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Shahneen K Sandhu,
Kyri Papadopoulos,
Peter C Fong,
Amita Patnaik,
Christina Messiou, David Olmos,
George Wang,
Brenda J Tromp,
Thomas A Puchalski,
Frances Balkwill,
Birge Berns,
Shobha Seetharam,
Johann S de Bono,
Anthony W Tolcher
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ABSTRACT: PURPOSE: The CC-chemokine ligand 2 (CCL2) is highly expressed in various malignancies and promotes carcinogenesis. Blocking CCL2 has preclinical antitumor activity. A phase 1 trial of carlumab (CNTO 888), a human anti-CCL2 IgG1κ mAb, was conducted to evaluate the safety, tolerability, pharmacokinetic-pharmacodynamic profile, and antitumor activity. METHODS: Patients with advanced solid malignancy received escalating doses of carlumab 0.3, 1, 3, 10, or 15 mg/kg by 90-min intravenous infusion on days 1, 28, and every 2 weeks thereafter (dose escalation) or 10 or 15 mg/kg every 2 weeks (dose-expansion). Pharmacodynamic assessments were also performed. RESULTS: Forty-four patients received 206 doses of carlumab. MTD was not established. Carlumab-related adverse events included grade 1-2 fatigue (9 %), nausea (7 %), headache (7 %), vomiting (5 %), and pruritus (5 %). The recommended phase II dose was 15 mg/kg every 2 weeks. Carlumab concentrations declined bi-exponentially with a terminal half-life of 6.6-9.6 days. Free CCL2 was transiently suppressed, while total CCL2 increased dose-dependently >1,000-fold post-treatment. A patient with ovarian cancer and a patient with prostate cancer achieved CA125 and PSA reductions of >50 % and RECIST SD for 10.5 and 5 months, respectively. Two other patients had RECIST SD for 7.2 and 15.7 months. CONCLUSIONS: Carlumab was well tolerated with evidence of transient free CCL2 suppression and preliminary antitumor activity.
Cancer Chemotherapy and Pharmacology 02/2013; · 2.83 Impact Factor
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Aurelius Omlin,
Carmel Pezaro,
Deborah Mukherji,
Amy Mulick Cassidy,
Shahneen Sandhu,
Diletta Bianchini, David Olmos,
Roberta Ferraldeschi,
Gal Maier,
Emilda Thompson,
Chris Parker,
Gerhardt Attard,
Johann de Bono
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ABSTRACT: BACKGROUND: Median overall survival (OS) in men with metastatic castration-resistant prostate cancer (CRPC) was 13-16 mo in the predocetaxel era. Prognostic nomograms for survival estimation in CRPC were constructed prior to the introduction of docetaxel and other novel treatments. OBJECTIVE: To examine whether prognostic models still accurately reflect survival in a large cohort of trial participants. DESIGN, SETTING, AND PARTICIPANTS: Survival analysis of 442 men with CRPC sequentially treated in clinical trials at our institution from June 2003 to December 2011. OUTCOME MEASURES AND STATISTICAL ANALYSIS: Predicted survival by Halabi and Smaletz nomograms was compared to observed survival. Cox model multivariate analysis (MVA) used variables at referral, including performance status (PS); levels of prostate-specific antigen (PSA), lactate dehydrogenase (LDH), alkaline phosphatase (ALP), haemoglobin (Hb), and albumin; presence of visceral disease, and metastatic disease at diagnosis. RESULTS AND LIMITATIONS: From point of referral, chemotherapy-naïve patients had a median OS of 30.6 mo (95% confidence interval [CI], 27.6-36.5 mo). In contrast, predicted survival using the Halabi and Smaletz models was 21 and 18 mo, respectively. In these patients, poor PS, lower Hb level, and increasing LDH level were the strongest predictors in the MVA. In patients referred after chemotherapy, survival from referral was 17.5 mo (95% CI, 16.0-19.5 mo) and increasing LDH level and presence of visceral metastases were the strongest predictors of survival. Median OS from diagnosis of CRPC was 40.7 mo in the overall cohort (95% CI, 36.8-44.0 mo). Clinical trial participation was safe, with low mortality rate. This cohort of men participated in phase 1, 2 and 3 trials and expanded access programs; their data may not reflect survival in all CRPC patients. CONCLUSIONS: Due to the impact of highly effective novel therapies on survival, prognostic nomograms in current use require revalidation regarding their ability to predict survival in CRPC.
