The Role of Cediranib in Ovarian Cancer
Cecilia Orbegoso, Gloria Marquina, Angela George & Susana Banerjee
To cite this article: Cecilia Orbegoso, Gloria Marquina, Angela George & Susana Banerjee (2017): The Role of Cediranib in Ovarian Cancer, Expert Opinion on Pharmacotherapy, DOI: 10.1080/14656566.2017.1383384
To link to this article: http://dx.doi.org/10.1080/14656566.2017.1383384
Accepted author version posted online: 21 Sep 2017.
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The Role of Cediranib in Ovarian Cancer
Cecilia Orbegoso1, Gloria Marguina1, Angela George1 and Susana Banerjee1,2*
⦁ Royal Marsden NHS Foundation Trust – Gynaecology Unit, London, London SW3 6JJ
⦁ The Institiute of Cancer Research – Division of Clinical Studies, 15 Cotswold Road, Sutton , London SM2 5NG
*Corresponding author
Dr Susana Banerjee MA MRCP PhD
Royal Marsden NHS Foundation Trust – Gynaecology Unit, London, London SW3 6JJ; [email protected]
Funding
This paper was not funded
Declaration of interest
S Banerjee’s institution has received an educational grant and honoraria for advisory board and lecture activities from Astrazeneca and S Banejee’s has also received honoraria from Roche. A George has received honoraria for advisory boards and travel support from Astrazeneca. C Orbegoso has received honoraria from lecture activities from Astrazeneca. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
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Abstract
Introduction: Treatment options for relapsed ovarian cancer have increased over the decade with the addition of targeted agents, such as PARP inhibitors and antiangiogenic agents. Bevacizumab, a monoclonal antibody binding vascular endothelial growth factor (VEGF), was the first anti-angiogenic agent to be incorporated in the ovarian cancer treatment landscape. Other molecules utilising different mechanisms of action to target angiogenesis have been developed, including Cediranib, an oral potent inhibitor of VEGF Tyrosine Kinase Inhibitor that has demonstrated activity in both phase II and phase III studies.
Areas Covered: Herein we will review Cediranib as well as the evidence for its use in ovarian cancer, both as monotherapy and in combination with chemotherapy, PARP inhibitors and immunotherapy. A literature search was made in PubMed and on ClinicalTrials.gov for clinical trials with cediranib.
Expert Opinion: The addition of Cediranib for the treatment of ovarian cancer is promising, and has demonstrated a significant improvement in progression free survival in a phase III trial in combination with chemotherapy and maintenance treatment. Cediranib is currently being explored in ovarian cancer and other gynaecological malignancies aiming to improve patient care; further research will help define its role in standard clinical practice for patients with ovarian cancer.
Keywords: Angiogenesis, cediranib, ovarian cancer, tyrosine kinase inhibitor
⦁ Introduction
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Ovarian cancer is the seventh leading cancer diagnosis and eighth leading cause of cancer mortality among women worldwide1. Despite initial good response rates to platinum-based chemotherapy, the majority of patients with advanced disease will relapse and require further treatment. This has fuelled the development of targeted therapies to further improve outcomes.
Tumour angiogenesis is one of the hallmarks of cancer biology, with tumour blood vessels providing oxygen, nutrients, and facilitating both growth and a route for metastatic dissemination2. This process involves activation of endothelial and perivascular cells, and modifications to the surrounding basement membrane and extracellular matrix. VEGF-A is a key stimulus of physiologic and pathologic angiogenesis, with its receptors (including VEGFR1 and VEGFR2) expressed on tumour cells and endothelial cells. These receptors are high affinity tyrosine kinase receptors, consisting of an extracellular region of seven immunoglobulin-like domains, a single trans-membrane domain and an intracellular tyrosine kinase domain3,4. With such a central role in tumour biology, and demonstration of overexpression of VEGFR in a number of tumour types including ovarian cancer, targeting the VEGF pathway is appealing5.
⦁ Bevacizumab and other antiangiogenic agents
The first angiogenesis inhibitor to demonstrate efficacy leading to approval was bevacizumab, a humanized monoclonal antibody against VEGF that recognises all soluble VEGF-A isoforms inhibiting angiogenesis by preventing VEGF-VEGFR interaction. This molecule was first approved in 2004 based on its efficacy in
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colorectal cancer and has subsequently been approved for use in other malignancies, including ovarian cancer6. Bevacizumab is currently the only approved anti-angiogenic agent for the treatment of ovarian cancer.
The GOG 2187 and ICON 78 phase III trials studied the activity of bevacizumab in combination with platinum based chemotherapy in newly diagnosed ovarian cancer patients. Both studies showed a significant increase in median progression free survival (PFS). An exploratory analysis of the ICON7 trial demonstrated an improvement in overall survival with the addition of bevacizumab for patients with high-risk disease- stage IV, stage III with residual disease of >1cm following debulking surgery (mean survival time 39.3 vs 34.5 months, HR 0.78; p=0.03)9.
The use of Bevacizumab in the neoadjuvant setting has also been studied and so far, does not appear to significantly negatively impact on interval debulking surgery (IDS). In a subgroup analysis of the phase IV MITO-16A-MaNGO OV2A10, trial in which seventy patients received bevacizumab in combination with neoadjuvant chemotherapy and were consider for IDS, surgery to less than 1 cm was achieved in 86.5% and the main postoperative complications were: anaemia (4%); fever (4%); wound healing delay (2.7%) and wound dehiscence (2.7%). The phase II ANTHALYA study11, compared the addition of bevacizumab to neoadjuvant chemotherapy in patients with initially unresectable FIGO stage IIIc/IV ovarian cancer. IDS surgery was undertaken in 69% of patients in the bevacizumab/chemotherapy group and 60% of patients in the chemotherapy alone group. The rates of grade 3 adverse events and post-operative complications were no greater in the bevacizumab treated group. Results of randomised phase III trials of neoadjuvant chemotherapy in combination with bevacizumab are awaited.
