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News Article | May 10, 2017
Site: www.prnewswire.com

"Finally, we look forward to presenting the more detailed and updated global Phase 3 STS results to the medical community at the upcoming 2017 American Society of Clinical Oncology (ASCO) Annual Meeting.  This Phase 3 trial, along with the combination trial of aldoxorubicin with ifosfamide/mesna, continue to build upon the body of clinical data supporting aldoxorubicin's potential as a new and better treatment for patients with STS," Mr. Kriegsman commented. Strengthened the Balance Sheet with $15 Million in Financing and $2 Million in Warrant Proceeds.  In early May 2017, CytRx completed the sale of approximately 30 million shares of common stock in a public offering at a price of $0.50 per share, resulting in net proceeds to the Company of approximately $13.9 million after deducting placement agent's fees and other estimated offering expenses.  Additionally, the Company received approximately $1.9 million from the exercise of warrants resulting in a total raise of $15.8 million subsequent to March 31, 2017. Concluded Phase 3 Trial Evaluating Aldoxorubicin in Relapsed or Refractory STS.  Based on its goal to submit a rolling NDA, subject to approval from the FDA, the Company has concluded its Phase 3 study evaluating aldoxorubicin compared to investigator's choice in patients with relapsed or refractory STS. Aldoxorubicin Clinical Trial Data in Patients with STS Selected for Oral Presentation at the 2017 American Society of Clinical Oncology Annual Meeting (ASCO).  In April 2017, CytRx announced that an abstract describing results from its global Phase 3 clinical trial evaluating aldoxorubicin versus investigators' choice in patients with relapsed and refractory STS was selected for an oral presentation at ASCO 2017, taking place June 2-6, 2017 in Chicago.  The oral presentation (abstract #11000) will be given by Principal Investigator, Sant Chawla, M.D., F.R.A.C.P., Director of the Sarcoma Oncology Center in Santa Monica, on Friday, June 2, 2017 between 3:00-6:00 pm CT.  In addition to the STS presentation, a poster (abstract #11051) highlighting updated data from CytRx's ongoing Phase 1/2 clinical trial combining aldoxorubicin with ifosfamide/mesna in patients with first-line soft tissue sarcomas will also be presented by Frederick C. Eilber, M.D., Director of the UCLA Sarcoma Translational Research Program within the Jonsson Comprehensive Cancer Center, on Sunday, June 4, 2017 between 8:00-11:00 am CT. Announced FDA Agreement on Regulatory Pathway to Approval for Aldoxorubicin in STS.  In April 2017, CytRx announced that it had reached an agreement with the FDA on the pathway for a NDA submission for aldoxorubicin as a treatment for STS.  The Company's goal is to submit a rolling NDA under section 505(b)(2) to the FDA in the fourth quarter of 2017.  The commercial launch of aldoxorubicin is projected for 2018 in the U.S.  Aldoxorubicin has received Orphan Drug Designation from the FDA for the treatment of STS, which provides for several benefits including seven years of market exclusivity after approval, certain R&D related tax credits and protocol assistance from the FDA.  CytRx also plans to discuss with the European Medicines Agency a path to filing a Marketing Authorization Application.  European regulators granted aldoxorubicin Orphan Medicinal Product Designation for STS which confers ten years of market exclusivity among other benefits. On May 2, 2017, CytRx completed a public offering of 30 million shares of its common stock at a price of $0.50 per share.  The net proceeds to CytRx from the offering, after deducting placement agent's fees and other estimated offering expenses, were approximately $13.9 million.  In addition, CytRx received $1.9 million in proceeds from the exercise of warrants in April and May 2017. Net loss for the quarter ended March 31, 2017, was $11.0 million, or $(0.10) per share, compared with a net loss of $12.6 million, or $(0.19) per share, for the quarter ended March 31, 2016.  During the first quarter of 2017, the Company recognized a non-cash loss of $0.03 million on the fair value adjustment of warrant derivative liability related to warrants issued in 2016, compared to a non-cash loss of $0.2 million during the first quarter of 2016 related to now expired warrants. Research and development (R&D) expenses were $6.8 million for the first quarter of 2017, and included development expenses of $4.0 million for aldoxorubicin, approximately $0.6 million for pre-clinical development of new albumin-binding, ultra-high potency cancer drugs (German lab), and approximately $2.2 million for general operation of our clinical programs.  