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Cesne A.L.,Institute Gustave Roussy | Judson I.,Royal Marsden Hospital | Maki R.,Mount Sinai Hospital NY | Grosso F.,Italian National Cancer Institute | And 7 more authors.
British Journal of Cancer | Year: 2013

Background:This retrospective pooled analysis assessed the effect of age on the efficacy and safety of trabectedin in young and elderly patients with recurrent advanced soft tissue sarcoma (STS).Methods:Data from 350 adults with STS treated in five phase II trials with trabectedin were divided in the younger (<60 years; n=267) and the older cohort (≥60 years; n=83).Results:The response rate did not differ with age (younger: 10.1% vs elderly 9.6%). No significant differences were found in median progression-free survival (PFS) in younger (2.5 months) and older (3.7 months) cohort with a comparable PFS rates at 3 (45.1% vs 55.1%) and 6 months (29.5% vs 36.4%). Similar median overall survival was observed in both cohorts (13.0 vs 14.0 months). Reversible neutropenia and aspartate aminotransferase/alanine aminotransferase elevation were the most common abnormalities. A higher incidence of grade 3/4 neutropenia (43.6% vs 60.2%) and fatigue (6.3% vs 14.4%) was observed in older patients. In 24 patients aged ≥70 years, no significant differences in efficacy or safety outcomes were found.Conclusion:This analysis demonstrated that trabectedin is a feasible treatment in young and elderly patients with STS, with meaningful clinical benefits and an acceptable safety profile, essential in palliative treatment of elderly patients. © 2013 Cancer Research UK.

Samuels B.L.,Kootenai Cancer Center | Chawla S.,Sarcoma Oncology Center | Patel S.,University of Houston | von Mehren M.,Chase Medical | And 5 more authors.
Annals of Oncology | Year: 2013

Background: This expanded access program (EAP) was designed to provide trabectedin access for patients with incurable soft tissue sarcoma (STS) following progression of disease with standard therapy. The outcomes of trial participants accrued over approximately 5 years are reported. Patients and methods: Adult patients with advanced STS of multiple histologies, including leiomyosarcoma and liposarcoma (L-sarcomas), following relapse or disease progression following standard-of-care chemotherapy, were enrolled. Trabectedin treatment cycles (1.5 mg/m2, intravenously over 24 h) were repeated q21 days. Objective response, overall survival (OS), and safety were evaluated. Results: Of 1895 patients enrolled, 807 (43%) had evaluable objective response data, with stable disease reported in 343 (43%) as best response. L-sarcoma patients exhibited longer, OS compared with other histologies [16.2 months (95% confidence interval (CI) 14.1-19.5) versus 8.4 months (95% CI 7.1-10.7)], and a slightly higher objective response rate [6.9% (95% CI 4.8-9.6) versus 4.0% (95% CI 2.1-6.8)]. The median treatment duration was 70 days representing a median of three treatment cycles; 30% of patients received ≥6 cycles. Safety and tolerability in this EAP were consistent with prior clinical trial data. Conclusion: Results of this EAP are consistent with previous reports of trabectedin, demonstrating disease control despite a low incidence of objective responses in advanced STS patients after failure of standard chemotherapy. NCT00210665. © The Author 2013. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

Chawla S.,Sarcoma Oncology Center | Henshaw R.,Georgetown University | Seeger L.,University of California at Los Angeles | Choy E.,Massachusetts General Hospital | And 12 more authors.
The Lancet Oncology | Year: 2013