European urology 01/2013; · 7.67 Impact Factor
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David Olmos,
Daniel Brewer,
Jeremy Clark,
Daniel C Danila,
Chris Parker,
Gerhardt Attard,
Martin Fleisher,
Alison Hm Reid,
Elena Castro,
Shahneen K Sandhu,
Lorraine Barwell,
Nikhil Babu Oommen,
Suzanne Carreira,
Charles G Drake,
Robert Jones,
Colin S Cooper,
Howard I Scher,
Johann S de Bono
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ABSTRACT: BACKGROUND: Biomarkers are urgently needed to dissect the heterogeneity of prostate cancer between patients to improve treatment and accelerate drug development. We analysed blood mRNA expression arrays to identify patients with metastatic castration-resistant prostate cancer with poorer outcome. METHODS: Whole blood was collected into PAXgene tubes from patients with castration-resistant prostate cancer and patients with prostate cancer selected for active surveillance. In stage I (derivation set), patients with castration-resistant prostate cancer were used as cases and patients under active surveillance were used as controls. These patients were recruited from The Royal Marsden Hospital NHS Foundation Trust (Sutton, UK) and The Beatson West of Scotland Cancer Centre (Glasgow, UK). In stage II (validation-set), patients with castration-resistant prostate cancer recruited from the Memorial Sloan-Kettering Cancer Center (New York, USA) were assessed. Whole-blood RNA was hybridised to Affymetrix U133plus2 microarrays. Expression profiles were analysed with Bayesian latent process decomposition (LPD) to identify RNA expression profiles associated with castration-resistant prostate cancer subgroups; these profiles were then confirmed by quantative reverse transcriptase (qRT) PCR studies and correlated with overall survival in both the test-set and validation-set. FINDINGS: LPD analyses of the mRNA expression data divided the evaluable patients in stage I (n=94) into four groups. All patients in LPD1 (14 of 14) and most in LPD2 (17 of 18) had castration-resistant prostate cancer. Patients with castration-resistant prostate cancer and those under active surveillance comprised LPD3 (15 of 31 castration-resistant prostate cancer) and LDP4 (12 of 21 castration-resistant prostate cancer). Patients with castration-resistant prostate cancer in the LPD1 subgroup had features associated with worse prognosis and poorer overall survival than patients with castration-resistant prostate cancer in other LPD subgroups (LPD1 overall survival 10·7 months [95% CI 4·1-17·2] vs non-LPD1 25·6 months [18·0-33·4]; p<0·0001). A nine-gene signature verified by qRT-PCR classified patients into this LPD1 subgroup with a very low percentage of misclassification (1·2%). The ten patients who were initially unclassifiable by the LPD analyses were subclassified by this signature. We confirmed the prognostic utility of this nine-gene signature in the validation castration-resistant prostate cancer cohort, where LPD1 membership was also associated with worse overall survival (LPD1 9·2 months [95% CI 2·1-16·4] vs non-LPD1 21·6 months [7·5-35·6]; p=0·001), and remained an independent prognostic factor in multivariable analyses for both cohorts. INTERPRETATION: Our results suggest that whole-blood gene profiling could identify gene-expression signatures that stratify patients with castration-resistant prostate cancer into distinct prognostic groups. FUNDING: AstraZeneca, Experimental Cancer Medicine Centre, Prostate Cancer Charity, Prostate Cancer Foundation.