R&D expenses were $8.2 million for the first quarter of 2016. General and administrative (G&A) expenses were $3.0 million for the first quarter of 2017, compared with $4.0 million for the first quarter of 2016. CytRx Corporation is a biopharmaceutical research and development company specializing in oncology. CytRx currently is focused on the clinical development of aldoxorubicin, its improved version of the widely used chemotherapeutic agent doxorubicin.  CytRx is also expanding its pipeline of oncology candidates at its laboratory facilities in Freiburg, Germany, through its LADR™ (Linker Activated Drug Release) technology platform, a discovery engine designed to leverage CytRx's expertise in albumin biology and linker technology for the development of a new class of anti-cancer therapies. This press release contains forward-looking statements. Such statements are not promises or guarantees, and involve numerous risks and uncertainties that could cause actual events or results to differ materially from the events or results described in the forward-looking statements.  These risks include: the timing and final results of CytRx's clinical testing of aldoxorubicin; timing of CytRx's preparation and submission of an NDA for aldoxorubicin for the treatment of STS and FDA acceptance and review of any NDA; the risk that CytRx may be unsuccessful in obtaining FDA approval or, if approval is obtained, in commercializing aldoxorubicin in the United States or elsewhere; risks related to CytRx's need for and ability to raise additional capital or enter into strategic partnerships to fund its ongoing working capital needs and development efforts; risks related to CytRx's ability to manufacture its drug candidates in a timely fashion, cost-effectively or in commercial quantities in compliance with stringent regulatory requirements; risks relating to preclinical testing of CytRx's LADR™ linker technology platform; risks related to pending lawsuits against CytRx and its officers and directors; and the other risks and uncertainties described in CytRx's Annual Report on Form 10-K for the year ended December 31, 2016 filed with the Securities and Exchange Commission. All forward-looking statements are based upon information available to CytRx on the date the statements are first published. CytRx undertakes no obligation to publicly update or revise any forward-looking statements, whether as a result of new information, future events or otherwise. To view the original version on PR Newswire, visit:http://www.prnewswire.com/news-releases/cytrx-reports-first-quarter-2017-financial-results-300455045.html


Daniel Levitt, M.D., Ph.D., Chief Operating Officer and Chief Medical Officer of CytRx, commented, "The data from both of these important clinical trials evaluating aldoxorubicin in sarcomas, along with our several other completed clinical and preclinical studies, will form the basis of our planned New Drug Application submission to the U.S. Food and Drug Administration, and we are pleased to share these more mature and detailed results in this peer-reviewed forum with the medical and scientific communities." Details for the presentations at ASCO 2017: Title: Phase III study of aldoxorubicin vs investigators' choice as treatment for relapsed/refractory soft tissue sarcomas Presenter: Sant Chawla, M.D., F.R.A.C.P., Director of the Sarcoma Oncology Center in Santa Monica, and Principal Investigator Abstract #: 11000 Session Title: Oral Abstract Session: Sarcoma Location: S100bc Date and Time: Friday, June 2, 2017; 3:00pm-6:00pm CT Summary:  This multicenter, randomized, open-label Phase 3 trial enrolled 433 patients at 79 sites.  The data summarized here are as of August 2016.  In patients with leiomyosarcoma and liposarcoma (n=246), aldoxorubicin demonstrated median progression-free survival (PFS) of 5.32 months, compared to a median PFS of 2.96 months for investigator's choice therapy, a statistically significant improvement of 2.36 months (p=0.007; hazard ratio (HR)=0.62, 95% CI 0.44-0.88), representing a 38% reduction in the risk of tumor progression.  