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

NCT01692496 | Completed Phase 2 Results

• 2 other identifiers: GEIS-302012-002745-38
• Study Type: interventional
• Target: 52
• Locations: 2 countries
• Sites: 15

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 Fluorescence In Situ Hybridization (FISH) (MDM2, CDK4 and HMGIC). They account for about 40% iv of liposarcomas with a 5 year Overall survival (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 confidence interval (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\<0.0001). The interim analysis for overall survival shows a statistically non-significant improvement of pazopanib vs placebo (median: 11.9 vs 10.4 months, HR=0.83, 95% CI 0.62-1.09). Soluble factors associated with efficacy and toxicity of pazopanib in these patients had been also reported. Decreases in VEGFR2 and increase in PlGF were both associated with toxicity (HTA and TSH elevation) and poorer prognosis.

Conditions

Advanced and / or Metastatic Liposarcoma

Keywords

Advanced; Metastatic; Liposarcoma; Pazopanib

Outcome Measures

Primary Outcomes (1)

• Progression-free Survival (PFS) Assessed 12 Weeks After Start of Treatment

  The primary objective of this study is to evaluate the activity of Pazopanib in patients with advanced and/or metastatic liposarcoma by means of progression-free survival (PFS) assessed 12 weeks after start of treatment. (According the RECIST criteria 1.1 and central radiology review). Progression was defined according to RECIST criteria 1.1 as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions

  12 weeks after start of treatment

Secondary Outcomes (6)

• Overall Progression Free Survival (Median PFS)

  Imaging studies repeated every 6 weeks for the first 12 weeks and every 8 weeks up to 36 months.

• Percentage of Patients With Objective Tumor Response (OR)

  6 weeks and 12 weeks

• Overall Survival (OS)

  Every 12 weeks from disease progression up to 36 months.

• Clinical Benefit Rate

  Imaging studies required to investigate known disease should be repeated every 6 weeks for the first 12 weeks and every 8 weeks up to 36 months.

• Growth Modulation Index (GMI)

  Imaging studies required to investigate known disease should be repeated every 6 weeks for the first 12 weeks and every 8 weeks up to 36 months. At patient progression confirmed by means RECIST criteria V 1.1

Study Arms (1)

Pazopanib

EXPERIMENTAL

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.

Drug: Pazopanib

Interventions

Pazopanib DRUG

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.

Pazopanib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• Age ≥ 18 years or legal age of consent if greater than 18 years
• 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
• Patient must have documentation of disease progression within 6 months prior to study entry.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
• 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.
• 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.
• 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.
• Tumor tissue must be provided for all subjects for biomarker analysis before/during treatment with investigational product.

You may not qualify if:

• Prior history of malignancies other than liposarcoma. Subjects who have had another malignancy and have been disease-free for 3 years, or subjects with a history of completely resected non-melanomatous skin carcinoma or successfully treated in situ carcinoma are eligible.
• Clinical evidence of central nervous system (CNS) metastases or leptomeningeal carcinomatosis, except for individuals who have previously-treated CNS metastases, are asymptomatic, and have had no requirement for steroids or anti-seizure medication for 6 months prior to first dose of study drug. Screening with CNS imaging studies (computed tomography \[CT\] or magnetic resonance imaging \[MRI\]) is required only if clinically indicated or if the subject has a history of CNS metastases.
• Clinically significant gastrointestinal abnormalities that may increase the risk for gastrointestinal bleeding including, but not limited to:
• Active peptic ulcer disease Known intraluminal metastatic lesion/s with risk of bleeding Inflammatory bowel disease (e.g. ulcerative colitis, Crohn's disease), or other gastrointestinal conditions with increased risk of perforation History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 28 days prior to beginning study treatment.
• Clinically significant gastrointestinal abnormalities that may affect absorption of investigational product including, but not limited to:
• Malabsorption syndrome Major resection of the stomach or small bowel.
• Corrected QT interval (QTc) \> 480 msecs
• 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)
• 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 \<140/90 mmHg (OR 150/90 mm Hg, if this criterion is approved by Safety Review Team) in order for a subject to be eligible for the study.
• History of cerebrovascular accident including transient ischemic attack (TIA), pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months.
• Subjects with recent DVT who have been treated with therapeutic anti-coagulating agents for at least 6 weeks are eligible
• 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 (procedures such as catheter placement not considered to be major surgery).
• Evidence of active bleeding or bleeding diathesis.

Sponsors & Collaborators

• Grupo Espanol de Investigacion en Sarcomas: lead
• GlaxoSmithKline: collaborator

Study Sites (15)

HELIOS Klinikum Berlin-Buch (Sarkomzentrum Berlin-Brandenburg)

Berlin, D-10707, Germany

Location

Universitätsklinikum EssenInnere Klinik (Tumorforschung)

Essen, D-45147, Germany

Location

Medizinische Hochschule Hannover (Zentrum Innere Medizin)

Hanover, D-30625, Germany

Location

Universitätsmedizin Mannheim (Sarkomzentrum)

Manheim, D-68169, Germany

Location

Klinikum Großhadern der LMU Universität München (Med. Klinik und Poliklinik II)

Munich, D-80336, Germany

Location

Hospital Universitario de Canarias

San Cristóbal de La Laguna, Canary Islands, 38320, Spain

Location

Hospital de Navarra

Pamplona, Navarre, 31008, Spain

Location

Complejo Hospitalario Universitario de Vigo

Vigo, Pontevedra, 36204, Spain

Location

Hospital Central de Asturias

Oviedo, Principality of Asturias, 33011, Spain

Location

Hospital Vall d'Hebrón

Barcelona, 08035, Spain

Location

Hospital 12 de Octubre

Madrid, 28041, Spain

Location

Hospital Universitari Son Espases

Palma de Mallorca, 07010, Spain

Location

Hospital Universitario Virgen del Rocío

Seville, 41013, Spain

Location

Instituto Valenciano de Oncología

Valencia, 46009, Spain

Location

Hospital Miguel Servet

Zaragoza, 50009, Spain

Location

MeSH Terms

Conditions

Liposarcoma; Neoplasm Metastasis

Interventions

pazopanib

Condition Hierarchy (Ancestors)

Neoplasms, Adipose Tissue; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Sarcoma; Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Results Point of Contact

• Title: Clinical Trial Coordinating Investigator
• Organization: GEIS

secretaria@grupogeis.org

912866807

Study Officials

• Claudia Valverde, MD

  Hospitals de la Vall de Hebron

  STUDY CHAIR

• Bernd Kasper, MD

  University Medical Centre Mannheim

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 14, 2012
• First Posted: September 25, 2012
• Study Start: January 29, 2013
• Primary Completion: March 1, 2018
• Study Completion: March 2, 2018
• Last Updated: July 23, 2020
• Results First Posted: July 23, 2020

Record last verified: 2020-07

Locations

DE (5); ES (10)