The lancet oncology 10/2012; · 14.47 Impact Factor
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ABSTRACT: Adrenal cortical carcinosarcoma is a rare variant of adrenal cortical carcinoma. Sarcomatous change in adrenal cortical carcinomas is exceptionally rare, with only 9 cases previously described. Adrenal cortical carcinosarcomas tend to be aggressive tumors, with locoregional recurrence and rapid metastases from the sarcomatoid component. We describe what seems to be the first case of sarcoma arising in oncocytic adrenal cortical carcinoma. The sarcomatous component here was pleomorphic rhabdomyosarcoma. This occurred in a 45-year-old man who had nodal and pulmonary metastases of the rhabdomyosarcomatous component at presentation and who died of progressive disease 11 months later. Here, we discuss the clinical, radiologic, and pathologic findings and review the literature on adrenal cortical carcinosarcomas.
The American journal of surgical pathology 03/2012; 36(3):470-7. · 4.06 Impact Factor
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ABSTRACT: Adipocytic tumors are the most common type of soft tissue neoplasms. Distinguishing atypical lipomatous tumor-well-differentiated liposarcoma (WDL) from benign adipocytic neoplasms and dedifferentiated liposarcoma (DDL) from pleomorphic or myxoid liposarcoma (LPS) can be difficult. WDL and DDL characteristically harbor amplifications of the MDM2 and CDK4 cell cycle oncogenes with protein overexpression and can also overexpress the cell cycle regulator p16. We assessed the utility of immunohistochemistry for CDK4, MDM2, and p16 in the routine histopathologic diagnosis of WDL/DDL from other adipocytic tumors. Immunohistochemistry for the trio of markers was performed on 216 adipocytic neoplasms (31 WDLs, 57 DDLs, 11 myxoid LPS, 2 pleomorphic LPS, 91 lipomas (including intramuscular, fibro, angio, and ossifying subtypes), 18 spindle/pleomorphic lipomas, and 6 hibernomas. Sixty-eight percent of WDLs and 72% of DDLs expressed all 3 antigens, whereas 100% of WDLs and 93% of DDLs expressed at least 2 antigens. The sensitivity and specificity of the trio for detecting WDLs/DDLs were 71% and 98%, respectively. The sensitivity and specificity of CDK4 for detecting WDLs/DDLs were 86% and 89%, those of MDM2 were 86% and 74%, and those of p16 were 93% and 92%, respectively. The immunohistochemical trio of CDK4, MDM2, and p16 is a useful ancillary diagnostic tool that provides strong support in distinguishing WDLs and DDLs from other adipocytic neoplasms and is potentially more sensitive than previously assessed combinations of CDK4 and MDM2. p16 was the most sensitive and specific marker for detecting WDL/DDL, and the combination of CDK4 and p16 is of more discriminatory value than the combination of either with MDM2, the least sensitive and specific of the 3 markers.
The American journal of surgical pathology 03/2012; 36(3):462-9. · 4.06 Impact Factor
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David Olmos,
Roger P A'hern,
Silvia Marsoni,
Rafael Morales,
Carlos Gomez-Roca,
Jaap Verweij,
Emile E Voest,
Patrick Schöffski,
Joo Ern Ang,
Nicolas Penel,
Jan H Schellens,
Gianluca Del Conte,
Andre T Brunetto,
T R Jeffry Evans,
Richard Wilson,
Elisa Gallerani,
Ruth Plummer,
Josep Tabernero,
Jean-Charles Soria,
Stan B Kaye
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ABSTRACT: The appropriate selection of patients for early clinical trials presents a major challenge. Previous analyses focusing on this problem were limited by small size and by interpractice heterogeneity. This study aims to define prognostic factors to guide risk-benefit assessments by using a large patient database from multiple phase I trials.
Data were collected from 2,182 eligible patients treated in phase I trials between 2005 and 2007 in 14 European institutions. We derived and validated independent prognostic factors for 90-day mortality by using multivariate logistic regression analysis.
The 90-day mortality was 16.5% with a drug-related death rate of 0.4%. Trial discontinuation within 3 weeks occurred in 14% of patients primarily because of disease progression. Eight different prognostic variables for 90-day mortality were validated: performance status (PS), albumin, lactate dehydrogenase, alkaline phosphatase, number of metastatic sites, clinical tumor growth rate, lymphocytes, and WBC. Two different models of prognostic scores for 90-day mortality were generated by using these factors, including or excluding PS; both achieved specificities of more than 85% and sensitivities of approximately 50% when using a score cutoff of 5 or higher. These models were not superior to the previously published Royal Marsden Hospital score in their ability to predict 90-day mortality.