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Bevacizumab has also demonstrated benefit for ovarian cancer patients with relapsed disease. The OCEANS12 trial was a randomized, placebo controlled, phase III study evaluating the efficacy and safety of bevacizumab in combination with gemcitabine and carboplatin for first platinum-sensitive ovarian cancer relapse. Patients were randomised to receive carboplatin and gemcitabine with or without bevacizumab for 6 to 10 cycles followed by maintenance bevacizumab/placebo until disease progression. The trial demonstrated a significant improvement in PFS for the bevacizumab combination arm (12.4 months versus 8.4 months, p < 0.0001, HR = 0.484), and an increased Overall Response Rate (ORR) (78.5% versus 57.4%; p < 0.0001). In the AURELIA trial13, a randomized open-label phase III trial in platinum- resistant ovarian cancer of chemotherapy (investigator’s choice of weekly paclitaxel; pegylated liposomal doxorubicin or topotecan) with or without bevacizumab, there was a significant increase in median PFS with the addition of bevacizumab (6.7 versus 3.4 months, p value < 0.001 and HR = 0.48). In exploratory analyses, the magnitude of benefit with the addition of bevacizumab was most pronounced in the weekly paclitaxel cohort: ORR (53.3% v 30.2%); median PFS 10.4 versus 3.9
months (HR=0.46 95% CI 0.30 to 0.71) and median OS 22.4 v 13.2 months (HR,
0.65; 95% CI, 0.42 to 1.02)14.
Trebananib, a selective Ang-1/2 neutralizing peptibody that inhibits the interaction of Ang-1 and Ang-2 with their target tie2 receptors, Trebananib was studied in women with recurrent epithelial ovarian cancer with a platinum-free interval of 12 months or less. The TRINOVA-1 phase III trial demonstrated that trebananib, in combination with weekly paclitaxel, led to a statistically significant increase in PFS when compared to paclitaxel alone (7.2 months compared with 5.4 months; HR, 0.66; 95%
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CI, 0.57–0.77; p < 0.0001) and no significant difference in OS (HR, 0.86; 95% CI, 0.69–1.08; P = 0.19)15,16.
A number of other antiangiogenic agents have now been studied in ovarian cancer with mixed results. Nintedanib, an oral tyrosine kinase inhibitor (TKI) targeting VEGF receptor 1-3, FGFR 1-3 and PDGFR α and β, has been studied in the first-line in chemotherapy-naïve patients in combination with carboplatin and paclitaxel in the randomised, double-blind, placebo-controlled phase 3 trial AGO-OVAR 12. A statistically significant improvement in PFS favouring the nintedanib/chemotherapy arm (17.2 months vs 16.6 months HR 0.84 [95% CI 0·72–0·98]; p=0·024) was noted although the actual magnitude of benefit in median PFS is modest clinically17. Pazopanib, a multi-targeted receptor tyrosine kinase inhibitor (VEGFR 1-3, PDGFR α and β and c-kit) has also been studied in the first-line setting in ovarian cancer. In a randomized, double-blind, placebo controlled, phase III trial of maintenance pazopanib (for up to 24 months) following no evidence of progression after surgery and platinum-taxane chemotherapy, progression-free survival was significantly improved (12.3 vs 17.9 months; HR 0.766 p=0.021)18. However, tolerability was a challenge: treatment discontinuation related to adverse events was higher among patients treated with pazopanib (33.3%) compared with placebo (5.6%). Grade 3-4 adverse events related to pazopanib were hypertension (30.8%), neutropenia (9.9%), liver related toxicity (9.4%), diarrhoea (8.2%), fatigue (2.7%),
thrombocytopenia (2.5%), and palmo-plantar erythrodysesthesia (1.9%); 3 fatal adverse events were reported to be related to the study drug18.
⦁ Cediranib
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Cediranib (AstraZeneca), previously known as AZD2171, is an oral inhibitor of VEGF signalling that binds all three VEGFR (VEGFR-1, VEGFR-2 and VEGFR-3) with pronounced selectivity for VEGFR2; together with c-Kit, the platelet derived growth factor receptor alpha and beta (PDGFRα and PDGFRβ)19. Cediranib has not yet been approved for the treatment of ovarian cancer.
⦁ Chemistry and Preclinical studies
Cediranib is a 4-[(4-Fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[3-pyrrolidin-1- yl)propoxy]quinazoline. This indole-ether quinazoline has a molecular weight of
450.51 and is a potent ATP-competitive inhibitor of VEGF signalling by binding to the intracellular domain of all three VEGF receptor tyrosine kinases, but mainly through inhibition of the tyrosine kinase of VEGFR-2/Flk-1/KDR. In addition, cediranib significantly inhibits tyrosine kinase activity for c-Kit, PDGFR-α, PDGFR-β. The cediranib concentrations required to produce 50% inhibition were <0.001µmol/L for VEGFR-2, <0.003 µmol/L for VEGFR-3, <0.002 µmol/L for c-Kit, <0.036 µmol/L for PDGFR-α and <0.005 µmol/L for VEGFR-1 and PDGFR-β20.
Cediranib has been shown to inhibit vessel growth and sprouting in vitro and in vivo. Cediranib prevents VEGF-induced angiogenesis in vivo and shows dose-dependent activity in a range of human tumour xenografts in mice, including colon; lung; prostate; breast; and ovary. Drug concentrations ranged from 0.75mg/kg up to 6mg/kg, and statistical significant tumour growth inhibition was obtained with 1.5mg/kg/day in all tumour models. The inhibition of tumour growth is not limited to preventing new blood vessel formation. Other mechanisms include vascular regression and inhibition of VEGFR-3 mediated lymphangiogenesis20–25.
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Preclinical studies in ovarian cancer have shown that cediranib significantly reduced progression and improved survival in patient-derived ovarian cancer xenografts26–28. In a study utilising patient-derived ovarian cancer xenografts, cediranib potentiated chemotherapy, inhibiting tumour progression and dissemination to metastatic organs, even in tumours poorly responsive to platinum26. Xenograft mouse models have suggested that the effect of cediranib on the vasculature is consistent with a process of vascular normalization-reduced extravasation, decreased micro vessel permeability and tortuosity resulting in lower tumour hypoxia rates and improved oxygenation27,28.
