on the liposarcoma cohort are inconclusive. Furthermore the positive results of the phase III study PALETTE have been recently communicated, encouraging this treatment in other sarcomas: progression-free survival (PFS) per independent review was significantly prolonged with pazopanib (median: 4.6 vs 1.5 months; HR=0.31, 95% CI 0.24-0.40; P
Detailed Description
Study Phase Phase 2
Study Type † Interventional
Study Design † Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Primary Outcome Measure † Progression-free survival (PFS) assessed 12 weeks after start of treatment
Secondary Outcome Measure † Overall progression free survival (median PFS)
Condition † Advanced and / or Metastatic Liposarcoma
Intervention † DrugPazopanib
Study Arms / Comparison Groups Pazopanib Patients will receive oral pazopanib, 800mg once daily and treatment will continue until disease progression, development of unacceptable toxicity, noncompliance, withdrawal of consent by the patient or investigator decision.
Publications *

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information
Recruitment Status † Drug
Estimated Enrollment † 74
Start Date † January 2013
Completion Date December 2015
Primary Completion Date December 2015
Eligibility Criteria † Inclusion Criteria: 1. 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. Informed consent must be obtained prior to start of the specified screening window. Procedures conducted as part of the subject's routine clinical management (e.g., blood count, imaging study such as bone scan) and obtained prior to signing of informed consent may be utilized for screening or baseline purposes provided these procedures are conducted as specified in the protocol. 2. Age ≥ 18 years or legal age of consent if greater than 18 years 3. Histological confirmed diagnosis of high or intermediate grade malignant liposarcoma with metastatic or locally advanced disease. Formalin fixed paraffin embedded tumour block and/or representative H/E (haematoxylin/eosin) slides must be available for central pathologic review to classify tumors in the 2 eligible subtypes: Well-differentiated liposarcoma/de-differentiated liposarcoma (ALT-WD) Myxoid/round cell liposarcoma 4. Patient must have documentation of disease progression within 6 months prior to study entry. 5. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. 6. Measurable disease by RECIST v1.1 criteria. At least one measurable lesion located outside of a previously irradiated area. If the only measurable lesion is in a previously irradiated area, RECIST progression should be documented after radiotherapy, in the previous 6 months before study entry. 7. The patient should not be considered eligible for surgery or radical radiotherapy. e.g. Patients to whom surgery/radiotherapy can not be performed with a curative intent due to the extension of the disease. In the case of radiotherapy, it may also be limited due to a previous treatment with radiotherapy in the same area. 8. The patient must have either been considered ineligible for systemic chemotherapy or received at least one previous regimen for relapsed, refractory or metastatic disease. A maximum of three previous lines for advanced/metastatic disease are allowed. Patients not eligible for systemic chemotherapy: Because of age, a biological condition or patient-refusal Generally, patients that received anthracyclines in the adjuvant setting are not eligible for first line therapy with this agent for advanced disease. Patients with a solitary kidney or >60 years old are usually not the best candidates for treatment with regular doses of ifosfamide. 9. Tumor tissue must be provided for all subjects for biomarker analysis before/during treatment with investigational product. 10. The patient should be able to swallow and retain study drug 11. Adequate organ system function as defined: Absolute neutrophil count (ANC)≥ 1.5 X 109/L Hemoglobin ≥ 9 g/dL (5.6 mmol/L) Platelets ≥ 100 X 109/L Prothrombin time (PT) or international normalized ratio (INR)≤ 1.2 X ULN Activated partial thromboplastin time (aPTT)≤ 1.2 X ULN Total bilirubin≤ 1.5 X ULN Alanine amino transferase (ALT) and Aspartate aminotransferase (AST) ≤ 2.5 X ULN Serum creatinine ≤ 1.5 mg/dL (133 µmol/L)Or, if >1.5 mg/dL: Calculated creatinine clearance (ClCR)≥ 30 mL/min to ≥ 50 mL/min Urine Protein to Creatinine Ratio (UPC) 40 mIU/mL and an estradiol value 480 msecs 6. History of any one or more of the following cardiovascular conditions within the past 6 months: Cardiac angioplasty or stenting Myocardial infarction Unstable angina Coronary artery bypass graft surgery Symptomatic peripheral vascular disease Class III or IV congestive heart failure, as defined by the New York Heart Association (NYHA) 7. Poorly controlled hypertension [defined as systolic blood pressure (SBP) of ≥140 mmHg or diastolic blood pressure (DBP) of ≥ 90mmHg]. Initiation or adjustment of antihypertensive medication(s) is permitted prior to study entry. Following antihypertensive medication initiation or adjustment, blood pressure (BP) must be re-assessed three times at approximately 2-minute intervals. At least 24 hours must have elapsed between anti-hypertensive medication initiation or adjustment and BP measurement. These three values should be averaged to obtain the mean diastolic blood pressure and the mean systolic blood pressure. The mean SBP / DBP ratio must be Grade 1 and/or that is progressing in severity, except alopecia.
Gender Both
Ages 18 Years - N/A
Accepts Healthy Volunteers No
Contacts †† Claudia Valverde, MD, +34 93 434 44 12, secretaria@grupogeis.org
Location Countries † Germany
Administrative Information
NCT ID † NCT01692496
Organization ID GEIS-30
Secondary IDs †† 2012-002745-38
Responsible Party Sponsor
Study Sponsor † Grupo Espanol de Investigacion en Sarcomas
Collaborators †† GlaxoSmithKline
Investigators † Study Chair: Claudia Valverde, MD, Hospitals de la Vall de Hebron
Information Provided By
Verification Date August 2014
First Received Date † September 14, 2012
Last Updated Date August 25, 2014
† Required WHO trial registration data element.
†† WHO trial registration data element that is required only if it exists.
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