Background: Giant cell tumour of bone (GCTB) is a very rare, aggressive, and progressive osteolytic tumour for which no standard medicinal treatment or chemotherapy exists. We report interim safety and efficacy results from a phase 2 study of denosumab in patients with GCTB. Methods: We did an international, open-label, parallel-group, phase 2 trial of patients with histologically confirmed GCTB and radiographically measurable active disease. Eligible patients were adults or skeletally mature adolescents with radiographic evidence of at least one mature long bone who were at least 12 years old and weighed at least 45 kg. We divided patients into three cohorts-those with surgically unsalvageable GCTB (cohort 1), those with salvageable GCTB whose surgery was associated with severe morbidity (cohort 2), and those who transferred from a previous study of denosumab for GCTB (cohort 3). Patients in cohorts 1 and 2 received 120 mg of subcutaneous denosumab every 4 weeks with loading doses on days 8 and 15 of the first cycle; those in cohort 3 continued the regimen from the previous study. Investigator-determined disease status and clinical benefit were assessed every 4 weeks. Our primary endpoint was the safety profile of denosumab in terms of adverse events and laboratory abnormalities. Prespecified secondary endpoints were time to disease progression in cohort 1 and the proportion of patients without any surgery at 6 months in cohort 2. Safety analyses included all patients who received at least one dose of denosumab. Efficacy analyses included all eligible patients who received at least one dose of denosumab. This study is registered with, identifier NCT00680992. Findings: 282 patients, including ten adolescents, were included between Sept 9, 2008, and March 25, 2011. Of the 281 patients analysable for safety, three (1%) had osteonecrosis of the jaw and 15 (5%) hypocalcaemia. The most common grade 3-4 adverse events were hypophosphataemia, which occurred in nine (3%) patients, and anaemia, back pain, and pain in extremities, each of which occurred in three patients (1%). Serious adverse events were reported in 25 (9%) patients. No treatment-related deaths were reported. On the basis of investigators' assessment of disease status, 163 of 169 (96%) analysable patients in cohort 1 had no disease progression after median follow-up of 13 months (IQR 5·8-21·0). In cohort 2, 74 of 100 (74%) analysable patients had no surgery and 16 of 26 (62%) patients who had surgery underwent a less morbid procedure than planned. Median follow-up in cohort 2 was 9·2 months (IQR 4·2-12·9). Interpretation: Adverse events were consistent with the known safety profile of denosumab. Denosumab was associated with tumour responses and reduced the need for morbid surgery in patients with GCTB. Denosumab represents a new treatment option for patients with GCTB. Funding: Amgen. © 2013 Elsevier Ltd.

Chawla S.P.,Sarcoma Oncology Center | Chua V.S.,Sarcoma Oncology Center | Fernandez L.,Sarcoma Oncology Center | Quon D.,Sarcoma Oncology Center | And 4 more authors.
Molecular Therapy | Year: 2010

Rexin-G, a nonreplicative pathology-targeted retroviral vector bearing a cytocidal cyclin G1 construct, was tested in a phase I/II study for gemcitabine-resistant pancreatic cancer. The patients received escalating doses of Rexin-G intravenously from 1 × 10 11 colony-forming units (cfu) 2-3× a week (dose 0-1) to 2 × 10 11 cfu 3× a week (dose 2) for 4 weeks. Treatment was continued if there was less than or equal to grade 1 toxicity. No dose-limiting toxicity (DLT) was observed, and no vector DNA integration, replication-competent retrovirus (RCR), or vector-neutralizing antibodies were noted. In nine evaluable patients, 3/3 patients had stable disease (SD) at dose 0-1. At dose 2, 1/6 patients had a partial response (PR) and 5/6 patients had SD. Median progression-free survival (PFS) was 3 months at dose 0-1, and 7.65 months at dose 2. Median overall survival (OS) was 4.3 months at dose 0-1, and 9.2 months at dose 2. One-year survival was 0% at dose 0-1 compared to 28.6% at dose 2, suggesting a dose-response relationship between OS and Rexin-G dosage. Taken together, these data indicate that (i) Rexin-G is safe and well tolerated, and (ii) Rexin-G may help control tumor growth, and may possibly prolong survival in gemcitabine-resistant pancreatic cancer, thus, earning US Food and Drug Administration's (FDA) fast-track designation as second-line treatment for pancreatic cancer. © The American Society of Gene & Cell Therapy.

Chawla S.P.,Sarcoma Oncology Center | Staddon A.,University of Pennsylvania | Hendifar A.,Sarcoma Oncology Center | Messam C.A.,Glaxosmithkline | And 2 more authors.
BMC Cancer | Year: 2013