⦁ Pharmacokinetics
Cediranib is an oral agent, administrated in the form of cediranib maleate tablets. The pharmacokinetics are linear within the dose range from 0.5 to 60mg29. The peak plasma concentration of cediranib is achieved within 1 to 8 hours post dose29,30. The apparent oral clearance is moderate and the overall mean terminal half-life is 22 h (12 to 36 hours)30. A 15mg to 20mg daily dose of cediranib is believed to be adequate for overall inhibition of in vitro estimated VEGFR-1,-2, and -3 activities29 and sustained anti-vascular effects with continuous cediranib has been shown for up to 16 weeks with significant reductions in dynamic contrast-enhanced magnetic resonance (DCE-MRI) parameters and CT enhancing fraction31.
The presence of food has been shown to reduce the cediranib area under curve (AUC) by 24% and the maximum plasma concentration (Cmax) by 33%31. Cediranib is recommended to be administered at least 1 h before or 2 h after food at doses of 15mg or 20mg daily; at 30mg dose daily level cediranib can be administrated with or
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without food, as adequate free systemic exposure for inhibition of VEGFR will be maintained, even after food reduces the exposure30.
Cediranib binds to serum albumin and α1-acid glycoprotein; protein binding in human plasma is approximately 95%. Cediranib is metabolized via flavin-containing monooxygenase 1 and 3 (FMO1, FMO3) and uridine 5'-diphospho- glucuronosyltransferase (UGT) 1A4. Cediranib and its metabolites are mainly excreted in faeces (59%), with <1% of unchanged drug being excreted in urine30.
Cediranib is a substrate of multidrug resistance-1 (MDR1) protein, co-administration with ketoconazole, a potent P-gp inhibitor, increases cediranib AUC at steady-state (AUCss) in patients by 21%, while co-administration with rifampicin, a potent inducer of P-gp, decreases cediranib AUC by 39%32. No dose adjustment is recommended for patients with mild or moderate hepatic; renal impairment; and no dose adjustment is needed on the basis of age and body weight33,29,30.
Cediranib has been administrated in combination with different chemotherapy agents (cisplatin, paclitaxel, carboplatin, oxaliplatin, 5-fluoracil, docetaxel, pemetrexed, irinotecan, gemcitabine). An increase in the terminal half-life of oxaliplatin was observed when administrated in combination with cediranib and an increase in irinotecan AUC and Cmax has been reported30. There has not been a specific clinical study to characterize cediranib PK in ovarian cancer. However, model-base simulations using pooled data from 19 phase I/II trials demonstrated that cediranib exposures from the 17 ovarian cancer patients are within the range of exposure of the non-ovarian cancer patients29. Of note, the clearance of carboplatin was similar when administrated with cediranib or alone, however; paclitaxel clearance when
administrated in combination with cediranib, decreased by approximately 20%
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compared with paclitaxel alone. The clinical relevance of this is not fully known- of note no increase in motor peripheral neuropathy was seen in the phase III trial, ICON6 which included patients whom received paclitaxel and cediranib30.
⦁ Efficacy in ovarian cancer
⦁ Cediranib single agent and combination with chemotherapy
The initial evidence for clinical activity was demonstrated in a phase I clinical trial34: In part A, patients with advanced solid tumours received once-daily oral cediranib from 0.5 mg/day to 60 mg/day and in part B patients with or without liver metastasis were randomly assigned to receive once-daily cediranib 20, 30, or 45mg (Table 1).
83 patients received cediranib, two confirmed radiological partial responses (PR) were reported (RECIST), one in a patient with prostate cancer in the 45mg cohort and the other in a renal cancer patient in the 60mg cohort. Stable disease was obtained in 22 patients; including one patient with ovarian cancer. There was evidence for dose-related control of tumour growth and cediranib was deemed to have biological activity at doses of 20mg or higher, with a suggested maximum tolerable dose (MTD) of 45mg34.
The encouraging results from the phase I trial led to the investigation of cediranib as a single agent in ovarian cancer patients. Several Phase II trials have now demonstrated efficacy and a more tolerable toxicity profile, after lowering the initial recommended dose of 45mg daily due to the toxicity profile (Table 2).
Matulonis et al35 conducted a phase II trial of cediranib in patients with recurrent epithelial ovarian cancer, fallopian tube or primary peritoneal cancer whom had
received up to two lines of chemotherapy for recurrence. The primary objective was
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to determine the clinical benefit of cediranib 45mg once-daily continuously in 28-day cycle, based on RECIST criteria or Gynaecological Cancer Intergroup (GCIG) modified CA125 response. Of note, the cediranib dose was modified to 30mg daily after the first 11 out of 47 patients were enrolled, due to the toxicities observed. The majority of patients included in this study had platinum resistant disease (65%); the median age was 56.5 years and the oldest patient enrolled was 78 years of age. Treatment was continued until disease progression or unacceptable toxicity. The overall clinical benefit (defined as complete response [CR] or partial response [PR], stable disease [SD] > 16 weeks, or CA-125 non-progression > 16 weeks) for the ITT population was 30% and overall ORR was 17% (all PR). 10 of 30 platinum-resistant and 4 of 16 platinum-sensitive patients achieved clinical benefit with cediranib. The median PFS was 5.2 months, which was independent of platinum sensitivity, and the mean overall survival (OS) was 16.3 months. The mean duration of response in the clinical benefit population was 3.9 months. Interestingly, all patients whom derived clinical benefit had high-grade serous histology and a maximum of one previous line of treatment for relapsed disease.
Hirte et al36 evaluated cediranib activity by assessing ORR at 16 weeks in patient who had persistent or recurrent ovarian/ primary peritoneal cancer after first line chemotherapy. The dose was reduced from 45 mg once-daily (continuous 28-day cycle) to 30mg once-daily after the first 23 patient were enrolled due to toxicity. The study enrolled 74 patients (35 with platinum-sensitive and 35 with platinum-resistant disease). In the platinum-sensitive cohort, 23% of patients achieved PR and 51% achieved stable disease (SD), clinical benefit rate was 77% (CR, PR, SD at 16 weeks). Although there were no confirmed responses in the platinum-resistant
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cohort, the clinical benefit rate for this population was 66%. Median PFS and OS for the entire cohort were 4.9 months and 18.9 months respectively. As expected, survival differences were observed between the platinum-sensitive and platinum- resistant cohorts, with significantly higher rates in the platinum-sensitive group for both PFS (7.2 months vs 3.7 months; p 0.02) and OS (27.7 months vs 11.9 months;
p 0.02).
Following these phases II trials demonstrating that single agent cediranib may have useful clinical activity, studies in combination with chemotherapy and other targeted therapies exploring combination options were developed. ICON 637,38 was a phase III, randomized, placebo-controlled of cediranib 30mg once-daily in combination with chemotherapy in patients with relapsed platinum-sensitive ovarian, fallopian tube or primary peritoneal cancer, with PFS as the primary endpoint (Table 2). Unfortunately, the ICON6 trial was prematurely terminated, due to a decision by AstraZeneca to discontinue the development of the molecule based on disappointing results in pivotal trials in other tumour types. Because of this, the primary endpoint was change to PFS and the trial consequently was underpowered for OS. By the time the study closed, 456 patients had been randomly allocated into three parallel treatment arms: Arm A platinum-based chemotherapy plus oral placebo tablets followed by placebo during the maintenance phase, Arm B platinum-based chemotherapy plus cediranib 30mg once-daily then switched to oral placebo during the maintenance phase; and Arm C platinum-based chemotherapy plus cediranib 30mg once-daily followed by maintenance cediranib at the same dose. Platinum- based treatment included carboplatin or cisplatin, single agent or in combination with paclitaxel or gemcitabine. Chemotherapy with cediranib/placebo was given for 6
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cycles and maintenance treatment was given until disease progression or unacceptable toxicity. The initial dose of cediranib 30mg was reduced after the first safety review, and the independent data monitoring committee recommended a reduction of cediranib dose to 20mg once-daily38. The median PFS was significantly higher in Arm C (cediranib with chemotherapy and continued as maintenance) at
11.0 months, compared to 8.7 months in the control arm (HR 0.56, 0.44-0.72 p<0.0001)37. The preliminary OS results with 52% of the events at cut off, showed no statistical significant differences in median OS between Arm C and A (26.3 months versus 21 months [HR 0.77, 95%CI 0.55-1.07; p=0.11]). Updated overall survival results were presented at ASCO 2017, after a median follow up of 25.6 month with 86% of the events at cut off, the median OS was 19.9 months for patients in Arm A and 27.3 months for those in Arm C (HR: 0.85 p=0.21)- this translates into a median difference of 7.4 months39.
The encouraging activity in terms of PFS in ICON6 and in trials of other malignancies helped resurrect the development of cediranib and further trials in ovarian cancer and other gynaecological malignancies are underway40.
6.2 Cediranib in combination with PARP inhibitors
Poly(ADP-ribose) polymerase (PARP) inhibitors are the latest class of agents to gain approval in ovarian cancer. There are several mechanisms of action including exploiting the DNA repair functions of PARP41. Olaparib has EMA (European Medicines Agency) approval as a maintenance therapy for patients with platinum sensitive relapsed BRCA mutated (germ-line or somatic) high-grade serous ovarian cancer and FDA (Food and Drug Administration) approval as a treatment for patients
with germ-line BRCA-mutated ovarian cancer who have received three or more lines
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of chemotherapy. More recently, niraparib gained FDA approval as maintenance therapy for ovarian cancer patients who have a response following platinum-based chemotherapy.
There has been growing interest in the combination of cediranib and PARP inhibitors. Enhanced PARP inhibition has been shown under hypoxic conditions. In addition, PARP inhibition has been reported to reduce VEGF-induced angiogenesis42 and increase VEGFR2 phosphorylation which can be reversed by a VEGFR2 inhibitor43. Therefore dual use of PARP-inhibitors and anti-angiogenics may have a synergistic effect44,45.
A phase I study aimed to explore the safety and tolerability of cediranib and olaparib in patients with ovarian, fallopian tube, primary peritoneal, and breast cancers46. 20 patients with ovarian, fallopian tube, or primary peritoneal cancer, and 8 patients with triple negative breast cancer were allocated to received cediranib plus olaparib capsules continuously in 28-day cycles until disease progression, unacceptable toxicity or patient withdrawal; the starting dose level was cediranib 20mg once-daily and olaparib 100mg BD and dose escalation occurred in a standard 3+3 design to cediranib 30mg once-daily and olaparib 400mg BD. Deleterious germline BRCA mutations were present in 60% of the ovarian cancer patients. Clinical activity amongst the 18 RECIST-evaluable ovarian cancer patients was observed, with an ORR of 44% (1 CR, 7 PR) and clinical benefit rate (ORR plus stable disease (SD) > 24 weeks) of 61%. Activity was observed in both platinum-sensitive and platinum- resistant patients, as well as in both BRCA mutated and BRCA wild type/unknown patients. Clinical activity with the combination of cediranib and olaparib was
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observed at all dose levels and the recommended phase II dose was cediranib 30mg once-daily and olaparib 200mg BD (capsules) on a continuous dosing schedule.
Subsequently, the combination of cediranib with olaprib was investigated in a randomized phase II study47 which included patients with relapsed platinum-sensitive high grade ovarian, fallopian tube or primary peritoneal cancers and primary endpoint of the study was PFS for the ITT population. Patients were allocated to olaparib capsules 400mg BD as a single agent or the combination of olaparib 200mg BD and cediranib 30mg once daily. Deleterious BRCA mutations were noted in 52% of patients in each arm, and approximately 20% had received three or more prior lines of therapy. The median PFS was 9 months in the olaparib arm and 17.7 months in the combination arm (HR 0.42, 95% CI 0.23 – 0.76, p=0.005). The ORR was 47.8% of patients in the olaparib only group and 76.6% of patients in the olaparib and cediranib arm. The OS at 24 months was 65% and 81% respectively (Table 2).
A post-hoc analysis of PFS and response rate demonstrated that the addition of cediranib improved PFS and response rate in the BRCA wild-type or BRCA unknown population, with a median PFS of 5.7 months in the olaparib arm and 16.5 months in the combination group, and an ORR of 32% and 75% respectively. For the BRCA mutated population, the combination of olaparib and cediranib led to significantly higher PFS (19.4 vs 16. 5 months) and ORR (84% vs 63%) compared to olaparib alone. Interestingly, the magnitude of improvement in PFS was greater in the BRCA wild-type/unknown group.
Updated results presented in ASCO 2017 confirmed the survival advantage of the
combination of cediranib and olaparib, with 74% of the patients having had a PFS event and 58% an OS event. There was a significant difference in median PFS, 8.2
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months for olaparib and 16.6 months for the combination arm (HR 0.50, 95% CI 0.30-0.83, p=0.007). Although the difference on median OS wasn’t statistically significant, there was a 10.9 month increase on median OS in those patients in the cediranib and olaparib arm (33.3 months for olaparib and 44.2 month for the cediranib and olaparib combination [HR 0.64, 95% CI 0.36-1.11, p=0.11]). This PFS survival advantage was particularly noted on the BRCA wild-type/unknown group, suggesting once more, that this group might benefit the most from the combination of cediranib and olaparib (PFS BRCA wild-type/unknown 5.7 vs 23.7 months HR 0.32, p=0.002)48.
The above results suggest that the combination of olaparib and cediranib has promising activity, with an improvement in both PFS and response rate irrespective of BRCA mutation status in both platinum-resistant and sensitive relapsed ovarian cancer. Further trials are underway, using the tablet formulation of olaparib.
6.3. Cediranib in combination with immunotherapy
Checkpoint inhibitors are currently under study for ovarian cancer with reported objective response rates between 10 to 17% in a subset of heavily pre-treated patients49. Generally so far, tumours with a higher mutational burden are associated with a greater response rate with checkpoint inhibitors than others50.
DNA damaged induced by antiangiogenic agents may complement the antitumor activity of immune checkpoint inhibition. The rationale behind this combination relies upon the knowledge that angiogenesis pathways interact with both DNA repair mechanisms and immune activity – tumour hypoxia induces downregulation of genes involved in DNA repair, leading to further DNA damage, genomic instability, and cell
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death51; PD-L1 expression is upregulated under hypoxic conditions, through a hypoxia-inducible factor–dependent mechanism52; VEGF suppresses lymphocyte trafficking across endothelia into neoplastic deposits and sites of inflammation to promote vessel growth53 and reduces the antitumor immune response including inhibition of T cell responses and increase of regulatory T cell proliferation.54
Cediranib was studied in combination with durvalumab, a monoclonal antibody against PD-L1 in a phase I trial55 and included women with advanced gynaecological tumours (Table 1). Patients were allocated to the cediranib plus durvalumab arm or olaparib plus durvalumab cohort. In both arms, three dose levels were tested. A total of 26 patients were enrolled in the study – 19 with ovarian cancer, the majority of whom had platinum resistant disease and no germline BRCA mutations. The recommended phase 2 doses for the cediranib in combination with durvalumab was cediranib 20 mg for 5 days on, 2 days off with durvalumab 1500 mg every 4 weeks. Daily cediranib with durvalumab was not well tolerated, cediranib was discontinued or dose reduced as a result of recurrent grade 2 or non-DLT grade 3 or 4 AEs in 7/8 patients.
6/12 patients in the cediranib plus durvalumab arm attained a partial response (50% ORR); 3 of those received dose level three (cediranib 20 mg 5day on 2 days off with durvalumab 1500 mg every 4 weeks), suggesting response was not attenuated with the intermittent cediranib schedule. There is currently a phase II expansion of the study ongoing (NTC02484404).
⦁ Toxicity and Quality of Life
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Drug induced toxicity is not uncommon among antiangiogenic agents, adequate selection of patients, awareness and correct management of drug-induced side effects helps improving treatment compliance.
Adverse events of special interest for antiangiogenic treatment are hypertension, thromboembolic events (arterial and venous), bleeding, wound healing impairment, proteinuria and gastrointestinal events including perforation and fistula. Monoclonal antibodies, such as bevacizumab, have a discontinuation rate between 14 to 20% due to adverse events. TKI toxicity profiles also include diarrhoea, haematological toxicity (neutropenia and thrombocytopenia), palmar-plantar eritrodicestesia and fatigue. Of note, 96% of patients on pazopanib, presented with an adverse event by week 6 and 33% discontinued treatment within the first 12 weeks due to and AE18.
⦁ Toxicity of cediranib single agent and in combination with chemotherapy
Drevs et al34, studied a wide range of cediranib doses in 83 patients with advance solid tumours. The most common adverse events in this trial were fatigue (n=47), diarrhoea (n=39), nausea (n=34), dysphonia (n=30), hypertension (n=29), vomiting (n=26), and anorexia (n=29). There were 21 dose-limiting toxicities (DLT) reported in this phase I study at doses of 20mg or higher. The most common DLTs were related to hypertension (hypertension in 7 patients and hypertensive crisis in 2 patients). Grade 3-4 drug related adverse events were hypertension (n=13), hypertensive crisis (n=3), GGT increase (n=3), palmar-plantar erythrodysesthesia (PPE) (n=3), and diarrhoea (n=2).
As discussed earlier, two phase II trials studied cediranib as monotherapy in patients with ovarian cancer; in both studies the initial dose was amended due to treatment-
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related toxicity (Table 3). Matulonis et al.35 reported toxicity results for 47 patients (first 11 patients treated at 45mg, subsequent patients with 30mg). The most common toxicities were diarrhoea (91%), fatigue (89%), hypertension (83%),
hypothyroidism (56%), mucositis (50%), voice changes (46%), nausea (41%),
headache (41%), abdominal pain (30%), proteinuria (24%), and vomiting (24%). The most common ≥grade 3 toxicities included hypertension (46%); fatigue (24%); and diarrhoea (13%). Dose reduction was necessary in 63% of patients. Indications for dose reductions were fatigue (52%); proteinuria (14%); hypertension (10%); mucositis (10%) and diarrhoea (3%)35. In the study by Hirte et al36, grade 3-4 dose- limiting toxicities including hypertension, myocardial ischaemia, liver enzymes increase and one fatal event of central nervous system haemorrhage. These adverse events led to a protocol amendment and dose modification from 45mg once- daily to 30mg once-daily. At this dose level, the most frequent adverse events were diarrhoea (84%), hypertension (71%) and fatigue (71%). Most common grade 3/4 toxicities were hypertension (27%), fatigue (20%), and diarrhoea (14%).