Patient selection using any of these prognostic scores will reduce non-drug-related 90-day mortality among patients enrolled in phase I trials by 50%. However, this can be achieved only by an overall reduction in recruitment to phase I studies of 20%, more than half of whom would in fact have survived beyond 90 days.
Journal of Clinical Oncology 02/2012; 30(9):996-1004. · 18.37 Impact Factor
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ABSTRACT: Life-expectancy superior to 3 months is a key-eligibility criterion for contemporary oncology phase 1 trials. Nevertheless, there is no reliable and consensual guidance for estimating this criterion. We have conducted a systematic review of published studies investigating the risk factor for 90-day mortality and the inherent generated scores. Nine studies have been published on this topic. Only two of these prognostic models have been validated on an independent dataset. Most of the models are based on a very subjective and investigator-dependent parameter: the performance status. The predictive performance of these prognostic models is poorly evaluated.
Critical reviews in oncology/hematology 01/2012; 83(2):242-8. · 5.27 Impact Factor
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Timothy A Yap,
Li Yan,
Amita Patnaik,
Ivy Fearen, David Olmos,
Kyriakos Papadopoulos,
Richard D Baird,
Liliana Delgado,
Adekemi Taylor,
Lisa Lupinacci,
Ruth Riisnaes,
Lorna L Pope,
Simon P Heaton,
George Thomas,
Michelle D Garrett,
Daniel M Sullivan,
Johann S de Bono,
Anthony W Tolcher
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ABSTRACT: AKT signaling is frequently deregulated in human cancers. MK-2206 is a potent, oral allosteric inhibitor of all AKT isoforms with antitumor activity in preclinical models. A phase I study of MK-2206 was conducted to investigate its safety, maximum-tolerated dose (MTD), pharmacokinetics (PKs), pharmacodynamics (PDs), and preliminary antitumor efficacy.
Patients with advanced solid tumors received MK-2206 on alternate days. Paired tumor biopsies were mandated at the MTD for biomarker studies. PD studies incorporated tumor and hair follicle analyses, and putative predictive biomarker studies included tumor somatic mutation analyses and immunohistochemistry for phosphatase and tensin homolog (PTEN) loss.
Thirty-three patients received MK-2206 at 30, 60, 75, or 90 mg on alternate days. Dose-limiting toxicities included skin rash and stomatitis, establishing the MTD at 60 mg. Drug-related toxicities included skin rash (51.5%), nausea (36.4%), pruritus (24.2%), hyperglycemia (21.2%), and diarrhea (21.2%). PKs (area under the concentration-time curve from 0 to 48 hours and maximum measured plasma concentration) were dose proportional. Phosphorylated serine 473 AKT declined in all tumor biopsies assessed (P = .015), and phosphorylated threonine 246 proline-rich AKT substrate 40 was suppressed in hair follicles at 6 hours (P = .008), on days 7 (P = .028) and 15 (P = .025) with MK-2206; reversible hyperglycemia and increases in insulin c-peptide were also observed, confirming target modulation. A patient with pancreatic adenocarcinoma (PTEN loss; KRAS G12D mutation) treated at 60 mg on alternate days experienced a decrease of approximately 60% in cancer antigen 19-9 levels and 23% shrinkage in tumor measurements. Two patients with pancreatic neuroendocrine tumors had minor tumor responses.
MK-2206 was well tolerated, with evidence of AKT signaling blockade. Rational combination trials are ongoing to maximize clinical benefit with this therapeutic strategy.
