Cediranib, an Oral Inhibitor of Vascular Endothelial Growth Factor Receptor Kinases, Is an Active Drug in Recurrent Epithelial Ovarian, Fallopian Tube, and Peritoneal Cancer (original) (raw)
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ESMO Open, 2021
Background: Cediranib, an oral anti-angiogenic VEGFR 1-3 inhibitor, was studied at a daily dose of 20 mg in combination with platinum-based chemotherapy and as maintenance in a randomised trial in patients with first relapse of 'platinumsensitive' ovarian cancer and has been shown to improve progression-free survival (PFS). Patients and methods: ICON6 (NCT00532194) was an international three-arm, double-blind, placebo-controlled randomised trial. Between December 2007 and December 2011, 456 women were randomised, using stratification, to receive either chemotherapy with placebo throughout (arm A, reference); chemotherapy with concurrent cediranib, followed by maintenance placebo (arm B, concurrent); or chemotherapy with concurrent cediranib, followed by maintenance cediranib (arm C, maintenance). Due to an enforced redesign of the trial in September 2011, the primary endpoint became PFS between arms A and C which we have previously published, and the overall survival (OS) was defined as a secondary endpoint, which is reported here. Results: After a median follow-up of 25.6 months, strong evidence of an effect of concurrent plus maintenance cediranib on PFS was observed [hazard ratio (HR) 0.56, 95% confidence interval (CI) 0.44-0.72, P < 0.0001]. In this final update of the survival analysis, 90% of patients have died. There was a 7.4-month difference in median survival and an HR of 0.86 (95% CI: 0.67-1.11, P ¼ 0.24) in favour of arm C. There was strong evidence of a departure from the assumption of non-proportionality using the GrambscheTherneau test (P ¼ 0.0031), making the HR difficult to interpret. Consequently, the restricted mean survival time (RMST) was used and the estimated difference over 6 years by the RMST was 4.8 months (95% CI: À0.09 to 9.74 months). Conclusions: Although a statistically significant difference in time to progression was seen, the enforced curtailment in recruitment meant that the secondary analysis of OS was underpowered. The relative reduction in the risk of death of 14% risk of death was not conventionally statistically significant, but this improvement and the increase in the mean survival time in this analysis suggest that cediranib may have worthwhile activity in the treatment of recurrent ovarian cancer and that further research should be undertaken.
British Journal of Cancer, 2011
BACKGROUND: Cediranib is a potent oral vascular endothelial growth factor (VEGF) signalling inhibitor with activity against all three VEGF receptors. The International Collaboration for Ovarian Neoplasia 6 (ICON6) trial was initiated based on evidence of singleagent activity in ovarian cancer with acceptable toxicity. METHODS: The ICON6 trial is a 3-arm, 3-stage, double-blind, placebo-controlled randomised trial in first relapse of platinum-sensitive ovarian cancer. Patients are randomised (2 : 3 : 3) to receive six cycles of carboplatin (AUC5/6) plus paclitaxel (175 mg m À2) with either placebo (reference), cediranib 20 mg per day, followed by placebo (concurrent), or cediranib 20 mg per day, followed by cediranib (concurrent plus maintenance). Cediranib or placebo was continued for 18 months or until disease progression. The primary outcome measure for stage I was safety, and the blinded results are presented here. RESULTS: Sixty patients were included in the stage I analysis. A total of 53 patients had received three cycles of chemotherapy and 42 patients had completed six cycles. In all, 19 out of 60 patients discontinued cediranib or placebo during chemotherapy because of adverse events/intercurrent illness (n ¼ 9); disease progression (n ¼ 1); death (n ¼ 3); patient decision (n ¼ 1); administrative reasons (n ¼ 1); and multiple reasons (n ¼ 4). Grade 3 and 4 toxicity was experienced by 30 (50%) and 3 (5%) patients, respectively. No gastrointestinal perforations were observed. CONCLUSION: The addition of cediranib to platinum-based chemotherapy is sufficiently well tolerated to expand the ICON6 trial and progress to stage II.
Cediranib in combination with various anticancer regimens: results of a phase I multi-cohort study
Investigational New Drugs
Background Cediranib is a highly potent vascular endothelial growth factor (VEGF) signaling inhibitor of all three VEGF receptors. This phase I, single-center, dose-finding study was designed primarily to investigate the safety and pharmacokinetics (PK) of cediranib with various anticancer regimens in patients with advanced solid tumors. Experimental design Oral cediranib 20, 30, and/or 45 mg/day was given in combination with standard mFOLFOX6; docetaxel; irinotecan; irinotecan and cetuximab; or pemetrexed. The novel study design allowed simultaneous evaluation of the safety and PK of these regimens with cediranib in one study. Secondary assessments included a preliminary evaluation of efficacy. Results Fifty-nine patients received cediranib and were evaluable for safety. The most common adverse events across the study were fatigue and diarrhea (both n = 52). The most common CTC grade ≥ 3 adverse events were neutropenia (n = 19) and fatigue (n = 16). Cediranib did not appear to have a major effect on the PK profile of any chemotherapy agent tested. A preliminary assessment of efficacy showed that objective responses were achieved in some patients (n = 6) who had previously progressed on similar regimens without cediranib. Conclusion In this group of heavily pretreated patients, the study design permitted simultaneous assessment of multiple treatment arms. Treatment with cediranib and the various anticancer regimens was generally well tolerated, with no apparent PK interaction and preliminary evidence of antitumor activity.