A stage I blinded safety analysis of the ICON6 trial 38 was carried out early to establish whether the addition of cediranib to platinum-based chemotherapy was sufficiently well tolerated to expand the ICON6 trial. Sixty patients taking cediranib 20< mg/placebo once daily met the predefined criteria. Grade 3/4 toxicity was experienced during chemotherapy by 55% of patients (n=33), and 19 patients discontinued trial drug. The most common grade 3 and grade 4 toxicities were neutropenia (14%), diarrhoea (12%), hypertension (7%), and fatigue (7%). Grade 2 hypertension was noted in 22% of the patients. The trial drug was administered
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without a dose reduction in 31 out of 60 patients during the first three cycles of chemotherapy, and 14 patients omitted at least one tablet of the trial drug.
The final tolerability results that included 456 patients enrolled within the ICON6 trial37 reported that 33% of patients discontinued treatment before progression or death. Discontinuation before progression was more common in the cediranib arms and overall, 28% of patients discontinued treatment due to adverse events (Arm A: 12%, Arm B 27%, and Arm C: 39%). The majority of toxicity-related discontinuations on the cediranib arms occurred while patients were receiving chemotherapy (21% chemotherapy vs 11% maintenance). Discontinuation due to toxicity was higher in the cediranib arms: 32% of patients discontinued cediranib during chemotherapy because of treatment-related side effects compared with 10% on the placebo arm, this was similar during the maintenance phase where 10% of the patients discontinued cediranib due to toxicity compared to 2% of the patients on placebo.
Side effects of all grades, during the chemotherapy phase were fatigue (93%), nausea/vomiting (80%), diarrhoea (79%), hypertension (51%), neutropenia (63%),
thrombocytopenia (43%), bleeding (21%), voice changes (15%), proteinuria (15%), and hypothyroidism (10%). Most common grade 3-4 adverse events in the cediranib arms during chemotherapy were neutropenia (26%), fatigue (16%), hypertension (12%), and diarrhoea (10%). During maintenance treatment, reported grade 3-4 adverse events in at least 5% of the patients on the cediranib arms were diarrhoea (12%), fatigue (6%), neutropenia (6%) and hypertension (5%).
⦁ Toxicity of cediranib in combination with olaparib
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The efficacy of the combination of cediranib and olaparib in ovarian cancer is encouraging, and the results of ongoing/planned phase III trials are awaited. However, this combination is not exempt from toxicity. In the phase I trial of the combination, 28 patients were enrolled to 4 dose levels (DL 0: cediranib 20mg; olaparib 100mg, DL1: cediranib 20mg; olaparib 200mg, DL2: cediranib 30mg; olaparib 200mg, and DL3: cediranib 30mg; olaparib 400mg). DLTs were reported at the highest dose level, including one grade 4 neutropenia and one grade 4 thrombocytopenia. All the patients experienced at least one treatment-related adverse event, most frequently fatigue (93%), diarrhoea (86%), nausea (57%) and hypertension (46%). Grade 3/4 adverse events were reported in 75% of patients (hypertension 25%, fatigue 18%, neutropenia 11%, diarrhoea 7%, and PPE 7%). The maximum tolerable dose (MTD) for the combination was cediranib 30mg once- daily with olaparib 200mg BD46.
The toxicity profile of the phase II trial of cediranib 30mg once-daily in combination with olaparib 200mg BD versus olaparib 400mg BD has also been reported47. Grade 3 or higher adverse events were more frequent in the combination arm: diarrhoea (23% vs. 0%, p = 0.0004), fatigue (27% vs. 11%, p = 0.06), and hypertension (41% vs. 0%, p<0.0001) and overall, more dose reductions occurred on the combination arm (77% vs 24%).
Adequate and early management of drug-induced toxicities is important for the safety of patients and treatment compliance in order to maximise patient outcomes and reduce the potential negative impact on quality of life. The quality of life (QOL) analysis of the ICON6 phase III trial reported no significant difference in global QOL between groups a year after treatment commenced, however self-reported symptom
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results showed that the main symptom reported by patients on cediranib was diarrhoea56.
⦁ Biomarkers
Biomarkers to identify patients most likely to benefit from antiangiogenic therapies and/or predict toxicity are much needed. Unfortunately, such biomarkers for clinical outcomes in women with epithelial ovarian cancer are lacking. VEGF-A, FGF, PDGF, Ang-2, and VEGFR-2 are among the most promising angiogenic biomarkers 57,58.
Results from the NCIC CTG BR.24 clinical trial in non-small cell lung cancer (NSCLC), showed that low baseline sVEGFR2 and sVEGFR3 were predictive for PFS benefit from cediranib, whereas increases in VEGF-A and decreases in sVEGFR2 or sVEGFR3 levels from baseline to on-treatment were predictive of an OS benefit from cediranib in chemotherapy treated NSCLC patients59. Further analysis from the same cohort of patients demonstrated that low baseline angiotensin-converting enzyme serum levels were prognostic of poor chemotherapy outcome and predictive of benefit from cediranib whereas an aldosterone increase with cediranib was correlated with better outcome60.
Pommier et al. studied treatment-related changes in circulating factors that may reflect physiological biomarkers or adaptive changes of the tumour following treatment with chemotherapy and cediranib/placebo in patients with colon cancer. 25 pharmacodynamic biomarker proteins were identified that correlated with PFS including MMP7, vWF, IL-8, MIF, TIE-2, KLK7, A-FABP, TNC or VEGFA. Patients
that were treated with chemotherapy and cediranib who showed an increase in
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MMP7, IL-8, CRP, A-FABP, TIMP1, VEGFD, IL-1RA, CTSD or COL-4 had a longer
OS time than those with decreased concentrations61.