Journal of Clinical Oncology 12/2011; 29(35):4688-95. · 18.37 Impact Factor
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European journal of cancer (Oxford, England: 1990) 12/2011; 48(4):594-6. · 4.12 Impact Factor
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Acta oncologica (Stockholm, Sweden) 10/2011; 51(4):550-4. · 2.27 Impact Factor
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ABSTRACT: INTRODUCTION: There are clear preclinical data that support the involvement of the insulin-like growth factor (IGF) signaling pathway in oncogenesis and cancer progression. Such evidence has led to the design and conduct of drug development programs targeting the IGF-I receptor (IGF-IR) over the past 10 years. AREAS COVERED: This review details the structure and function of different members of the IGF system and related pathways, describes the rationale for targeting IGF-IR in cancer and updates the current advances in drug development. The preclinical development of figitumumab, the furthest developed mAb against IGF-IR, is examined as well as the reported data from Phase I - III clinical trials. Future prospects for this target and pathway are also discussed. EXPERT OPINION: While there have been both successes and failures in the development of novel targeted therapeutics targeting the IGF pathway, the evaluation of such agents should continue, with greater emphasis placed on combinatorial strategies and the development of predictive biomarkers that enhance antitumor responses through appropriate patient selection.
Expert Opinion on Investigational Drugs 09/2011; 20(9):1293-304. · 5.27 Impact Factor
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David Olmos,
Richard D Baird,
Timothy A Yap,
Christophe Massard,
Lorna Pope,
Shahneen K Sandhu,
Gerhardt Attard,
Juliet Dukes,
Dionysis Papadatos-Pastos,
Philippa Grainger,
Stan B Kaye,
Johann S de Bono
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ABSTRACT: High circulating tumor cell (CTC) counts are associated with poor prognosis in several cancers. Enrollment of patients on phase I oncology trials requires a careful assessment of the potential risks and benefits. Many patients enrolled on such trials using established eligibility criteria have a short life expectancy and are less likely to benefit from trial participation. We hypothesized that the incorporation of CTC counts might improve patient selection for phase I trials.
This retrospective analysis evaluated patients who had baseline CTCs enumerated prior to their starting on a phase I trial. CTCs were enumerated using the CellSearch System.
Between January 2006 and December 2009 a total of 128 patients enrolled in phase I trials had CTC counts evaluated. Higher CTC counts as a continuous variable independently correlated with risk of death in this patient population (P = 0.006). A multivariate point-based risk model was generated using CTCs as a dichotomous variable (≥3 or <3), and incorporated other established prognostic factors, including albumin <35 g/L, lactate dehydrogenase greater than upper limit of normal, and >2 metastatic sites. Comparison of receiver operating characteristic curves demonstrated that the addition of baseline CTC counts improved the performance of the prospectively validated Royal Marsden Hospital phase I prognostic score, which now identifies three risk groups (P < 0.0001): good prognosis [score 0-1, median overall survival (OS) 63.7 weeks], intermediate prognosis (score 2-3, median OS 37.3 weeks), and poor prognosis (score 4, median OS 13.4 weeks).
CTC enumeration improved the performance of a validated prognostic score to help select patients for phase I oncology trials.
Clinical Cancer Research 04/2011; 17(15):5188-96. · 7.74 Impact Factor
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David Olmos,
Douglas Barker,
Rohini Sharma,
Andre T Brunetto,
Timothy A Yap,
Anne B Taegtmeyer,
Jorge Barriuso,
Hanine Medani,
Yan Y Degenhardt,
Alicia J Allred,
Deborah A Smith,
Sharon C Murray,
Thomas A Lampkin,
Mohammed M Dar,
Richard Wilson,
Johann S de Bono,
Sarah P Blagden
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ABSTRACT: GSK461364 is an ATP-competitive inhibitor of polo-like kinase 1 (Plk1). A phase I study of two schedules of intravenous GSK461364 was conducted.
GSK461364 was administered in escalating doses to patients with solid malignancies by two schedules, either on days 1, 8, and 15 of 28-day cycles (schedule A) or on days 1, 2, 8, 9, 15, and 16 of 28-day cycles (schedule B). Assessments included pharmacokinetic and pharmacodynamic profiles, as well as marker expression studies in pretreatment tumor biopsies.
