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A Phase II Trial of Pazopanib in Patients with Metastatic Alveolar Soft Part Sarcoma.

ABSTRACT: LESSONS LEARNED:Pazopanib shows a modest efficacy in metastatic alveolar soft part sarcoma.Clinical outcomes were comparable to those in previous studies using antiangiogenic drugs.Further prospective studies evaluating the benefit of pazopanib in alveolar soft part sarcoma with a larger sample are warranted to validate results. BACKGROUND:Alveolar soft part sarcoma (ASPS) is a rare mesenchymal malignant tumor characterized by an unbalanced translocation, t(X;17)(p11.2;q25), which leads to the fusion of ASPSCR1 to the TFE3 transcription factor. Because this results in the upregulation of angiogenesis-related transcripts, antiangiogenic drugs have been used in ASPS patients. METHODS:This open-label, single-arm, multicenter, investigator-initiated phase II trial was designed to evaluate efficacy and safety of pazopanib 800 mg once daily in patients with metastatic ASPS. The primary endpoint was investigator-assessed overall response rate (ORR), and secondary endpoints were toxicity, progression-free survival (PFS), and overall survival (OS). 68Ga-RGD (Arg-Gly-Asp) positron emission tomography (PET) scan and gene expression profiling using NanoString platform were performed for biomarker analysis. RESULTS:Six patients with histologically confirmed metastatic ASPS were enrolled between December 2013 and November 2014. Among six patients, one achieved a partial response (PR) (ORR 16.7%) and five patients showed stable disease (SD). With a median follow-up of 33 months (range 18.7-39.3 months), median PFS was 5.5 months (95% confidence interval [CI] 3.4-7.6 months), and median OS was not reached. There were no severe toxicities except one patient with grade 3 diarrhea. CONCLUSION:Pazopanib showed modest antitumor activity with manageable toxicities for patients with metastatic ASPS.

SUBMITTER: Kim M

PROVIDER: S-EPMC6324645 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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A Phase II Trial of Pazopanib in Patients with Metastatic Alveolar Soft Part Sarcoma.

Kim Miso M Kim Tae Min TM Keam Bhumsuk B Kim Yu Jung YJ Paeng Jin Chul JC Moon Kyung Chul KC Kim Dong-Wan DW Heo Dae Seog DS

The oncologist 20180925 1

<h4>Lessons learned</h4>Pazopanib shows a modest efficacy in metastatic alveolar soft part sarcoma.Clinical outcomes were comparable to those in previous studies using antiangiogenic drugs.Further prospective studies evaluating the benefit of pazopanib in alveolar soft part sarcoma with a larger sample are warranted to validate results.<h4>Background</h4>Alveolar soft part sarcoma (ASPS) is a rare mesenchymal malignant tumor characterized by an unbalanced translocation, t(X;17)(p11.2;q25), which ...[more]

PMID: 30254189

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Project description:BACKGROUND:Alveolar soft part sarcoma (ASPS) is an exceedingly rare and orphan disease, without active drugs approved in the front line. Pazopanib and trabectedin are licensed for sarcoma treatment from second-line, but very little and contradictory data are available on their activity in ASPS. Lacking ongoing and/or planned clinical trials, we conducted a multi-institutional study involving the reference sites for sarcoma in Europe, U.S., and Japan, within the World Sarcoma Network, to investigate the efficacy of pazopanib and trabectedin. MATERIALS AND METHODS:From May 2007, 14 of the 27 centers that were asked to retrospectively review their databases had identified 44 advanced ASPS patients treated with pazopanib and/or trabectedin. Response was evaluated by Response Evaluation Criteria in Solid Tumors 1.1. Progression-free survival (PFS) and overall survival (OS) were computed by Kaplan-Meier method. RESULTS:Among 30 patients who received pazopanib, 18 were pretreated (13 with other antiangiogenics). Response was evaluable in 29/30 patients. Best responses were 1 complete response, 7 partial response (PR), 17 stable disease (SD), and 4 progressions. At a 19-month median follow-up, median PFS was 13.6 months (range: 1.6-32.2+), with 59% of patients progression-free at 1 year. Median OS was not reached.Among 23 patients treated with trabectedin, all were pretreated and evaluable for response. Best responses were 1 PR, 13 SD, and 9 progressions. At a 27-month median follow-up, median PFS was 3.7 months (range: 0.7-109), with 13% of patients progression-free at 1 year. Median OS was 9.1 months. CONCLUSION:The value of pazopanib in advanced ASPS is confirmed, with durable responses, whereas the value of trabectedin appears limited. These results are relevant to defining the best approach to advanced ASPS. IMPLICATIONS FOR PRACTICE:This retrospective study, conducted among the world reference centers for treatment of sarcoma, confirms the value of pazopanib in patients with advanced alveolar soft part sarcoma (ASPS), with dimensional and durable responses, whereas trabectedin shows a limited activity. Alveolar soft part sarcoma is resistant to conventional cytotoxic chemotherapy. Pazopanib and trabectedin are licensed for treatment of sarcoma from second line; in the lack of prospective clinical trials, these results are relevant to defining ASPS best management and strongly support initiatives aimed at obtaining the approval of pazopanib in the front line of the disease.