Molecular Cancer Therapeutics, 2011
Cediranib is a potent inhibitor of the VEGF receptor (VEGFR)-2 and VEGFR-3 tyrosine kinases. This study assessed the activity of cediranib against the VEGFR-1 tyrosine kinase and the platelet-derived growth factor receptor (PDGFR)-associated kinases c-Kit, PDGFR-a, and PDGFR-b. Cediranib inhibited VEGF-A-stimulated VEGFR-1 activation in AG1-G1-Flt1 cells (IC 50 ¼ 1.2 nmol/L). VEGF-A induced greatest phosphorylation of VEGFR-1 at tyrosine residues Y1048 and Y1053; this was reversed by cediranib. Potency against VEGFR-1 was comparable with that previously observed versus VEGFR-2 and VEGFR-3. Cediranib also showed significant activity against wild-type c-Kit in cellular phosphorylation assays (IC 50 ¼ 1-3 nmol/L) and in a stem cell factor-induced proliferation assay (IC 50 ¼ 13 nmol/L). Furthermore, phosphorylation of wildtype c-Kit in NCI-H526 tumor xenografts was reduced markedly following oral administration of cediranib (!1.5 mg/kg/d) to tumor-bearing nude mice. The activity of cediranib against PDGFR-b and PDGFR-a was studied in tumor cell lines, vascular smooth muscle cells (VSMC), and a fibroblast line using PDGF-AA and PDGF-BB ligands. Both receptor phosphorylation (IC 50 ¼ 12-32 nmol/L) and PDGF-BB-stimulated cellular proliferation (IC 50 ¼ 32 nmol/L in human VSMCs; 64 nmol/L in osteosarcoma cells) were inhibited. In vivo, ligand-induced PDGFR-b phosphorylation in murine lung tissue was inhibited by 55% following treatment with cediranib at 6 mg/kg but not at 3 mg/kg or less. In contrast, in C6 rat glial tumor xenografts in mice, ligand-induced phosphorylation of both PDGFR-a and PDGFR-b was reduced by 46% to 61% with 0.75 mg/kg cediranib. Additional selectivity was showed versus Flt-3, CSF-1R, EGFR, FGFR1, and FGFR4. Collectively, these data indicate that cediranib is a potent pan-VEGFR kinase inhibitor with similar activity against c-Kit but is significantly less potent than PDGFR-a and PDGFR-b. Mol Cancer Ther; 10(5); 861-73. Ó2011 AACR.
Journal of Thoracic Oncology, 2010
Background: Inhibition of angiogenesis is a novel strategy for the treatment of cancer. We evaluated the safety and efficacy of cediranib, a potent small molecule inhibitor of the vascular endothelial growth factor receptor, in patients with refractory or recurrent small cell lung cancer (SCLC). Methods: Patients with SCLC with progression after prior platinum-based chemotherapy only; performance status (PS) of 0 to 2; and adequate bone marrow, renal, and hepatic function were included. The dose of cediranib was 45 mg PO once a day for the first 12 patients and was reduced to 30 mg PO once a day for the subsequent patients because of intolerance of the higher dose. Treatment was given on a daily continuous schedule. The primary end point was determination of the response rate. Results: Twenty-five patients were enrolled. Patient characteristics were as follows: 13 men; median age 61 years; PS 0 (12 pts), PS 1 (12 pts). A median of two cycles were administered. Salient grade 3/4 toxicities were fatigue, diarrhea, hypertension, proteinuria, and elevated liver enzymes. Tolerability was better with the 30 mg dose once a day. Nine patients had stable disease, but none had a confirmed partial response. The median progression-free survival and overall survival were 2 and 6 months, respectively. Response criteria to proceed to full accrual were not met. Increase in circulating endothelial cell count was noted at the time of progression in several patients. Conclusions: Cediranib failed to demonstrate objective responses in recurrent or refractory SCLC at the dose and schedule evaluated. The 45 mg dose was intolerable in a majority of SCLC patients.
2021
Background: Angiogenesis plays a crucial role in tumor development and metastasis, and several clinical trials of anti-angiogenic agents have been conducted in advanced and recurrent endometrial cancer. Both bevacizumab and cediranib have demonstrated activity as single agents, though subsequent studies of bevacizumab combined with chemotherapy failed to improve outcomes compared to chemotherapy alone. Our group has previously established that chemotherapy plus an angiokinase inhibitor promotes catastrophic cell death in a xenograft model of endometrial cancer. Our objective was to compare the efficacy of cediranib and bevacizumab in endometrial cancer models.Methods: The cellular effects of the bevacizumab and cediranib were examined in endometrial cancer cell lines using ERK phosphorylation, ligand shedding, cell viability and cell cycle progression as readouts. Cellular viability following exposure to bevacizumab or cediranib as single agents or in combination with chemotherapy w...