Arthur Staddon - Academia.edu (original) (raw)

Papers by Arthur Staddon

Research paper thumbnail of Efficacy and safety of stereotactic body radiation therapy for the treatment of pulmonary metastases from sarcoma: A potential alternative to resection

Journal of surgical oncology, 2016

Oligometastatic sarcoma pulmonary metastases (PM) are typically treated with resection and/or che... more Oligometastatic sarcoma pulmonary metastases (PM) are typically treated with resection and/or chemotherapy. We hypothesize that stereotactic body radiotherapy (SBRT) can be an alternative to surgery that can achieve high rates of local control (LC) with limited toxicity. Thirty consecutive sarcoma patients received SBRT to 39 PM's from 2011 to 2015 at two university hospitals to a median dose of 50 Gy in 4-5 fractions with CyberKnife or linear accelerator. Patients underwent CT or PET/CT scans q3 months after SBRT. 77% received prior chemotherapy, 70% had 1-3 prior pulmonary resections, and 26% received prior thoracic radiotherapy. Median lesion size was 2.4 cm (range 0.5-8.1 cm). Median follow-up was 16 and 23 months for patients alive at last follow-up. At 12 and 24 months, LC was 94% and 86%, and OS was 76% and 43%. LC and OS did not differ by SBRT technique, fractionation regimen, lesion location, histology, or size (all P > 0.05). Three developed grade 2 chest-wall toxic...

Research paper thumbnail of Activated c-Met; a Potential Therapeutic Target in Chordoma

American Journal of Clinical Pathology, 2012

Research paper thumbnail of Denosumab in patients with giant-cell tumour of bone: an open-label, phase 2 study

Data Revues 14702045 V11i3 S1470204510700103, Sep 26, 2012

Giant-cell tumour (GCT) of bone is a primary osteolytic bone tumour with low metastatic potential... more 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. 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. 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. Further investigation of denosumab as a therapy for GCT is warranted. Amgen, Inc.

Research paper thumbnail of Ombrabulin plus cisplatin versus placebo plus cisplatin in patients with advanced soft-tissue sarcomas after failure of anthracycline and ifosfamide chemotherapy: a randomised, double-blind, placebo-controlled, phase 3 trial

The Lancet Oncology, 2015

Ombrabulin (AVE8062) disrupts the vasculature of established tumours and has shown preclinical sy... more Ombrabulin (AVE8062) disrupts the vasculature of established tumours and has shown preclinical synergistic anti-tumour activity when combined with cisplatin. In this phase 3 trial, we aimed to assess the efficacy and safety of ombrabulin plus cisplatin compared with placebo plus cisplatin in patients with advanced soft-tissue sarcomas. We did this multinational, randomised, double-blind, placebo-controlled phase 3 study at 44 centres in ten countries. Patients aged 18 years and older with metastatic soft-tissue sarcomas, an Eastern Cooperative Oncology Group performance status of 0-2, and who had previously received treatment with anthracycline and ifosfamide were randomly assigned (1:1) to intravenous infusion of ombrabulin 25 mg/m(2) plus cisplatin 75 mg/m(2) or intravenous infusion of placebo plus cisplatin 75 mg/m(2) every 3 weeks. Patients were allocated to treatment using a permuted blocks randomisation scheme (block size of four) via an interactive voice-response system, and stratified by histological subtype. Patients, medical staff, study investigators, and individuals who handled and analysed the data were masked to treatment assignment. Our primary endpoint was median progression-free survival in the intention-to-treat population. Safety analyses were done on all randomised patients who received at least one dose of study drug. This trial is now closed, and is registered with ClinicalTrials.gov, number NCT00699517. Between June 13, 2008, and April 26, 2012, we randomly assigned 355 patients to ombrabulin plus cisplatin (n=176) or placebo plus cisplatin (n=179). Median duration of follow-up was 27·9 (IQR 20·9-33·2) in the placebo group and 30·5 months (20·7-37·6) in the ombrabulin group. Progression-free survival was slightly, but significantly, improved in the ombrabulin group compared with the placebo group (median 1·54 months [95% CI 1·45-2·69] vs 1·41 [1·38-1·58] months; hazard ratio 0·76 [95% CI 0·59-0·98]; p=0·0302). Grade 3 or 4 adverse events occurred more frequently in individuals in the ombrabulin group than in those in the placebo group and included neutropenia (34 [19%] in the ombrabulin group vs 14 [8%] in the placebo group) and thrombocytopenia (15 [8%] vs six [3%] for placebo). Adverse events leading to death occurred in 18 patients in the ombrabulin group and 10 patients in the placebo group. The combination of ombrabulin and cisplatin significantly improved progression-free survival; however, it did not show a sufficient clinical benefit in patients with advanced soft-tissue sarcomas to support its use as a therapeutic option. Predictive biomarkers are needed for the rational clinical development of tumour vascular-disrupting drugs for soft-tissue sarcomas. Sanofi.

Research paper thumbnail of Chronic low dose-intensity pegylated liposomal doxorubicin for advanced malignancies

Community Oncology, 2007

A retrospective analysis was conducted to evaluate the tolerability and effectiveness of pegylate... more A retrospective analysis was conducted to evaluate the tolerability and effectiveness of pegylated liposomal doxorubicin (PLD) in patients with advanced malignancies. Eighty patients received an initial dose of PLD of 20 mg/m² every 2 weeks (Q2W), including 47 with Kaposi's sarcoma (KS), 9 with hematologic tumors, and 24 with solid tumors. The median cumulative dose of PLD was 230 mg/m² (range, 20-2,320 mg/m²). PLD appeared to be effective in 94%, 46%, and 56% of patients with KS, solid tumors, and hematologic tumors, respectively. The rates of adverse events commonly reported with PLD were 31% for nausea, 21% for neutropenia, and 14% for thrombocytopenia. Most events were mild to moderate. No clinical signs or symptoms of cardiotoxicity were reported. Six percent of patients had mucositis (all grades), and 6% had hand-foot syndrome (all grades). Chronic low dose-intensity PLD has a good therapeutic index, and prospective tumor-specific studies further evaluating this regimen are warranted.

Research paper thumbnail of Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial

The Lancet, 2012

Background Pazopanib, a multitargeted tyrosine kinase inhibitor, has single-agent activity in pat... more Background Pazopanib, a multitargeted tyrosine kinase inhibitor, has single-agent activity in patients with advanced non-adipocytic soft-tissue sarcoma. We investigated the eff ect of pazopanib on progression-free survival in patients with metastatic non-adipocytic soft-tissue sarcoma after failure of standard chemotherapy.

Research paper thumbnail of Phase II Trial of Oral Rubitecan in Previously Treated Pancreatic Cancer Patients

The Oncologist, 2005

Additional systemic treatments for locally advanced or metastatic pancreatic cancer are needed, a... more Additional systemic treatments for locally advanced or metastatic pancreatic cancer are needed, as current treatment options produce only modest survival benefits. Rubitecan (Orathecin ™ ; Supergen Inc., Dublin, CA, http://www.supergen.com) is an orally active camptothecin derivative with demonstrated responses in patients with pancreatic cancer in early clinical trials. This phase II, open-label trial was developed to assess the safety and efficacy of rubitecan in patients with locally advanced or metastatic pancreatic cancer refractory to conventional chemotherapy.

Research paper thumbnail of Osteogenic Sarcoma Presenting with Lung Metastasis

The Oncologist, 2002

A patient with osteogenic sarcoma presenting with lung metastases is discussed with attention to ... more A patient with osteogenic sarcoma presenting with lung metastases is discussed with attention to appropriate diagnosis, staging, and treatment. Multimodality treatment options using chemotherapy, orthopedic surgery and thoracic surgery are presented. Physical medicine and rehabilitation evaluation and treatment are included. Current research options are discussed. The Oncologist

Research paper thumbnail of Phospho-S6 ribosomal protein: a potential new predictive sarcoma marker for targeted mTOR therapy

Modern Pathology, 2008

Metastatic sarcomas are commonly resistant to chemotherapy. The serine/threonine kinase, mammalia... more Metastatic sarcomas are commonly resistant to chemotherapy. The serine/threonine kinase, mammalian target of rapamycin (mTOR), is a protein kinase of the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway thought to have a key role in controlling cancer growth and thus is an important target for cancer therapy. Several inhibitors of mTOR are in clinical trials, including AP23573, which is being tested on metastatic sarcomas and other tumors. We hypothesized that a marker for the activity of mTOR, phosphorylated S6 ribosomal protein, would be predictive of clinical response to the drug, that is, high tumor expression would signify better response than low expression. This was a blinded study. Of 26 patients treated, 20 remained on study, with available paraffin blocks. Fourteen patients received AP23573 alone and six patients received AP23573 in combination with adriamycin. An antibody to the phosphorylated S6 ribosomal protein was used to stain the tumors, all high-grade sarcomas. Pretreatment biopsy or resection material was tested: the original tumor (n ¼ 6) or tumor recurrence/metastasis (n ¼ 14); either of these may have been after treatment with other agents. Staining was scored for both quantity/percentage of tumor cells and intensity. Scoring was performed without knowledge of tumor response. Staining quantity could be categorized into two natural groups: high expressors (Z20% of tumor cells, 11 cases) and low expressors (0-10% of tumor cells, 9 cases). The highexpression group had eight stable and three progressive cases (73% stable disease); the low-expression group had three stable and six progressive cases (67% progressive disease). Chi-square analysis showed statistical significance (Pr0.05) at this initial cutoff (10%) selected blindly. The level of phosphorylated S6 ribosomal protein expression was predictive of early tumor response to the mTOR inhibitor, suggesting that this is a promising new predictive sarcoma marker for targeted mTOR inhibitor therapy.

Research paper thumbnail of Improved Survival after Pulmonary Metastasectomy for Soft Tissue Sarcoma

Journal of Thoracic Oncology, 2011

Research paper thumbnail of Phase II Study of the Mammalian Target of Rapamycin Inhibitor Ridaforolimus in Patients With Advanced Bone and Soft Tissue Sarcomas

Journal of Clinical Oncology, 2012

Ridaforolimus is an inhibitor of mammalian target of rapamycin, an integral component of the phos... more Ridaforolimus is an inhibitor of mammalian target of rapamycin, an integral component of the phosphatidyl 3-kinase/AKT signaling pathway, with early evidence of activity in sarcomas. This multicenter, open-label, single-arm, phase II trial was conducted to assess the antitumor activity of ridaforolimus in patients with distinct subtypes of advanced sarcomas.

Research paper thumbnail of Results of an International Randomized Phase III Trial of the Mammalian Target of Rapamycin Inhibitor Ridaforolimus Versus Placebo to Control Metastatic Sarcomas in Patients After Benefit From Prior Chemotherapy

Journal of Clinical Oncology, 2013

Aberrant mammalian target of rapamycin (mTOR) signaling is common in sarcomas and other malignanc... more Aberrant mammalian target of rapamycin (mTOR) signaling is common in sarcomas and other malignancies. Drug resistance and toxicities often limit benefits of systemic chemotherapy used to treat metastatic sarcomas. This large randomized placebo-controlled phase III trial evaluated the mTOR inhibitor ridaforolimus to assess maintenance of disease control in advanced sarcomas. Patients with metastatic soft tissue or bone sarcomas who achieved objective response or stable disease with prior chemotherapy were randomly assigned to receive ridaforolimus 40 mg or placebo once per day for 5 days every week. Primary end point was progression-free survival (PFS); secondary end points included overall survival (OS), best target lesion response, safety, and tolerability. A total of 711 patients were enrolled, and 702 received blinded study drug. Ridaforolimus treatment led to a modest, although significant, improvement in PFS per independent review compared with placebo (hazard ratio [HR], 0.72; 95% CI, 0.61 to 0.85; P = .001; median PFS, 17.7 v 14.6 weeks). Ridaforolimus induced a mean 1.3% decrease in target lesion size versus a 10.3% increase with placebo (P < .001). Median OS with ridaforolimus was 90.6 weeks versus 85.3 weeks with placebo (HR, 0.93; 95% CI, 0.78 to 1.12; P = .46). Adverse events (AEs) more common with ridaforolimus included stomatitis, infections, fatigue, thrombocytopenia, noninfectious pneumonitis, hyperglycemia, and rash. Grade ≥ 3 AEs were more common with ridaforolimus than placebo (64.1% v 25.6%). Ridaforolimus delayed tumor progression to a small statistically significant degree in patients with metastatic sarcoma who experienced benefit with prior chemotherapy. Toxicities were observed with ridaforolimus, as expected with mTOR inhibition. These data provide a foundation on which to further improve control of sarcomas.

Research paper thumbnail of Effect of trabectedin on the QT interval in patients with advanced solid tumor malignancies

Cancer Chemotherapy and Pharmacology, 2012

Purpose The primary objective of this study was to access the potential eVects of trabectedin on ... more Purpose The primary objective of this study was to access the potential eVects of trabectedin on the QT/QTc interval in patients with locally advanced or metastatic solid tumors. Methods Patients (n = 75) who had received ·3 previous lines of chemotherapy and had either relapsed or had progressive disease were enrolled. Patients were administered 3-h intravenous infusions of placebo (saline) on day 1 and trabectedin (1.3 mg/m 2 ) on day 2. Time-matched serial triplicate ECG recordings and pharmacokinetic blood samples were collected over 24 h on both days. Heart rate corrected mean QT intervals and changes from predose baseline in QTc ( QTc) were assessed. The diVerence in QTc between trabectedin and placebo was calculated at each time point ( QTc).

Research paper thumbnail of Results of a phase I dose escalation study of eltrombopag in patients with advanced soft tissue sarcoma receiving doxorubicin and ifosfamide

BMC Cancer, 2013

Background: The objective of this Phase I dose escalation study was to explore the safety and tol... more 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.

Research paper thumbnail of Chemotherapy treatment patterns and clinical outcomes in patients with metastatic soft tissue sarcoma. The SArcoma treatment and Burden of Illness in North America and Europe (SABINE) study

Annals of Oncology, 2012

To describe chemotherapy treatment patterns and clinical outcomes in metastatic soft tissue sarco... more To describe chemotherapy treatment patterns and clinical outcomes in metastatic soft tissue sarcoma (mSTS) patients with favorable response to chemotherapy. Multicenter (25) multi-country (9) retrospective chart review of mSTS patients with favorable response to chemotherapy, defined as stable disease or better following four cycles. Two hundred and thirteen patients (58% female; mean age 54.7 years) received a mean of 2.7 lines of chemotherapy and 5.2 cycles per line. The most common first-line regimens were doxorubicin (34%) and anthracycline plus ifosfamide (30%). Favorable response was achieved by 83% to first-line and 42% and 38% in second- and third-line chemotherapy. The most common reason for chemotherapy discontinuation in lines with a favorable response was reaching a predefined number of cycles in first line (64% of 213) and disease progression in second or later lines (41% of 138). The mean time off chemotherapy was 38.0 weeks after first line, falling to 2.7-6.4 weeks in second or later lines. Median overall and progression-free survival were 23.5 (95% confidence interval 20.5-28.1) and 8.3 (7.4-9.9) months from first favorable response to chemotherapy. mSTS patients achieving favorable response to chemotherapy have poor outcomes. Additional treatment options are needed.

Research paper thumbnail of Denosumab in patients with giant-cell tumour of bone: an open-label, phase 2 study

The Lancet Oncology, 2010

Giant-cell tumour (GCT) of bone is a primary osteolytic bone tumour with low metastatic potential... more 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. 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. 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. Further investigation of denosumab as a therapy for GCT is warranted. Amgen, Inc.

Research paper thumbnail of Phase 2 study of dasatinib in patients with alveolar soft part sarcoma, chondrosarcoma, chordoma, epithelioid sarcoma, or solitary fibrous tumor

Cancer, Jan 3, 2016

Alveolar soft part sarcoma (ASPS), chondrosarcoma (CS), chordoma, epithelioid sarcoma, and solita... more Alveolar soft part sarcoma (ASPS), chondrosarcoma (CS), chordoma, epithelioid sarcoma, and solitary fibrous tumor (SFT) are malignant tumors that are relatively resistant to chemotherapy and for which more effective drug therapy is needed. The 5 listed subtypes were enrolled into a single indolent sarcoma cohort in a phase 2 study of dasatinib using a Bayesian continuous monitoring rule for enrollment. The primary objective was to estimate the 6-month progression-free survival (PFS) rate according to the Choi criteria with a target of ≥50%. Cross-sectional imaging was performed before the start of treatment, every 2 months for 6 months, and then every 3 months during treatment. The 2- and 5-year survival rates were determined. One hundred sixteen patients were enrolled within 45 months, and 109 began treatment with dasatinib. The 6-month PFS rate and the median PFS were 48% and 5.8 months, respectively. The PFS rate at 6 months was highest with ASPS (62%) and lowest with SFT (30%). ...

Research paper thumbnail of Severe, irreversible renal failure after ifosfamide treatment. A clinicopathologic report of two patients

Cancer, Aug 1, 1995

tive doses of ifosfamide nor prior cisplatin treatment are necessary for this toxicity to occur. ... more tive doses of ifosfamide nor prior cisplatin treatment are necessary for this toxicity to occur. Because a rising serum creatinine may develop months after completion of treatment with ifosfamide, renal function should be monitored closely both during and after ifosfamide treatment. Cancer 1995; 76:497-500.

Research paper thumbnail of Phase ii study of weekly docetaxel (Doc) and gemcitabine (Gem) in relapsed patients (Pts) with advanced, platinum???exposed non???small cell lung cancer (NSCLC): P2-275

Research paper thumbnail of SARC009: Phase 2 study of dasatinib in patients with previously treated, high-grade, advanced sarcoma

Cancer, Jan 28, 2015

Dasatinib exhibited activity in preclinical models of sarcoma. The Sarcoma Alliance for Research ... more Dasatinib exhibited activity in preclinical models of sarcoma. The Sarcoma Alliance for Research through Collaboration (SARC) conducted a multicenter, phase 2 trial of dasatinib in patients with advanced sarcoma. Patients received dasatinib twice daily. The primary objective was to estimate the clinical benefit rate (CBR) (complete response or partial response within 6 months or stable disease duration of ≥6 months) with a target of ≥25%. Patients were enrolled into 1 of 7 different cohorts and assessed by imaging every 8 weeks using Choi criteria tumor response and a Bayesian hierarchical design. For each subtype, enrollment was stopped after a minimum of 9 patients were treated if there was a <1% chance the CBR was ≥25%. A total of 200 patients were enrolled. Accrual was stopped early in 5 cohorts because of low CBR. The leiomyosarcoma (LMS) and undifferentiated pleomorphic sarcoma (UPS) cohorts fully accrued and 6 of 47 and 8 of 42 evaluable patients, respectively, exhibited c...

Research paper thumbnail of Efficacy and safety of stereotactic body radiation therapy for the treatment of pulmonary metastases from sarcoma: A potential alternative to resection

Journal of surgical oncology, 2016

Oligometastatic sarcoma pulmonary metastases (PM) are typically treated with resection and/or che... more Oligometastatic sarcoma pulmonary metastases (PM) are typically treated with resection and/or chemotherapy. We hypothesize that stereotactic body radiotherapy (SBRT) can be an alternative to surgery that can achieve high rates of local control (LC) with limited toxicity. Thirty consecutive sarcoma patients received SBRT to 39 PM's from 2011 to 2015 at two university hospitals to a median dose of 50 Gy in 4-5 fractions with CyberKnife or linear accelerator. Patients underwent CT or PET/CT scans q3 months after SBRT. 77% received prior chemotherapy, 70% had 1-3 prior pulmonary resections, and 26% received prior thoracic radiotherapy. Median lesion size was 2.4 cm (range 0.5-8.1 cm). Median follow-up was 16 and 23 months for patients alive at last follow-up. At 12 and 24 months, LC was 94% and 86%, and OS was 76% and 43%. LC and OS did not differ by SBRT technique, fractionation regimen, lesion location, histology, or size (all P > 0.05). Three developed grade 2 chest-wall toxic...

Research paper thumbnail of Activated c-Met; a Potential Therapeutic Target in Chordoma

American Journal of Clinical Pathology, 2012

Research paper thumbnail of Denosumab in patients with giant-cell tumour of bone: an open-label, phase 2 study

Data Revues 14702045 V11i3 S1470204510700103, Sep 26, 2012

Giant-cell tumour (GCT) of bone is a primary osteolytic bone tumour with low metastatic potential... more 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. 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. 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. Further investigation of denosumab as a therapy for GCT is warranted. Amgen, Inc.

Research paper thumbnail of Ombrabulin plus cisplatin versus placebo plus cisplatin in patients with advanced soft-tissue sarcomas after failure of anthracycline and ifosfamide chemotherapy: a randomised, double-blind, placebo-controlled, phase 3 trial

The Lancet Oncology, 2015

Ombrabulin (AVE8062) disrupts the vasculature of established tumours and has shown preclinical sy... more Ombrabulin (AVE8062) disrupts the vasculature of established tumours and has shown preclinical synergistic anti-tumour activity when combined with cisplatin. In this phase 3 trial, we aimed to assess the efficacy and safety of ombrabulin plus cisplatin compared with placebo plus cisplatin in patients with advanced soft-tissue sarcomas. We did this multinational, randomised, double-blind, placebo-controlled phase 3 study at 44 centres in ten countries. Patients aged 18 years and older with metastatic soft-tissue sarcomas, an Eastern Cooperative Oncology Group performance status of 0-2, and who had previously received treatment with anthracycline and ifosfamide were randomly assigned (1:1) to intravenous infusion of ombrabulin 25 mg/m(2) plus cisplatin 75 mg/m(2) or intravenous infusion of placebo plus cisplatin 75 mg/m(2) every 3 weeks. Patients were allocated to treatment using a permuted blocks randomisation scheme (block size of four) via an interactive voice-response system, and stratified by histological subtype. Patients, medical staff, study investigators, and individuals who handled and analysed the data were masked to treatment assignment. Our primary endpoint was median progression-free survival in the intention-to-treat population. Safety analyses were done on all randomised patients who received at least one dose of study drug. This trial is now closed, and is registered with ClinicalTrials.gov, number NCT00699517. Between June 13, 2008, and April 26, 2012, we randomly assigned 355 patients to ombrabulin plus cisplatin (n=176) or placebo plus cisplatin (n=179). Median duration of follow-up was 27·9 (IQR 20·9-33·2) in the placebo group and 30·5 months (20·7-37·6) in the ombrabulin group. Progression-free survival was slightly, but significantly, improved in the ombrabulin group compared with the placebo group (median 1·54 months [95% CI 1·45-2·69] vs 1·41 [1·38-1·58] months; hazard ratio 0·76 [95% CI 0·59-0·98]; p=0·0302). Grade 3 or 4 adverse events occurred more frequently in individuals in the ombrabulin group than in those in the placebo group and included neutropenia (34 [19%] in the ombrabulin group vs 14 [8%] in the placebo group) and thrombocytopenia (15 [8%] vs six [3%] for placebo). Adverse events leading to death occurred in 18 patients in the ombrabulin group and 10 patients in the placebo group. The combination of ombrabulin and cisplatin significantly improved progression-free survival; however, it did not show a sufficient clinical benefit in patients with advanced soft-tissue sarcomas to support its use as a therapeutic option. Predictive biomarkers are needed for the rational clinical development of tumour vascular-disrupting drugs for soft-tissue sarcomas. Sanofi.

Research paper thumbnail of Chronic low dose-intensity pegylated liposomal doxorubicin for advanced malignancies

Community Oncology, 2007

A retrospective analysis was conducted to evaluate the tolerability and effectiveness of pegylate... more A retrospective analysis was conducted to evaluate the tolerability and effectiveness of pegylated liposomal doxorubicin (PLD) in patients with advanced malignancies. Eighty patients received an initial dose of PLD of 20 mg/m² every 2 weeks (Q2W), including 47 with Kaposi's sarcoma (KS), 9 with hematologic tumors, and 24 with solid tumors. The median cumulative dose of PLD was 230 mg/m² (range, 20-2,320 mg/m²). PLD appeared to be effective in 94%, 46%, and 56% of patients with KS, solid tumors, and hematologic tumors, respectively. The rates of adverse events commonly reported with PLD were 31% for nausea, 21% for neutropenia, and 14% for thrombocytopenia. Most events were mild to moderate. No clinical signs or symptoms of cardiotoxicity were reported. Six percent of patients had mucositis (all grades), and 6% had hand-foot syndrome (all grades). Chronic low dose-intensity PLD has a good therapeutic index, and prospective tumor-specific studies further evaluating this regimen are warranted.

Research paper thumbnail of Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial

The Lancet, 2012

Background Pazopanib, a multitargeted tyrosine kinase inhibitor, has single-agent activity in pat... more Background Pazopanib, a multitargeted tyrosine kinase inhibitor, has single-agent activity in patients with advanced non-adipocytic soft-tissue sarcoma. We investigated the eff ect of pazopanib on progression-free survival in patients with metastatic non-adipocytic soft-tissue sarcoma after failure of standard chemotherapy.

Research paper thumbnail of Phase II Trial of Oral Rubitecan in Previously Treated Pancreatic Cancer Patients

The Oncologist, 2005

Additional systemic treatments for locally advanced or metastatic pancreatic cancer are needed, a... more Additional systemic treatments for locally advanced or metastatic pancreatic cancer are needed, as current treatment options produce only modest survival benefits. Rubitecan (Orathecin ™ ; Supergen Inc., Dublin, CA, http://www.supergen.com) is an orally active camptothecin derivative with demonstrated responses in patients with pancreatic cancer in early clinical trials. This phase II, open-label trial was developed to assess the safety and efficacy of rubitecan in patients with locally advanced or metastatic pancreatic cancer refractory to conventional chemotherapy.

Research paper thumbnail of Osteogenic Sarcoma Presenting with Lung Metastasis

The Oncologist, 2002

A patient with osteogenic sarcoma presenting with lung metastases is discussed with attention to ... more A patient with osteogenic sarcoma presenting with lung metastases is discussed with attention to appropriate diagnosis, staging, and treatment. Multimodality treatment options using chemotherapy, orthopedic surgery and thoracic surgery are presented. Physical medicine and rehabilitation evaluation and treatment are included. Current research options are discussed. The Oncologist

Research paper thumbnail of Phospho-S6 ribosomal protein: a potential new predictive sarcoma marker for targeted mTOR therapy

Modern Pathology, 2008

Metastatic sarcomas are commonly resistant to chemotherapy. The serine/threonine kinase, mammalia... more Metastatic sarcomas are commonly resistant to chemotherapy. The serine/threonine kinase, mammalian target of rapamycin (mTOR), is a protein kinase of the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway thought to have a key role in controlling cancer growth and thus is an important target for cancer therapy. Several inhibitors of mTOR are in clinical trials, including AP23573, which is being tested on metastatic sarcomas and other tumors. We hypothesized that a marker for the activity of mTOR, phosphorylated S6 ribosomal protein, would be predictive of clinical response to the drug, that is, high tumor expression would signify better response than low expression. This was a blinded study. Of 26 patients treated, 20 remained on study, with available paraffin blocks. Fourteen patients received AP23573 alone and six patients received AP23573 in combination with adriamycin. An antibody to the phosphorylated S6 ribosomal protein was used to stain the tumors, all high-grade sarcomas. Pretreatment biopsy or resection material was tested: the original tumor (n ¼ 6) or tumor recurrence/metastasis (n ¼ 14); either of these may have been after treatment with other agents. Staining was scored for both quantity/percentage of tumor cells and intensity. Scoring was performed without knowledge of tumor response. Staining quantity could be categorized into two natural groups: high expressors (Z20% of tumor cells, 11 cases) and low expressors (0-10% of tumor cells, 9 cases). The highexpression group had eight stable and three progressive cases (73% stable disease); the low-expression group had three stable and six progressive cases (67% progressive disease). Chi-square analysis showed statistical significance (Pr0.05) at this initial cutoff (10%) selected blindly. The level of phosphorylated S6 ribosomal protein expression was predictive of early tumor response to the mTOR inhibitor, suggesting that this is a promising new predictive sarcoma marker for targeted mTOR inhibitor therapy.

Research paper thumbnail of Improved Survival after Pulmonary Metastasectomy for Soft Tissue Sarcoma

Journal of Thoracic Oncology, 2011

Research paper thumbnail of Phase II Study of the Mammalian Target of Rapamycin Inhibitor Ridaforolimus in Patients With Advanced Bone and Soft Tissue Sarcomas

Journal of Clinical Oncology, 2012

Ridaforolimus is an inhibitor of mammalian target of rapamycin, an integral component of the phos... more Ridaforolimus is an inhibitor of mammalian target of rapamycin, an integral component of the phosphatidyl 3-kinase/AKT signaling pathway, with early evidence of activity in sarcomas. This multicenter, open-label, single-arm, phase II trial was conducted to assess the antitumor activity of ridaforolimus in patients with distinct subtypes of advanced sarcomas.

Research paper thumbnail of Results of an International Randomized Phase III Trial of the Mammalian Target of Rapamycin Inhibitor Ridaforolimus Versus Placebo to Control Metastatic Sarcomas in Patients After Benefit From Prior Chemotherapy

Journal of Clinical Oncology, 2013

Aberrant mammalian target of rapamycin (mTOR) signaling is common in sarcomas and other malignanc... more Aberrant mammalian target of rapamycin (mTOR) signaling is common in sarcomas and other malignancies. Drug resistance and toxicities often limit benefits of systemic chemotherapy used to treat metastatic sarcomas. This large randomized placebo-controlled phase III trial evaluated the mTOR inhibitor ridaforolimus to assess maintenance of disease control in advanced sarcomas. Patients with metastatic soft tissue or bone sarcomas who achieved objective response or stable disease with prior chemotherapy were randomly assigned to receive ridaforolimus 40 mg or placebo once per day for 5 days every week. Primary end point was progression-free survival (PFS); secondary end points included overall survival (OS), best target lesion response, safety, and tolerability. A total of 711 patients were enrolled, and 702 received blinded study drug. Ridaforolimus treatment led to a modest, although significant, improvement in PFS per independent review compared with placebo (hazard ratio [HR], 0.72; 95% CI, 0.61 to 0.85; P = .001; median PFS, 17.7 v 14.6 weeks). Ridaforolimus induced a mean 1.3% decrease in target lesion size versus a 10.3% increase with placebo (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; .001). Median OS with ridaforolimus was 90.6 weeks versus 85.3 weeks with placebo (HR, 0.93; 95% CI, 0.78 to 1.12; P = .46). Adverse events (AEs) more common with ridaforolimus included stomatitis, infections, fatigue, thrombocytopenia, noninfectious pneumonitis, hyperglycemia, and rash. Grade ≥ 3 AEs were more common with ridaforolimus than placebo (64.1% v 25.6%). Ridaforolimus delayed tumor progression to a small statistically significant degree in patients with metastatic sarcoma who experienced benefit with prior chemotherapy. Toxicities were observed with ridaforolimus, as expected with mTOR inhibition. These data provide a foundation on which to further improve control of sarcomas.

Research paper thumbnail of Effect of trabectedin on the QT interval in patients with advanced solid tumor malignancies

Cancer Chemotherapy and Pharmacology, 2012

Purpose The primary objective of this study was to access the potential eVects of trabectedin on ... more Purpose The primary objective of this study was to access the potential eVects of trabectedin on the QT/QTc interval in patients with locally advanced or metastatic solid tumors. Methods Patients (n = 75) who had received ·3 previous lines of chemotherapy and had either relapsed or had progressive disease were enrolled. Patients were administered 3-h intravenous infusions of placebo (saline) on day 1 and trabectedin (1.3 mg/m 2 ) on day 2. Time-matched serial triplicate ECG recordings and pharmacokinetic blood samples were collected over 24 h on both days. Heart rate corrected mean QT intervals and changes from predose baseline in QTc ( QTc) were assessed. The diVerence in QTc between trabectedin and placebo was calculated at each time point ( QTc).

Research paper thumbnail of Results of a phase I dose escalation study of eltrombopag in patients with advanced soft tissue sarcoma receiving doxorubicin and ifosfamide

BMC Cancer, 2013

Background: The objective of this Phase I dose escalation study was to explore the safety and tol... more 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.