In ovarian cancer, a translational sub-study which included 13 self-selected participants with platinum-sensitive ovarian cancer treated with the olaparib 200mg BD/cediranib 30mg OD combination (n=6) or olaparib 400mg BD single agent (n=7) within a multi-institutional randomized phase II study47 has been performed. Blood samples were collected prior the start of treatment and on day 3 of treatment. Patients on the combination arm had a median 3.5-fold increase in circulating endothelial cells (CEC) compared to 0.7 for patients on olaparib alone (p=0.032), along with a greater decrease in IL-8 concentration at day 3 (p< =< 0.026). PFS correlated with the fold increase in CEC on day 3 (R2< =< 0.77, 95% CI 0.55–0.97, p< << 0.001) and IL-8 post-pretreatment changes (p< =< 0.028). This exploratory translational study suggests that olaparib and cediranib caused vascular injury and decrease in angiogenesis indicated by an increase of CEC and decrease in IL-8, and these changes might be used as biomarkers for response to the olaparib/cediranib combination62.
Imaging biomarkers have also been studied in clinical trials of antiangiogenic agents. In the sub-analysis of the phase II trial conducted by Lie et al, dynamic contrast- enhanced magnetic resonance (DCE MRI) was performed to assess changes in vascular permeability and perfusion to characterize tumour vasculature changes. From the 13 self-selected patients, all except one had a reduction in both vascular permeability and perfusion, regardless of treatment arm. In this study, vascular flow
changes was not correlated with clinical outcome62. Dynamic contrast-enhanced
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magnetic resonance (DCE MRI) may be used as markers of vascular activity and serve as indicators of early response to cediranib treatment63.
⦁ Conclusion
Cediranib has demonstrated interesting encouraging activity in ovarian cancer, both in platinum sensitive and platinum resistant disease. The combination of this drug with standard chemotherapy in ovarian cancer has led to promising results in terms of PFS. Encouraging data, especially in combination with olaparib, has restored the enthusiasm for the molecule, in platinum sensitive patients, combination of cediranib and olaparib have shown benefit in PFS and ORR. These results need to be further investigated, but suggest that there may be several potential roles for the use of cediranib in a wide population of ovarian cancer patients.
⦁ Expert opinion
The addition of cediranib to the treatment landscape of ovarian cancer appears promising. Cediranib has demonstrated a significant improvement in PFS in a phase III trial when given with chemotherapy and continued as maintenance in platinum- sensitive relapsed ovarian cancer relapse. In addition, notable encouraging activity in combination with olaparib has been seen which is undergoing further evaluation in prospective clinical trials. Currently, the only antiangiogenic therapy with EMA or FDA approval for the treatment of ovarian cancer is bevacizumab.
There are a number of key questions that remain to be addressed for the future of cediranib in ovarian cancer. When, how and who should cediranib be used for? At the current time, a significant and increasing number of patients will have received bevacizumab either in the first line or relapsed setting. The efficacy of cediranib in
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patients who have previously received bevacizumab is unclear. Several ongoing trials permit the use of prior bevacizumab and may have specific restrictions eg. no bevacizumab within last 6 months, no bevacizumab for relapse. These will help answer the question regarding the activity post prior antiangiogenic agent. The different mechanism of action of VEGFR TKI compared with bevacizumab has the potential for activity after the development of bevacizumab resistance. The current clinical trials involving cediranib are in the recurrent setting- platinum-resistant and platinum-sensitive and the majority assess cediranib combinations. There is enthusiasm for the cediranib/PARP inhibitor combination and several studies are investigating cediranib and olaparib in a number of settings in relapsed disease- maintenance for platinum-sensitive ovarian cancer (ICON9), platinum- resistant/refractory (NCT0288990070, NCT0234526572, NCT0250226674), platinum- sensitive (NCT0234526572, NCT0244660075). The increased use of PARP inhibitors for patients with relapsed ovarian cancer poses additional complexity when assessing cediranib/PARP inhibitor combinations. The OCTOVA trial (NCT0311793373) assesses the combination of cediranib and olaparib in BRCA- mutated platinum resistant ovarian cancer and allows patients who have been treated with a prior PARP inhibitor or bevacizumab (> 6 months interval since treatment). In this randomised study that has recently opened to recruitment, patients receive either the combination, olaparib alone or weekly paclitaxel. Treating patients with the cediranib-olaparib combination at the time of progression on a PARP inhibitor to restore sensitivity is an interesting concept also being explored (NCT0234061169, NCT0268123771).
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Other combinations of interest include cediranib with immunotherapy, which is being explored currently in the phase I/II setting (durvalumab, antiPD-L1 (Medimmune/Astrazeneca, NCT0248440467)
Cediranib has also been explored in other gynaecological tumours beyond ovarian cancer (Table 4). In the CIRCCa trial, a phase II study in which patients with metastatic or relapsed cervical cancer were randomised to receive platinum based chemotherapy with or without cediranib combination and maintenance, cediranib significant improved PFS (median 8.1 months vs 6.7 months; HR= 0.58 80% CI 0·40- 0·85; one-sided p=0·032) and the toxicity profile was as expected, in keeping with the experience in other tumours (mainly diarrhoea, hypertension, and febrile neutropenia).40 Cediranib has also been studied in recurrent/persistent endometrial cancer64. The further development of cediranib in ovarian cancer and other gynaecological malignancies are currently being explored66-75.
Clinical trials will help define whether cediranib has a role in standard clinical practice for patients with ovarian cancer and which clinical scenario provides the optimal benefit. The tolerability of cediranib has the potential to limit its use and therefore, awareness of side effects, adequate evaluation and timely management of drug- induced adverse events is critical. Finally, there is an urgent need to develop biomarkers for the identification of patients most likely to derive the maximum benefit as the escalating costs of targeted therapies remains prohibitive.