Background: The objective of this Phase I dose escalation study was to explore the safety and tolerability of eltrombopag, an oral, nonpeptide, thrombopoietin receptor agonist, in patients with advanced soft tissue sarcoma (STS) and thrombocytopenia due to treatment with doxorubicin and ifosfamide (AI) combination chemotherapy.Methods: Patients aged 18 or older with histologically confirmed, locally advanced or metastatic STS were treated with 1 cycle of AI followed by AI with eltrombopag starting at Cycle 2, using 2 different dosing schedules. The study design included an eltrombopag dose escalation phase starting at 75 mg daily to determine the optimal biological dose (OBD).Results: Eighteen patients were enrolled and 15 received at least 1 dose of chemotherapy; 3 patients withdrew prior to receiving eltrombopag. Seven, 4, and 1 patients received 75 mg, 100 mg, and 150 mg eltrombopag daily, respectively. No dose-limiting toxicities were reported. Due to slow recruitment, the study was closed prior to identifying an OBD. The most common hematologic adverse events (AEs) were thrombocytopenia (80%), neutropenia (73%), and anemia (67%). The most common nonhematologic AEs were fatigue (53%), alanine aminotransferase increased, constipation, and nausea (47% each). Eleven of 12 patients who received eltrombopag completed at least 2 chemotherapy cycles; all had increased platelet counts on Day 1 of Cycle 2 (cycle with eltrombopag) compared to Day 1 of Cycle 1 (cycle without eltrombopag).Conclusions: Although data are limited, safety data were consistent with the known toxicities of AI combination chemotherapy or the side effect profile of eltrombopag seen in other studies. Available data suggest a potential pre- and post-chemotherapy dosing scheme for eltrombopag when administered with AI chemotherapy, and support further investigation of eltrombopag treatment in patients with chemotherapy-induced thrombocytopenia. © 2013 Chawla et al.; licensee BioMed Central Ltd.

Thomas D.,Peter MacCallum Cancer Center | Henshaw R.,Georgetown University | Skubitz K.,Transplantation and Masonic Cancer Center | Chawla S.,Sarcoma Oncology Center | And 8 more authors.
The Lancet Oncology | Year: 2010

Background: Giant-cell tumour (GCT) of bone is a primary osteolytic bone tumour with low metastatic potential and is associated with substantial skeletal morbidity. GCT is rich in osteoclast-like giant cells and contains mononuclear (stromal) cells that express RANK ligand (RANKL), a key mediator of osteoclast activation. We investigated the potential therapeutic effect of denosumab, a fully human monoclonal antibody against RANKL, on tumour-cell survival and growth in patients with GCT. Methods: In this open-label, single-group study, 37 patients with recurrent or unresectable GCT were enrolled and received subcutaneous denosumab 120 mg monthly (every 28 days), with loading doses on days 8 and 15 of month 1. The primary endpoint was tumour response, defined as elimination of at least 90% of giant cells or no radiological progression of the target lesion up to week 25. Study recruitment is closed; patient treatment and follow-up are ongoing. The study is registered with Clinical, NCT00396279. Findings: Two patients had insufficient histology or radiology data for efficacy assessment. 30 of 35 (86%; 95% CI 70-95) of evaluable patients had a tumour response: 20 of 20 assessed by histology and 10 of 15 assessed by radiology. Adverse events were reported in 33 of 37 patients; the most common being pain in an extremity (n=7), back pain (n=4), and headache (n=4). Five patients had grade 3-5 adverse events, only one of which (grade 3 increase in human chorionic gonadotropin concentration not related to pregnancy) was deemed to be possibly treatment related. Five serious adverse events were reported although none were deemed treatment related. Interpretation: Further investigation of denosumab as a therapy for GCT is warranted. Funding: Amgen, Inc. © 2010 Elsevier Ltd. All rights reserved.

Federman N.,University of California at Los Angeles | Brien E.W.,Cedars Sinai Medical Center | Narasimhan V.,Sarcoma Oncology Center | Dry S.M.,University of California at Los Angeles | And 2 more authors.
Pediatric Drugs | Year: 2014

Giant cell tumor of bone (GCTB) is a rare primary bone tumor that primarily affects young adults, but can be seen in children. The primary modality of treatment is surgical resection; however, this is not always possible given the location and extent of the neoplasm. Recent developments in the understanding of the underlying molecular pathogenesis of disease have pointed to interactions between the stromal component producing receptor activator of nuclear factor-kappaB (RANK) and RANK-ligand (RANKL) causing the formation of osteoclast-like giant cells that drive bone destruction. The development of a monoclonal humanized antibody to RANKL, denosumab, has been shown to reduce skeletal-related events from osteoporosis and from bony metastases from solid tumors. Recent phase II clinical trials with denosumab in skeletally mature adolescents over age 12 years and adults with GCTB, have shown both safety and efficacy, leading to its accelerated US FDA approval on 13 June 2013. In children who are skeletally immature, safety and efficacy has not been established, and there has been only published anecdotal use. © Springer International Publishing 2013.