Project description:BackgroundAlveolar soft-part sarcoma (ASPS) is a rare soft-tissue sarcoma that is unresponsive to chemotherapy. Cediranib, a tyrosine-kinase inhibitor, has shown substantial activity in ASPS in non-randomised studies. The Cediranib in Alveolar Soft Part Sarcoma (CASPS) study was designed to discriminate the effect of cediranib from the intrinsically indolent nature of ASPS.MethodsIn this double-blind, placebo-controlled, randomised, phase 2 trial, we recruited participants from 12 hospitals in the UK (n=7), Spain (n=3), and Australia (n=2). Patients were eligible if they were aged 16 years or older; metastatic ASPS that had progressed in the previous 6 months; had an ECOG performance status of 0-1; life expectancy of more than 12 weeks; and adequate bone marrow, hepatic, and renal function. Participants had to have no anti-cancer treatment within 4 weeks before trial entry, with exception of palliative radiotherapy. Participants were randomly assigned (2:1), with allocation by use of computer-generated random permuted blocks of six, to either cediranib (30 mg orally, once daily) or matching placebo tablets for 24 weeks. Treatment was supplied in number-coded bottles, masking participants and clinicians to assignment. Participants were unblinded at week 24 or sooner if they had progression defined by Response Evaluation Criteria in Solid Tumors (version 1.1); those on placebo crossed over to cediranib and all participants continued on treatment until progression or death. The primary endpoint was percentage change in sum of target marker lesion diameters between baseline and week 24 or progression if sooner, assessed in the evaluable population (all randomly assigned participants who had a scan at week 24 [or sooner if they progressed] with target marker lesions measured). Safety was assessed in all participants who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01337401; the European Clinical Trials database, number EudraCT2010-021163-33; and the ISRCTN registry, number ISRCTN63733470 recruitment is complete and follow-up is ongoing.FindingsBetween July 15, 2011, and July 29, 2016, of 48 participants recruited, all were randomly assigned to cediranib (n=32) or placebo (n=16). 23 (48%) were female and the median age was 31 years (IQR 27-45). Median follow-up was 34·3 months (IQR 23·7-55·6) at the time of data cutoff for these analyses (April 11, 2018). Four participants in the cediranib group were not evaluable for the primary endpoint (one did not start treatment, and three did not have their scan at 24 weeks). Median percentage change in sum of target marker lesion diameters for the evaluable population was -8·3% (IQR -26·5 to 5·9) with cediranib versus 13·4% (IQR 1·1 to 21·3) with placebo (one-sided p=0·0010). The most common grade 3 adverse events on (blinded) cediranib were hypertension (six [19%] of 31) and diarrhoea (two [6%]). 15 serious adverse reactions in 12 patients were reported; 12 of these reactions occurred on open-label cediranib, and the most common symptoms were dehydration (n=2), vomiting (n=2), and proteinuria (n=2). One probable treatment-related death (intracranial haemorrhage) occurred 41 days after starting open-label cediranib in a patient who was assigned to placebo in the masked phase.InterpretationGiven the high incidence of metastatic disease and poor long-term prognosis of ASPS, together with the lack of efficacy of conventional chemotherapy, our finding of significant clinical activity with cediranib in this disease is an important step towards the goal of long-term disease control for these young patients. Future clinical trials in ASPS are also likely to involve immune checkpoint inhibitors.FundingCancer Research UK and AstraZeneca.

