New London, CT, United States
New London, CT, United States

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Gualberto A.,Pf Izer Oncology | Gualberto A.,Brown University | Hixon M.L.,Brown University | Karp D.D.,University of Texas M. D. Anderson Cancer Center | And 8 more authors.
British Journal of Cancer | Year: 2011

Background:Phase III trials of the anti-insulin-like growth factor type 1 receptor (IGF-IR) antibody figitumumab (F) in unselected non-small-cell lung cancer (NSCLC) patients were recently discontinued owing to futility. Here, we investigated a role of free IGF-1 (fIGF-1) as a potential predictive biomarker of clinical benefit from F treatment.Materials and method:Pre-treatment circulating levels of fIGF-1 were tested in 110 advanced NSCLC patients enrolled in a phase II study of paclitaxel and carboplatin given alone (PC) or in combination with F at doses of 10 or 20 mg kg -1 (PCF10, PCF20).Results:Cox proportional hazards model interactions were between 2.5 and 3.5 for fIGF-1 criteria in the 0.5-0.9 ng ml 1 range. Patients above each criterion had a substantial improvement in progression-free survival on PCF20 related to PC alone. Free IGF-1 correlated inversely with IGF binding protein 1 (IGFBP-1, 0.295, P=0.005), and the pre-treatment ratio of insulin to IGFBP-1 was also predictive of F clinical benefit. In addition, fIGF-1 levels correlated with tumour vimentin expression (0.594, P=0.021) and inversely with E-cadherin (-0.389, P=0.152), suggesting a role for fIGF-1 in tumour de-differentiation. Conclusion:Free IGF-1 may contribute to the identification of a subset of NSCLC patients who benefit from F therapy. © 2011 Cancer Research UK All rights reserved.


Molife L.R.,Institute of Cancer Research | Fong P.C.,Institute of Cancer Research | Paccagnella L.,Pf Izer Oncology | Reid A.H.M.,Institute of Cancer Research | And 14 more authors.
British Journal of Cancer | Year: 2010

Background:This phase Ib trial assessed safety, tolerability, and maximum tolerated dose (MTD) of figitumumab (CP-751,871), a fully human monoclonal antibody targeting the insulin-like growth factor type 1 receptor (IGF-IR), in combination with docetaxel.Methods:Patients with advanced solid tumours were treated with escalating dose levels of figitumumab plus 75 mg m-2 docetaxel every 21 days. Safety, efficacy, pharmacokinetics (PKs), and biomarker responses were evaluated.Results:In 46 patients, no dose-limiting toxicities were attributable to the treatment combination. Grade 3 and 4 toxicities included neutropaenia (n=28), febrile neutropaenia (n=11), fatigue (n=10), leukopaenia (n=7), diarrhoea (n=5), hyperglycaemia, lymphopaenia, cellulitis, DVT, and pain (all n=1). The MTD was not reached. Four partial responses were observed; 12 patients had disease stabilisation of 6≥months. Pharmacokinetic and biomarker analyses showed a dose-dependent increase in plasma exposure, and complete sIGF-IR downregulation at doses of 3≥mg kg-1. Pharmacokinetics of docetaxel in combination was similar to when given alone. Out of 18 castration-resistant prostate cancer patients, 10 (56%) had 5 circulating tumour cells (CTCs) per 7.5 ml of blood at baseline: 6 out of 10 (60%) had a decline from ≥5 to <5 CTCs and 9 out of 10 (90%) had a ≥30% decline in CTCs after therapy.Conclusions:Figitumumab and docetaxel in combination are well tolerated. Further evaluation is warranted. © 2010 Cancer Research UK All rights reserved.


Michael M.,Peter MacCallum Cancer Center | Vlahovic G.,Duke University | Khamly K.,Peter MacCallum Cancer Center | Pierce K.J.,Pf Izer Oncology | And 2 more authors.
British Journal of Cancer | Year: 2010

Background:Tumoural interstitial hypertension, possibly modulated by platelet-derived and vascular endothelial growth factor receptors (PDGFR and VEGFR), may mediate resistance to chemotherapy.Methods:Forty-eight patients with advanced solid tumours received oral PDGFR inhibitor CP-868,596 (60-100 mg twice daily (BID)) and docetaxel (75-100 mg m-2), or CP-868,596 (60 mg BID), docetaxel (75 mg m-2), and VEGFR inhibitor axitinib (5 mg BID).Results:The CP-868,596/docetaxel was escalated as above. The CP-868,596/docetaxel/axitinib was not dose escalated because of increased incidence of mucositis-like adverse events (AEs) with concurrent neutropenia relative to that expected for docetaxel. All tested regimens were tolerable, including 100 mg BID CP-868,596 (recommended phase II dose) plus 100 mg m -2 docetaxel (maximum approved dose). Most treatment-emergent AEs were mild-moderate and reversible, commonly including nausea, diarrhoea, vomiting, constipation, fatigue, and anaemia (CP-868,596/docetaxel), and hypertension, lethargy, diarrhoea, and fatigue (CP-868,596/docetaxel/axitnib). Pharmacokinetics were unaffected by co-administration. Twenty-one patients achieved stable disease, including all seven evaluable on CP-868,596/docetaxel/ axitinib. All nine CP-868,596/docetaxel/axitinib patients received therapy for a median of six (range, 3-16) cycles.Conclusions:The CP-868,596/docetaxel was well tolerated, but increased efficacy was not observed. Addition of axitinib delivered greater benefits than expected in the number of patients achieving prolonged stable disease with a moderate increase in AEs. © 2010 Cancer Research UK All rights reserved.


Cella D.,Northwestern University | Michaelson M.D.,Massachusetts General Hospital | Bushmakin A.G.,Pf Izer Global Research and Development | Cappelleri J.C.,Pf Izer Global Research and Development | And 4 more authors.
British Journal of Cancer | Year: 2010

Background: In a randomised phase III trial, sunitinib significantly improved efficacy over interferon-α (IFN-α) as first-line therapy for metastatic renal cell carcinoma (mRCC). We report the final health-related quality of life (HRQoL) results. Methods:Patients (n=750) received oral sunitinib 50 mg per day in 6-week cycles (4 weeks on, 2 weeks off treatment) or subcutaneous IFN-α 9 million units three times weekly. Health-related quality of life was assessed with nine end points: the Functional Assessment of Cancer Therapy-General and its four subscales, FACT-Kidney Symptom Index (FKSI-15) and its Disease-Related Symptoms subscale (FKSI-DRS), and EQ-5D questionnaire's EQ-5D Index and visual analogue scale. Data were analysed using mixed-effects model (MM), SUPPL.emented with pattern-mixture models (PMM), for the total sample and the US and European Union (EU) subgroups.results: Patients receiving sunitinib reported better scores in the primary end point, FKSI-DRS, across all patient populations (P<0.05), and in nine, five, and six end points in the total sample, in the US and EU groups respectively (P<0.05). There were no significant differences between the US and EU groups for all end points with the exception of the FKSI item I am bothered by side effects of treatment (P=0.02). In general, MM and PMM results were similar.Conclusion: Patients treated with sunitinib in this study had improved HRQoL, compared with patients treated with IFN-α. Treatment differences within the US cohort did not differ from those within the EU cohort. © 2010 Cancer Research UK All rights reserved.

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