Forty patients received GSK461364: 23 patients in schedule A and 17 in schedule B. Dose-limiting toxicities (DLT) in schedule A at 300 mg (2 of 7 patients) and 225 mg (1 of 8 patients) cohorts included grade 4 neutropenia and/or grade 3-4 thrombocytopenia. In schedule B, DLTs of grade 4 pulmonary emboli and grade 4 neutropenia occurred at 7 or more days at 100 mg dose level. Venous thrombotic emboli (VTE) and myelosuppression were the most common grade 3-4, drug-related events. Pharmacokinetic data indicated that AUC (area under the curve) and C(max) (maximum concentration) were proportional across doses, with a half-life of 9 to 13 hours. Pharmacodynamic studies in circulating tumor cells revealed an increase in phosphorylated histone H3 (pHH3) following drug administration. A best response of prolonged stable disease of more than 16 weeks occurred in 6 (15%) patients, including 4 esophageal cancer patients. Those with prolonged stable disease had greater expression of Ki-67, pHH3, and Plk1 in archived tumor biopsies.
The final recommended phase II dose for GSK461364 was 225 mg administered intravenously in schedule A. Because of the high incidence (20%) of VTE, for further clinical evaluation, GSK461364 should involve coadministration of prophylactic anticoagulation.
Clinical Cancer Research 04/2011; 17(10):3420-30. · 7.74 Impact Factor
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Timothy A Yap, David Olmos,
Andre T Brunetto,
Nina Tunariu,
Jorge Barriuso,
Ruth Riisnaes,
Lorna Pope,
Jeremy Clark,
Andrew Futreal,
Michael Germuska,
David Collins,
Nandita M deSouza,
Martin O Leach,
Ronald E Savage,
Carol Waghorne,
Feng Chai,
Edward Garmey,
Brian Schwartz,
Stan B Kaye,
Johann S de Bono
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ABSTRACT: The hepatocyte growth factor/c-MET axis is implicated in tumor cell proliferation, survival, and angiogenesis. ARQ 197 is an oral, selective, non-adenosine triphosphate competitive c-MET inhibitor. A phase I trial of ARQ 197 was conducted to assess safety, tolerability, and target inhibition, including intratumoral c-MET signaling, apoptosis, and angiogenesis.
Patients with solid tumors amenable to pharmacokinetic and pharmacodynamic studies using serial biopsies, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), and circulating endothelial cell (CEC) and circulating tumor cell (CTC) enumeration were enrolled.
Fifty-one patients received ARQ 197 at 100 to 400 mg twice per day. ARQ 197 was well tolerated, with the most common toxicities being grade 1 to 2 fatigue, nausea, and vomiting. Dose-limiting toxicities included grade 3 fatigue (200 mg twice per day; n = 1); grade 3 mucositis, palmar-plantar erythrodysesthesia, and hypokalemia (400 mg twice per day; n = 1); and grade 3 to 4 febrile neutropenia (400 mg twice per day, n = 2; 360 mg twice per day, n = 1). The recommended phase II dose was 360 mg twice per day. ARQ 197 systemic exposure was dose dependent and supported twice per day oral dosing. ARQ 197 decreased phosphorylated c-MET, total c-MET, and phosphorylated focal adhesion kinase and increased terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick-end labeling (TUNEL) staining in tumor biopsies (n = 15). CECs decreased in 25 (58.1%) of 43 patients, but no significant changes in DCE-MRI parameters were observed after ARQ 197 treatment. Of 15 patients with detectable CTCs, eight (53.3%) had ≥ 30% decline in CTCs after treatment. Stable disease, as defined by Response Evaluation Criteria in Solid Tumors (RECIST), ≥ 4 months was observed in 14 patients, with minor regressions in gastric and Merkel cell cancers.
ARQ 197 safely inhibited intratumoral c-MET signaling. Further clinical evaluation focusing on combination approaches, including an erlotinib combination in non-small-cell lung cancer, is ongoing.