Research paper thumbnail of Chemotherapy treatment patterns and clinical outcomes in patients with metastatic soft tissue sarcoma. The SArcoma treatment and Burden of Illness in North America and Europe (SABINE) study

Annals of Oncology, 2012

To describe chemotherapy treatment patterns and clinical outcomes in metastatic soft tissue sarco... more To describe chemotherapy treatment patterns and clinical outcomes in metastatic soft tissue sarcoma (mSTS) patients with favorable response to chemotherapy. Multicenter (25) multi-country (9) retrospective chart review of mSTS patients with favorable response to chemotherapy, defined as stable disease or better following four cycles. Two hundred and thirteen patients (58% female; mean age 54.7 years) received a mean of 2.7 lines of chemotherapy and 5.2 cycles per line. The most common first-line regimens were doxorubicin (34%) and anthracycline plus ifosfamide (30%). Favorable response was achieved by 83% to first-line and 42% and 38% in second- and third-line chemotherapy. The most common reason for chemotherapy discontinuation in lines with a favorable response was reaching a predefined number of cycles in first line (64% of 213) and disease progression in second or later lines (41% of 138). The mean time off chemotherapy was 38.0 weeks after first line, falling to 2.7-6.4 weeks in second or later lines. Median overall and progression-free survival were 23.5 (95% confidence interval 20.5-28.1) and 8.3 (7.4-9.9) months from first favorable response to chemotherapy. mSTS patients achieving favorable response to chemotherapy have poor outcomes. Additional treatment options are needed.

Research paper thumbnail of Denosumab in patients with giant-cell tumour of bone: an open-label, phase 2 study

The Lancet Oncology, 2010

Giant-cell tumour (GCT) of bone is a primary osteolytic bone tumour with low metastatic potential... more 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. 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. 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. Further investigation of denosumab as a therapy for GCT is warranted. Amgen, Inc.

Research paper thumbnail of Phase 2 study of dasatinib in patients with alveolar soft part sarcoma, chondrosarcoma, chordoma, epithelioid sarcoma, or solitary fibrous tumor

Cancer, Jan 3, 2016

Alveolar soft part sarcoma (ASPS), chondrosarcoma (CS), chordoma, epithelioid sarcoma, and solita... more Alveolar soft part sarcoma (ASPS), chondrosarcoma (CS), chordoma, epithelioid sarcoma, and solitary fibrous tumor (SFT) are malignant tumors that are relatively resistant to chemotherapy and for which more effective drug therapy is needed. The 5 listed subtypes were enrolled into a single indolent sarcoma cohort in a phase 2 study of dasatinib using a Bayesian continuous monitoring rule for enrollment. The primary objective was to estimate the 6-month progression-free survival (PFS) rate according to the Choi criteria with a target of ≥50%. Cross-sectional imaging was performed before the start of treatment, every 2 months for 6 months, and then every 3 months during treatment. The 2- and 5-year survival rates were determined. One hundred sixteen patients were enrolled within 45 months, and 109 began treatment with dasatinib. The 6-month PFS rate and the median PFS were 48% and 5.8 months, respectively. The PFS rate at 6 months was highest with ASPS (62%) and lowest with SFT (30%). ...

Research paper thumbnail of Severe, irreversible renal failure after ifosfamide treatment. A clinicopathologic report of two patients

Cancer, Aug 1, 1995

tive doses of ifosfamide nor prior cisplatin treatment are necessary for this toxicity to occur. ... more tive doses of ifosfamide nor prior cisplatin treatment are necessary for this toxicity to occur. Because a rising serum creatinine may develop months after completion of treatment with ifosfamide, renal function should be monitored closely both during and after ifosfamide treatment. Cancer 1995; 76:497-500.

Research paper thumbnail of Phase ii study of weekly docetaxel (Doc) and gemcitabine (Gem) in relapsed patients (Pts) with advanced, platinum???exposed non???small cell lung cancer (NSCLC): P2-275

Research paper thumbnail of SARC009: Phase 2 study of dasatinib in patients with previously treated, high-grade, advanced sarcoma

Cancer, Jan 28, 2015

Dasatinib exhibited activity in preclinical models of sarcoma. The Sarcoma Alliance for Research ... more Dasatinib exhibited activity in preclinical models of sarcoma. The Sarcoma Alliance for Research through Collaboration (SARC) conducted a multicenter, phase 2 trial of dasatinib in patients with advanced sarcoma. Patients received dasatinib twice daily. The primary objective was to estimate the clinical benefit rate (CBR) (complete response or partial response within 6 months or stable disease duration of ≥6 months) with a target of ≥25%. Patients were enrolled into 1 of 7 different cohorts and assessed by imaging every 8 weeks using Choi criteria tumor response and a Bayesian hierarchical design. For each subtype, enrollment was stopped after a minimum of 9 patients were treated if there was a <1% chance the CBR was ≥25%. A total of 200 patients were enrolled. Accrual was stopped early in 5 cohorts because of low CBR. The leiomyosarcoma (LMS) and undifferentiated pleomorphic sarcoma (UPS) cohorts fully accrued and 6 of 47 and 8 of 42 evaluable patients, respectively, exhibited c...