Singh A.S.,University of California at Los Angeles | Chawla N.S.,Sarcoma Oncology Center | Chawla S.P.,Sarcoma Oncology Center
Biologics: Targets and Therapy | Year: 2015

Giant-cell tumor of bone is a rare, locally aggressive tumor that typically occurs in the bones of skeletally mature young adults in their second to fourth decades. Traditionally, surgery has been the mainstay of therapy for this disease, but the disease can recur even with optimal procedures. Furthermore, it may occur in locations where a surgical approach would be morbid. The maturation of the understanding of the role of the receptor activator of nuclear factor-κB ligand (RANKL) in the pathophysiology of giant-cell tumor of bone has led to the use of denosumab, a monoclonal antibody against RANKL, in this disease. In 2013, the US Food and Drug Administration approved denosumab for use in patients with recurrent/unresectable/metastatic giant-cell tumor of bone or for patients in whom surgery would be morbid. © 2015 Singh et al.

Branstetter D.G.,Amgen Inc. | Nelson S.D.,University of California at Los Angeles | Manivel J.C.,University of Minnesota | Blay J.-Y.,University of Lyon | And 4 more authors.
Clinical Cancer Research | Year: 2012

Purpose: Giant-cell tumor of bone (GCTB) is a locally aggressive, benign osteolytic tumor in which bone destruction is mediated by RANK ligand (RANKL). The RANKL inhibitor denosumab is being investigated for treatment of GCTB. We describe histologic analyses of GCTB tumor samples from a phase II study of denosumab in GCTB. Experimental Design: Adult patients with recurrent or unresectable GCTB received subcutaneous denosumab 120 mg every 4 weeks (with additional doses on days 8 and 15). The primary histologic efficacy endpoint was the proportion of patientswhohad a90%or more elimination of giant cells from their tumor. Baseline and on-study specimens were also evaluated for overall tumor morphology and expression of RANK and RANKL. Results: Baseline tumor samples were typically composed of densely cellular proliferative RANKL-positive tumor stromal cells, RANK-positive rounded mononuclear cells, abundant RANK-positive tumor giant cells, and areas of scant de novo osteoid matrix and woven bone. In on-study samples from 20 of 20 patients (100%), a decrease of 90% or more in tumor giant cells and a reduction in tumor stromal cells were observed. In these analyses, thirteen patients (65%) had an increased proportion of dense fibro-osseous tissue and/or new woven bone, replacing areas of proliferative RANKL-positive stromal cells. Conclusions: Denosumab treatment of patients with GCTB significantly reduced or eliminated RANK-positive tumor giant cells.Denosumab also reduced the relative content of proliferative, densely cellular tumor stromal cells, replacing them with nonproliferative, differentiated, densely woven new bone. Denosumab continues to be studied as a potential treatment for GCTB. © 2012 AACR.

Sonis S.,Dana-Farber Cancer Institute | Sonis S.,Harvard University | Treister N.,Dana-Farber Cancer Institute | Treister N.,Harvard University | And 4 more authors.
Cancer | Year: 2010

BACKGROUND: Mammalian target of rapamycin (mTOR) inhibitors may have efficacy as an intervention for advanced malignancies. Oral ulceration (OU), reported as mucositis, has been a dose-limiting toxicity for this new class of agents. An analysis of the appearance, course, and toxicity associations of mTOR inhibitor-associated stomatitis (mIAS) demonstrated that the condition is distinct from conventional mucositis (CM) and more closely resembles aphthous stomatitis. METHODS: Safety data from 78 solid tumor patients enrolled in 2 Phase 1, multicenter trials of the mTOR inhibitor deforolimus (AP23573, MK-8669) were evaluated. Adverse events (AEs) based on National Cancer Institute Common Toxicity Criteria for National Cancer Institute Common Terminology Criteria for Adverse Events (version 3.0) criteria were coded, consolidated, and stratified according to the presence or absence and duration of concordant OU. The relation between OU and other AEs was analyzed. RESULTS: Treatment-emergent AEs were reported in 91% of 78 study participants. OUs were reported in 66%, appeared within 5 days of deforolimus administration, and were discrete, ovoid, superficial, well demarcated, and surrounded by an erythematous halo. Their clinical appearance and distribution were similar to that of aphthous stomatitis but inconsistent with CM. Patients with OU were more likely to have nonspecific rashes and acneiform dermatitis but not gastrointestinal AEs. CONCLUSIONS: OU associated with mTOR inhibitor therapy differed from CM. Lesions more closely resembled those of aphthous stomatitis. The lack of other gastrointestinal involvement but the presence of a higher incidence of concomitant cutaneous AEs provided additional evidence to suggest a distinction between mIAS and CM. Treatment strategies for aphthous stomatitis may be a rational approach for the prevention and control of mIAS. © 2010 American Cancer Society.

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