In patients treated in North America plus Australia (n=312), aldoxorubicin demonstrated a median PFS of 4.21 months, compared to a median PFS of 2.96 months for investigator's choice therapy, a statistically significant improvement of 1.25 months (p=0.023, HR=0.71, 95% CI 0.53-0.96).  In the overall intent to treat (ITT) trial population (n=433), aldoxorubicin performed better than investigator's choice demonstrating a median PFS of 4.11 months, compared to a median PFS of 2.96 months for investigator's choice therapy, narrowly missing statistical significance (p=0.087; HR=0.81, 95% CI 0.64-1.03).  All responses in this study were determined by an independent, blinded central lab assessment of scans. Key safety findings included that aldoxorubicin caused no clinically significant cardiac, renal, or hepatic toxicities.  Aldoxorubicin administered at 350mg/m2 per cycle showed no cardiotoxicity up to 40 cycles.  Importantly, left ventricular ejection fraction (LVEF) below 50% of expected values were reported in 4.2% of patients treated with aldoxorubicin, compared to 19.1% for patients receiving investigator's choice.  Additionally, ≥20% decreases in LVEF from baseline were reported in 3.8% of patients treated with aldoxorubicin, compared to 8.5% for patients receiving investigator's choice.  For the global trial population, the most commonly reported (≥10%) Grade ≥3 adverse events were neutropenia, anemia, febrile neutropenia, stomatitis and decreased white blood cell count, and were manageable with standard supportive care.  The non-cardiac Grade ≥3 adverse events associated with aldoxorubicin were similar to doxorubicin despite exposure up to 3-4 times the standard doxorubicin dose. Updated data relating to the trials other secondary endpoints, including objective response rate (ORR), disease control rate (DCR), overall survival, and other safety parameters were in line with what has previously been reported by CytRx and will be included in the oral presentation being given at ASCO 2017. Following conclusion of Dr. Chawla's presentation, a PDF copy of the oral presentation slides will be available at http://cytrx.com/investors/presentations. Title: Administration of aldoxorubicin and 14 days continuous infusion of ifosfamide/Mesna in metastatic or locally advanced sarcomas Presenter: Frederick C. Eilber, M.D., Director of the UCLA Sarcoma Translational Research Program within the Jonsson Comprehensive Cancer Center Abstract #: 11051 Session Title: Poster Session: Sarcoma Location: Hall A Poster board#: 374 Date and Time:  Sunday, June 4, 2017; 8:00am-11:30am CT Summary:  This ongoing open-label Phase 1/2 clinical trial is designed to assess the preliminary safety and activity of aldoxorubicin plus I-M as a first- or second-line treatment in patients with STS.  Patients were administered 1 of 2 dose levels of aldoxorubicin (170mg/m2 or 250mg/m2 [125mg/m2 or 185mg/m2 doxorubicin equivalent]) on Day 1, then I-M (1g/m2 of each per day) was administered for up to 14 days as a continuous infusion.  Chemotherapy cycles were repeated at 28 day intervals, but I-M was limited to a maximum of 6 cycles to avoid cumulative bone marrow toxicity.  Aldoxorubicin was continued per investigator decision in either responding or stable disease (SD) patients.  Patients were followed for tumor response by CT scans and echocardiogram for cardiac toxicity every 8 weeks along with standard labs. Of the 44 evaluable patients as of May 10, 2017, 16 patients (36%) achieved a partial response (PR), 25 patients (57%) achieved SD, with 20 patients (45%) achieving SD for ≥4 months, for an overall disease control rate (DCR) of 82% (PR+SD≥4).  Twenty-two of 44 (50%) patients received at least 6 cycles of aldoxorubicin (>1,300 mg/m2 cumulative doxorubicin equivalent).  As of the data cutoff date, the median PFS had not been reached.  The most commonly reported Grade ≥3 adverse event (AEs; >20%) were neutropenia and anemia.  Reported serious adverse events (SAEs) included febrile neutropenia (14%, n=6), anemia (5%, n=2), thrombocytopenia (2%, n=1), stomatitis (2%, n=1) and pyrexia (2%, n=1).  No clinically significant cardiotoxicity has been observed and no patients had a clinically significant decrease in LVEF or QTc prolongation, despite administration of median cumulative doses of doxorubicin equivalents of 1364-1965mg/m2.  No treatment related deaths occurred.  These results support the thesis that aldoxorubicin can be administered safely and for prolonged periods with continuous infusion I-M and achieves high response rates and SD, with substantial tumor necrosis.  