Advanced and / or Metastatic Liposarcoma 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
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.
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