Journal of Clinical Oncology 03/2011; 29(10):1271-9. · 18.37 Impact Factor
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ABSTRACT: Epithelioid sarcoma is a rare soft tissue sarcoma subtype. The response of this disease to chemotherapy is not well described. The aim of this study was to investigate the response rate and progression-free survival in a series of epithelioid sarcoma patients treated with chemotherapy at a single referral center.
A retrospective search of a prospectively maintained database was made to identify epithelioid sarcoma patients treated with chemotherapy between 1990 and 2009. Radiological response and histological diagnosis were re-reviewed for this study.
Twenty-one epithelioid sarcoma patients treated with chemotherapy were identified; follow-up data on palliative chemotherapy was available on 20 of these patients. The median age was 36.5 years (range, 17.4 to 64.8 y) and the male/female ratio was 19:2. Ten patients (50%) were treated with single-agent anthracycline, 9 patients (45%) were treated with a combination therapy (anthracycline and ifosfamide), and 1 patient received trabectedin (5%). Three patients achieved a partial response, 12 had stable disease, and 5 progressed. The median progression-free survival was 29 weeks (95% confidence interval [CI]: 23-35). Seven and 3 patients received second-line and third-line palliative chemotherapy, respectively. The median overall survival from commencing palliative chemotherapy in our series was 51 weeks (95% confidence interval; 29-73).
Systemic chemotherapy provides satisfactory palliation in patients with epithelioid sarcoma. However, this is an aggressive disease, responses to chemotherapy are of short duration and there is a need for more effective novel therapies in the treatment of this condition.
American journal of clinical oncology 03/2011; 35(4):351-7. · 2.21 Impact Factor
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ABSTRACT: Introduction. A survey was sent to referring oncologists (ROs) to explore the reasons behind their referral patterns and perceptions of Phase I studies before and after being provided with outcome data from advanced colorectal cancer (ACRC) patients who participated in Phase I trials at the Royal Marsden Hospital (RMH). Results. The response rate was 32/50 (64%). The most common reason for referral was exhaustion of standard treatments (31%), and the main reason for referring to the RMH was proximity to patients (28%). The most frequent clinical parameter assessed prior to referral was performance status (93%). ROs spent a median of 15 min (range: 5-45 min) discussing general aspects of Phase I trials. In the second part of the questionnaire, after reviewing clinical outcome data of ACRC patients who participated in Phase I trials, 47% would change their approach, specifically, spend more time to discuss risks and benefits of Phase I trials (9%), consider prognostic factors before referral (13%), and increase the number of referrals (25%). Conclusion. This is the first report focusing on communication between ROs and a specialist Phase I unit. Outcome reporting can improve communication with ROs and importantly has the potential for better patient selection considered for Phase I oncology trials.
Journal of Oncology 01/2011; 2011:861401.
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ABSTRACT: Ewing's sarcoma family of tumours comprises a group of very aggressive diseases that are potentially curable with multimodality treatment. Despite the undoubted success of current treatment, approximately 30% of patients will relapse and ultimately die of disease. The insulin-like growth factor 1 receptor (IGF-1R) has been implicated in the genesis, growth, proliferation, and the development of metastatic disease in Ewing's sarcoma. In addition, IGF1-R has been validated, both in vitro and in vivo, as a potential therapeutic target in Ewing's sarcoma. Phase I studies of IGF-1R monoclonal antibodies reported several radiological and clinical responses in Ewing's sarcoma patients, and initial reports of several Phase II studies suggest that about a fourth of the patients would benefit from IGF-1R monoclonal antibodies as single therapy, with approximately 10% of patients achieving objective responses. Furthermore, these therapies are well tolerated, and thus far severe toxicity has been rare. Other studies assessing IGF-1R monoclonal antibodies in combination with traditional cytotoxics or other targeted therapies are expected. Despite, the initial promising results, not all patients benefit from IGF-1R inhibition, and consequently, there is an urgent need for the identification of predictive markers of response.
Sarcoma 01/2011; 2011:402508.
