Phase 2 N=52 Treatment

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

Advanced and / or Metastatic Liposarcoma

Bottom Line

View on ClinicalTrials.gov: NCT01692496 ↗

Enrolled (actual)

Serious AEs

26.9%

Results posted

Jul 2020

Primary outcome: Primary: Progression-free Survival (PFS) Assessed 12 Weeks After Start of Treatment — 54.1; 46.2 percentage of participants

Study Design & Population

Study type: Interventional
Phase: Phase 2
Interventions: Pazopanib (Drug)
Age: Adult, Older Adult · 18+ yrs
Sex: All
Sponsor: Grupo Espanol de Investigacion en Sarcomas
Primary completion: Mar 2018

Outcome Measures

Outcome	Result	p-value
PRIMARY Progression-free Survival (PFS) Assessed 12 Weeks After Start of Treatment	54.1; 46.2	—
SECONDARY Overall Progression Free Survival (Median PFS)	12.14; 15; 10.29	—
SECONDARY Percentage of Patients With Objective Tumor Response (OR)	8; 4	—
SECONDARY Overall Survival (OS)	70.43; 70.43; 71.29	—
SECONDARY Clinical Benefit Rate	26; 32.4; 7.7	—
SECONDARY Growth Modulation Index (GMI)	0.4; 0.7; 0.2	—
SECONDARY Safety Profile (According CTCAE, Version 4.0)	52; 37; 15; 46; 33; 13	—

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.

Eligibility Criteria

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.

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.
The patient should be able to swallow and retain study drug
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

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 appro

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Data sourced from ClinicalTrials.gov (NCT01692496). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication.