A phase II study of cediranib (AZD2171) in recurrent or persistent ovarian, peritoneal or fallopian tube cancer: Final results of a PMH, Chicago and California consortia trial

Hirte, Hal W.; Vidal, Liat; Fleming, Gini F.; Sugimoto, Aya; Morgan, RJ; Biagi, James; Wang, L.; McGill, Shauna; Ivy, S. Percy; Oza, Amit M.

doi:10.1200/jco.2008.26.15_suppl.5521

Cited by 61 publications

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“…Patient demographics are summarized in Table 1. A total of 150 cycles of therapy were administered (median, 6; range, [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]. All patients were evaluable for toxicity and 14 patients were evaluable for response.…”

Section: Resultsmentioning

confidence: 99%

Phase I Study of Cediranib in Combination with Oxaliplatin and Infusional 5-Fluorouracil in Patients with Advanced Colorectal Cancer

Chen

Jonker

Gauthier

et al. 2009

Clinical Cancer Research

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Purpose: Cediranib is a potent oral inhibitor of the tyrosine kinase activity associated with all subtypes of vascular endothelial growth factor receptor. Purposes of this study were to determine the recommended phase II dose of cediranib in combination with standard doses of modified FOLFOX-6 (mFOLFOX-6), and the tolerability, safety, pharmacokinetics, and antitumor activity of this combination in patients with untreated metastatic colorectal cancer. Experimental Design: Cediranib was administered daily orally at a starting dose of 30 mg and escalated to 45 mg daily, and mFOLFOX-6 was repeated every 14 days. Pharmacokinetic studies were done for oxaliplatin, 5-fluorouracil, and cediranib. Response was assessed by Response Evaluation Criteria in Solid Tumors every four cycles. Results: Sixteen patients received 150 cycles of treatment (median, 6; range, 1-20 cycles). Of 9 patients enrolled at the 30-mg dose level, 1patient experienced grade 3 diarrhea during cycle 1. No dose-limiting toxicity was observed in 7 patients at the 45-mg dose level. Common grade 3 toxicities related to cediranib included hypertension, diarrhea, fatigue, and anorexia. Of 14 patients evaluable for response, there were 6 partial responses (42.9 %; 95 % confidence interval, 17.7-71.1%) and 6 stable disease. The median progression-free survival was 9.3 months. There were no pharmacokinetic interactions between cediranib and 5-fluorouracil or free plasma intact oxaliplatin. Conclusions: Toxicities of this combination were manageable and consistent with previous studies. The recommended phase II dose is cediranib at 30 mg daily continuously in combination with standard doses of mFOLFOX-6. Cediranib and mFOLFOX-6 has promising antitumor activity and this combination warrants further investigation.

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Section: Resultsmentioning

confidence: 99%

Phase I Study of Cediranib in Combination with Oxaliplatin and Infusional 5-Fluorouracil in Patients with Advanced Colorectal Cancer

Chen

Jonker

Gauthier

et al. 2009

Clinical Cancer Research

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“…On subsequent phase II trials, the 45 mg/d dose was judged to be intolerable, and the dose was de-escalated to 30 mg/d. 4,5 Common toxicities in adults on monotherapy trials were fatigue, diarrhea, dysphonia, nausea, hypertension, headache, vomiting, and anorexia. 2,3 Fatigue, muscle weakness, and hypertension were the primary DLTs.…”

Section: Introductionmentioning

confidence: 99%

A Phase 1 Trial and Pharmacokinetic Study of Cediranib, an Orally Bioavailable Pan–Vascular Endothelial Growth Factor Receptor Inhibitor, in Children and Adolescents With Refractory Solid Tumors

Fox

Aplenc

Bagatell

et al. 2010

JCO

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A B S T R A C T PurposeTo determine the toxicity profile, dose-limiting toxicities (DLTs), maximum-tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of cediranib administered orally, once daily, continuously in children and adolescents with solid tumors. Patients and MethodsChildren and adolescents with refractory solid tumors, excluding primary brain tumors, were eligible. DLT at the starting dose of 12 mg/m 2 /d resulted in de-escalation to 8 mg/m 2 /d and subsequent re-escalation to 12 and 17 mg/m 2 /d. Pharmacokinetic and pharmacodynamic studies were performed during cycle 1. Response was evaluated using WHO criteria. ResultsSixteen patients (median age, 15 years; range, 8 to 18 years) were evaluable for toxicity. DLTs (grade 3 nausea, vomiting, fatigue in one; hypertension and prolonged corrected QT interval in another) occurred in patients initially enrolled at 12 mg/m 2 /d. Subsequently, 8 mg/m 2 /d was well tolerated in three patients. An additional seven patients were enrolled at 12 mg/m 2 /d; one had DLT (grade 3 diarrhea). At 17 mg/m 2 /d, two of four patients had DLTs (grade 3 nausea; intolerable grade 2 fatigue). Non-dose-limiting toxicities included left ventricular dysfunction, elevated thyroid stimulating hormone, palmar-plantar erythrodysesthesia, weight loss, and headache. The MTD of cediranib was 12 mg/m 2 /d (adult fixed dose equivalent, 20 mg). At 12 mg/m 2 /d, the median area under the plasma concentration-time curve extrapolated to infinity (AUC 0-ϱ ) was 900 ng⅐h/mL, which is similar to adults receiving 20 mg. Objective responses were observed in patients with Ewing sarcoma, synovial sarcoma, and osteosarcoma. ConclusionThe recommended monotherapy dose of cediranib for children with extracranial solid tumors is 12 mg/m 2 /d administered orally, once daily, continuously. A phase II study is in development.