Based on these results, the decision was made to stop further aldoxorubicin dose escalation and continue to enroll only in the 250mg/m2 cohort. Following conclusion of the poster presentation, a PDF copy of the poster will be available at http://cytrx.com/investors/presentations. Soft tissue sarcoma is a cancer occurring in muscle, fat, blood vessels, tendons, fibrous tissues and connective tissue.  It can arise anywhere in the body at any age.  STS remains a high unmet medical need because of the difficulty in treating the more than 50 types of this aggressive cancer.  According to the American Cancer Society, in 2016 more than 12,300 new cases were diagnosed in the U.S. and approximately 5,000 Americans died from this disease.  In addition, approximately 40,000 new cases and 13,000 deaths in the U.S. and Europe are part of a growing underserved market. Aldoxorubicin is a rationally-engineered cytotoxic which combines doxorubicin, a widely used chemotherapeutic agent, with a novel linker molecule that binds directly and specifically to circulating albumin, the most abundant protein in the bloodstream.  Protein-hungry tumors concentrate albumin, which facilitates the delivery of the linker molecule with the attached doxorubicin to tumor sites.  In the acidic environment of the tumor, but not the neutral environment of healthy tissues, doxorubicin is released. Typically, doxorubicin is delivered systemically and is highly toxic, which limits its dose to a level below its maximum therapeutic benefit. Doxorubicin also is associated with many side effects, especially the potential for damage to heart muscle at cumulative doses greater than 450 mg/m2. Using this acid-sensitive linker technology, aldoxorubicin delivers greater doses of doxorubicin (3 ½ to 4 times). To date, there has been no evidence of clinically significant effects of aldoxorubicin on heart muscle, even at cumulative doses of drug well in excess of 6,500 mg/m2 of doxorubicin equivalents. Aldoxorubicin is the first-ever single agent to show superiority over doxorubicin in a randomized clinical trial in first-line STS. CytRx Corporation is a biopharmaceutical research and development company specializing in oncology. CytRx currently is focused on the clinical development of aldoxorubicin, its improved version of the widely used chemotherapeutic agent doxorubicin.  CytRx is also expanding its pipeline of oncology candidates at its laboratory facilities in Freiburg, Germany, through its LADR™ (Linker Activated Drug Release) technology platform, a discovery engine designed to leverage CytRx's expertise in albumin biology and linker technology for the development of a new class of anti-cancer therapies. This press release contains forward-looking statements. Such statements involve risks and uncertainties that could cause actual events or results to differ materially from the events or results described in the forward-looking statements, including risks and uncertainties relating to the preparation and submission of an NDA for aldoxorubicin for the treatment of STS and FDA acceptance and review of any NDA, the risk that CytRx may be unsuccessful in obtaining FDA approval or, if approval is obtained, in commercializing aldoxorubicin in the United States or elsewhere, and other risks and uncertainties described in the most recent annual and quarterly reports filed by CytRx with the Securities and Exchange Commission and current reports filed since the date of CytRx's most recent annual report. All forward-looking statements are based upon information available to CytRx on the date the statements are first published. CytRx undertakes no obligation to publicly update or revise any forward-looking statements, whether as a result of new information, future events or otherwise. To view the original version on PR Newswire, visit:http://www.prnewswire.com/news-releases/cytrx-to-present-global-phase-3-aldoxorubicin-clinical-data-in-patients-with-soft-tissue-sarcomas-at-the-2017-american-society-of-clinical-oncology-annual-meeting-300459626.html


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. ClinicalTrials.gov: 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 ClinicalTrials.gov, 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 Trials.gov, 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.


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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