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ABSTRACT: Rhabdomyosarcomas (RMS) are a heterogeneous group of tumors that share features of skeletal myogenesis and represent the most common pediatric soft tissue sarcoma. Even though significant advances have been achieved in RMS treatment, prognosis remains very poor for many patients. Several elements of the Insulin-like Growth Factor (IGF) pathway are involved in sarcomas, including RMS. The IGF2 ligand is highly expressed in most, if not all, RMS, and frequent overexpression of the receptor IGF1R is also found. This is confirmed here through mining expression profiling data of a large series of RMS samples. IGF signaling is implicated in the genesis, growth, proliferation, and metastasis of RMS. Blockade of this pathway is therefore a potential therapeutic strategy for the treatment of RMS. In this paper we examine the biological rationale for targeting the IGF pathway in RMS as well as the current associated preclinical and clinical experience.
Sarcoma 01/2011; 2011:209736.
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ABSTRACT: Standard systemic treatment options for patients with advanced sarcoma are limited. Depending on the histological subtype, patients receive differing lines of therapy usually consisting of doxorubicin, ifosfamide and/or trabectedin. After progression on conventional therapies, some patients are offered more experimental options including Phase I clinical trials. The aim of this study was to evaluate the clinical benefit for sarcoma patients treated within the Phase I Unit of a single referral centre.
The response, toxicity and outcome of sarcoma patients treated within Phase I clinical trials at the Royal Marsden between August 1998 and December 2010 were analysed.
One hundred and thirty-three patients were treated. The median number of prior systemic therapies was 3 (range 0-6). The median age of these patients was 48.0 years (range 12.5-81.9), with a male/female ratio of 71/62. One patient (0.8%) achieved a complete response and 2 (1.6%) partial responses. The non-progression rate at 3 and 6 months was 31.5% (95% CI, 23.4-39.6%) and 11.0% (95% CI 5.6-16.5%), respectively. The median progression-free survival was 2.1 months (95% CI, 1.7-2.5), and median overall survival was 7.6 months (95% CI, 4.8-10.4). Twenty-four (18.0%) patients experienced grade 3 or 4 toxicity, and 16 (12.0%) stopped trial treatment due to toxicity.
Phase I clinical trials could be considered a therapeutic option in sarcoma patients with no remaining standard treatment due to the low risk of toxicity and the potential for clinical benefit.
Cancer Chemotherapy and Pharmacology 11/2010; 68(2):423-9. · 2.83 Impact Factor
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Andre T Brunetto,
Joo Ern Ang, David Olmos,
Daniel Tan,
Jorge Barriuso,
Hendrik-Tobias Arkenau,
Timothy A Yap,
L Rhoda Molife,
Udai Banerji,
Johann de Bono,
Ian Judson,
Stan Kaye
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ABSTRACT: Unplanned hospital admissions (UHAs) in the context of oncology Phase I trials are important, yet rarely reported.
All patients admitted to the Royal Marsden Hospital Phase I clinical trials unit during February and March of 2005-2007 were included. The patient-, admission- and trial-related variables were collected. Correlations were sought between the occurrence of UHAs and the baseline patient/trial-related characteristics.
Of the 308 admissions involving 177 patients, UHAs constituted 21% of all the admissions and 38% of the total bed occupancy. The majority of UHAs were cancer related (78%) and their occurrence was associated with a significant early patient attrition. Using multivariate analysis, the factors significantly associated with UHAs included age >60 years (RR 2.32, confidence interval (CI)-95% 1.12-4.81), ≥3 metastatic sites (RR 3.26, CI-95% 1.54-6.90) and LDH>ULN (RR 2.18, CI-95% 1.06-4.46), with albumin <35 g/dL trending to significance (p=0.052). The trials that contained cytotoxic chemotherapy incurred disproportionately higher rates of admissions (69.5%) than the trials that did not.
UHAs constitute a substantial workload and impact on the speed and cost of, as well as resource allocation in Phase I oncology trials. The majority of UHAs are cancer rather than treatment related. The risk stratification to guide patient selection may help reduce the incidence of UHAs.
European journal of cancer (Oxford, England: 1990) 10/2010; 46(15):2739-45. · 4.12 Impact Factor