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“…Many other TKIs, currently undergoing clinical trials for the disruption of tumour angiogenesis and specific for a VEGFR have been examined as therapies for platinumresistant ovarian cancer or NSCLC; cediranib (Hirte et al, 2008;Matulonis et al, 2009); pazopanib (Friedlander et al, 2010);sorafenib (NCT01047891;Blumenschein, Jr. et al, 2009); sunitinib (Biagi et al, 2010;Ping et al, 2010;Novello et al, 2009;Socinski et al, 2008); vandetanib (Annunziata et al, 2010;Natale et al, 2009a). This strategy so far appears to have had limited success in chemo-resistant NSCLC or ovarian cancer.…”

Section: Other Tki Therapeutic Strategies For Platinum-resistant Cancersmentioning

confidence: 99%

Erlotinib or gefitinib for the treatment of relapsed platinum pretreated non-small cell lung cancer and ovarian cancer: A systematic review

Murphy

Stordal

2011

Drug Resistance Updates

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Copyright and moral rights to this thesis/research project are retained by the author and/or other copyright owners. The work is supplied on the understanding that any use for commercial gain is strictly forbidden. A copy may be downloaded for personal, non-commercial, research or study without prior permission and without charge. Any use of the thesis/research project for private study or research must be properly acknowledged with reference to the work's full bibliographic details.This thesis/research project may not be reproduced in any format or medium, or extensive quotations taken from it, or its content changed in any way, without first obtaining permission in writing from the copyright holder(s).If you believe that any material held in the repository infringes copyright law, please contact the Repository Team at Middlesex University via the following email address:The item will be removed from the repository while any claim is being investigated. Methods: A systematic review was conducted to investigate whether two EGFR-TKIs, erlotinib and gefitinib, have efficacy in the platinum-resistance setting. Preclinical studies of platinum-resistant cancer cell lines, which had been subsequently treated with EGFRTKIs, were sought to establish proof-of-concept. Clinical trials reporting administration of EGFR-TKIs to ovarian cancer and NSCLC patients relapsed after therapy with platinum drugs were investigated to determine sensitivity of these cohorts to EGFR-TKI treatment. The role of EGFR mutation, copy number and protein expression on response to EGFR-TKIs after failure of platinum chemotherapy were also investigated.Results: Preclinical models of platinum-resistant cancer were found which display a spectrum of cross-resistance profiles to EGFR-TKIs. Sensitivity to EGFR-TKIs is dependent on the activation of the EGFR pathway or EGFR interacting proteins such as HER-2. EGFR-TKIs show favourable response rates in platinum-pretreated NSCLC, 11.14% and 15.25% for 150 mg/day erlotinib and 250 mg/day gefitinib, respectively. These response rates significantly improve in patients of Asian descent (28.3% and 29.17%, respectively) and patients with EGFR activation mutations (41.6% and 63.89%, respectively) or increased copy number (33.3% and 45.45%, respectively). Gefitinib significantly outperformed erlotinib and should therefore be the EGFR-TKI of choice in platinum-pretreated relapsed NSCLC. In contrast, response rates are very poor to both erlotinib and gefitinib in platinum pretreated ovarian cancer, 0-5.9% and they should not be used in this cohort of patients.Preclinical models demonstrate that, while cross resistance can occur between platinums and EGFR-TKIs, there is not a generalised cross-resistance phenotype. Erlotinib and gefitinib are suitable for the treatment of platinum-pretreated NSCLC, particularly in patients with EGFR mutations or increases in copy number. Unfortunately, the high rates of EGFR protein overexpression in ovarian cancer are not translating to a clinically useful therapeutic target for ...

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A phase II study of cediranib (AZD2171) in recurrent or persistent ovarian, peritoneal or fallopian tube cancer: Final results of a PMH, Chicago and California consortia trial

Cited by 61 publications

References 0 publications

Phase I Study of Cediranib in Combination with Oxaliplatin and Infusional 5-Fluorouracil in Patients with Advanced Colorectal Cancer

Phase I Study of Cediranib in Combination with Oxaliplatin and Infusional 5-Fluorouracil in Patients with Advanced Colorectal Cancer

A Phase 1 Trial and Pharmacokinetic Study of Cediranib, an Orally Bioavailable Pan–Vascular Endothelial Growth Factor Receptor Inhibitor, in Children and Adolescents With Refractory Solid Tumors

Erlotinib or gefitinib for the treatment of relapsed platinum pretreated non-small cell lung cancer and ovarian cancer: A systematic review

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