Project description:BackgroundAnthracycline-based treatment remains the backbone of chemotherapy for nonresectable soft tissue sarcomas (STS). More than 30 % of patients with STS are aged 60 years or older, limiting the choice of treatment to single-agent approaches for this elderly population. Hematological toxicity is frequent during doxorubicin monotherapy, grade 4 neutropenia is reported in 34 %, with a febrile neutropenia rate of 9 % in STS. We assume that comorbidities in the elderly population may limit tolerability of doxorubicin, and novel agents may improve tolerability and health-related quality of life while maintaining efficacy. We therefore investigated whether the tyrosine kinase inhibitor pazopanib exerts such a clinical benefit in elderly patients with STS (pazopanib for elderly [the EPAZ study]).Methods/designThis study is a randomized, controlled, open-label, multicenter, phase II noninferiority trial in which pazopanib 800 mg once daily is being compared six cycles of intravenous doxorubicin 75 mg/m(2) as first-line treatment in elderly patients (≥60 years) with metastatic or advanced STS. A total of 120 patients will be randomized 1:2 to receive doxorubicin or pazopanib, stratified by Eastern Cooperative Oncology Group performance status (0-1 vs. 2) and liposarcoma histology (yes vs. no). The primary endpoint is progression-free survival based on local tumor assessment according to Response Evaluation Criteria in Solid Tumors criteria. Secondary endpoints include grade 4 neutropenia and febrile neutropenia in hierarchical order, as well as overall survival, objective response rate, health-related quality of life, and geriatric assessments.DiscussionPazopanib is associated with promising tolerability according to previous studies and may offer a significant clinical advantage in first-line treatment of STS compared with doxorubicin. The elderly population seems especially appealing for such an approach, since these patients are not suitable for aggressive combination therapy. The EPAZ study will confirm whether pazopanib may be an alternative to toxic chemotherapy for elderly patients with STS.Trial registrationClinicalTrials.gov NCT01861951 ; registered on 11 April 2013. EudraCT 2011-004168-30; registered on 4 June 2012.

Project description:BackgroundAlveolar soft part sarcoma (ASPS) is an extremely rare metastatic soft tissue tumor with a poor prognosis for which no effective systemic therapies have yet been established. Therefore, the development of novel effective treatment approaches is required. Tyrosine kinases (TKs) are being increasingly used as therapeutic targets in a variety of cancers. The purpose of this study was to identify novel therapeutic target TKs and to clarify the efficacy of TK inhibitors (TKIs) in the treatment of ASPS.Experimental designTo identify novel therapeutic target TKs in ASPS, we evaluated the antitumor effects and kinase activity of three TKIs (pazopanib, dasatinib, and cabozantinib) against ASPS cells using an in vitro assay. Based on these results, we then investigated the phosphorylation activities of the identified targets using western blotting, in addition to examining antitumor activity through in vivo assays of several TKIs to determine both the efficacy of these substances and accurate targets.ResultsIn cell proliferation and invasion assays using pazopanib, cabozantinib, and dasatinib, all three TKIs inhibited the cell growth in ASPS cells. Statistical analyses of the cell proliferation and invasion assays revealed that dasatinib had a significant inhibitory effect in cell proliferation assays, and cabozantinib exhibited marked inhibitory effects on cellular functions in both assays. Through western blotting, we also confirmed that cabozantinib inhibited c-MET phosphorylation and dasatinib inhibited SRC phosphorylation in dose-dependent fashion. Mice that received cabozantinib and dasatinib had significantly smaller tumor volumes than control animals, demonstrating the in vivo antitumor activity of, these substances.ConclusionsOur findings suggest that cabozantinib and dasatinib may be more effective than pazopanib against ASPS cells. These in vitro and in vivo data suggest that c-MET may be a potential therapeutic target in ASPS, and cabozantinib may be a particularly useful therapeutic option for patients with ASPS, including those with pazopanib-resistant ASPS.

Dataset Information

A Phase II Trial of Pazopanib in Patients with Metastatic Alveolar Soft Part Sarcoma.

Publications

A Phase II Trial of Pazopanib in Patients with Metastatic Alveolar Soft Part Sarcoma.

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