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Drug summery
Drug Name Cediranib
Phase III
Indication License not granted, currently under study for recurrent ovarian cancer
Pharmacology description/
mechanism of action Inhibitor of VEGF signalling that binds all three VEGFR (VEGFR- 1, VEGFR-2 and VEGFR-3), with pronounced selectivity for VEGFR2; together with c-Kit, the platelet derived growth factor receptor alpha and beta (PDGFRα and PDGFRβ)
Route of administration Oral
Chemical structure 4-[(4-Fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[3-pyrrolidin- 1-yl)propoxy]quinazoline
Pivotal trials ⦁ Cediranib in patients with relapsed platinum-sensitive ovarian cancer (ICON6): a randomised, double-blind, placebo- controlled phase 3 trial. Ledermann JA et al. 2016 (37)
⦁ Combination cediranib and olaparib versus olaparib alone for women with recurrent platinum-sensitive ovarian cancer: a randomised phase 2 study. Liu JF et al. (47)
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Abbreviations
A-FABP: fatty acid-binding protein A AUC: area under curve
AUCss: area under curve steady-steate BD: twice daily
CEC: circulating endothelial cells CI: confidence interval
Cmax: maximum plasma concentration COL-4: Collagen, Type IV
CRP: C-Reactive Protein CTSD: Cathepsin D
DCE-MR: dynamic contrast-enhanced magnetic resonance DLT: dose-limiting toxicity
EMA: European Medicines Agency FDA: Food and Drug Administration
FGFR1: fibroblast growth factor receptor 1 HR: hazard ratio
IDS: interval debulking surgery
IL-1RA: Interleukin 1 Receptor Antagonist IL-8: interleukin 8
ITT: intent to treat
KLK7: kallikrein-related peptidase 7 MDT: maximum tolerable dose
MIF: macrophage migration inhibitory factor MMP-7: matrix metalloproteinase-7 NSCLC: non-small cell lung cancer
OD: once daily
ORR: objective response rate OS: overall survival
PARP: Poly(ADP-ribose)polymerase
PDGFRα: Platelet derived growth factor receptor alpha PDGFRβ: Platelet derived growth factor receptor beta PFS: progression free survival
PPE: palmar-plantar erythrodysesthesia PR: partial response
QOL: quality of life SD: stable disease
TIE-2: receptor tyrosine kinase, endothelial, TIE-2 TIMP1: TIMP Metallopeptidase Inhibitor 1
TKI: Tyrosine kinase inhibitor TNC: tenascin C
VEGF: Vascular endothelial growth factor vWF: Von Willebrand factor
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References
Papers of special interest have been highlighted as:
*of interest
**of considerable interest
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Table 1: Cediranib Phase I trials including gynaecological malignancies
Study N Tumour type Treatment Response Grade 3-4 toxicities Ref.
Drevs et al. (2007) 36 Advanced Solid Tumours
(included ovarian and cervical tumours) Cediranib 20, 30, or 45 mg OD 2 PR and 22 SD Grade 3 hypertension:13 patients Grade 4 hypertensive crisis: 3 patients. [34]
Liu et al. (2013) 28 Recurrent epithelial ovarian or triple-negative breast cancer DL 0: cediranib 20mg OD; olaparib 100mg BD
DL1: cediranib 20mg OD; olaparib 200mg BD DL2: cediranib 30mg OD; olaparib 200mg BD
DL3: cediranib 30mg OD; olaparib
400mg BD ORR 44% (ovarian cancer) Clinical benefit rate 61% 75% of patients experienced grade 3/4 AE Grade 3 hypertension:25%
Grade 3 fatigue:18%
Grade 3/4 neutropenia:11% Grade 3 diarrhoea: 7%
Grade 3/4 platelet decrease: 7%
Grade 3 PPE: 7% [46]
Hong et al. (2014) 51 Advanced solid tumours (included 2 endometrial cancer and 2 ovarian tumours) Bevacizumab d1 and 15 concurrent with cediranib orally on days 1 to every 28 days. 4 PR Grade 3 chest pain (1 patient)
Grade 3 fatigue (1 patient)
Grade 3 thrombocytopenia (2 patients)
Grade 3 hypertension (3 patients)
Grade 5 haemoptysis (1 patient)
Grade 3 intracranial bleeding (2 patients) [65]
Lee et al. (2017) 26 Advance gynaecological cancer
⦁ Ovarian cancer: 19 pts
⦁ Triple negative breast cancer: 2pts
⦁ Squamous cervical cancer:2pts
⦁ Uterine cancer: 3 pts Cohort 1: Olaparib (O) plus Durvalumab (D)
DL1: O 200mg BD and D 10mg/kg every 2 weeks.
DL2: O 300mg BD and D 10mg/kg every 2 weeks.
DL3: O 300mg BD and D 1500mg every 4 weeks.
Cohort 2: Cediranib (C) plus Durvalumab (D)
DL1: C 20mg OD and D 10mg/kg
every 2 weeks ORR 17% (2/12pts)
Disease control rate 83% (10/12 pts)
ORR 50% (6/12 pts) Olaparib plus Durvalumab: Grade 3 lymphopenia
Grade 3 anaemia
Cediranib daily plus Durvalumab: Grade 3-4 lymphopenia
Grade 3 anaemia
Grade 3 nausea
Grade 3 diarrhoea
Grade 3 colitis
Grade 3 fatigue
Grade 3 headache
Grade 3 hypertension [55]
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DL2: C 30mg OD and D 10mg/kg every 2 weeks
DL3: C20mg (5 days on 2 days off) and D 1500mg every 4 weeks. Grade 3 PE
Grade 3 pulmonary hypertension
Cediranib intermittent plus Durvalumab: Grade 3 fatigue
Grade 4 hypertension
PR: partial response, SD: Stable disease, ORR: Objective response rate, OD: once daily, BID: twice daily, DL: dose level, AE adverse events, PPE: palmar- plantar erythrodysesthesia, PE: pulmonary embolism.
Table 2: Cediranib Phase II and III trials ovarian, primary peritoneal and fallopian tube cancer
Study Phase N Drug & Schedule PFS OS ORR Ref.
Matulonis et al (2009) II 47 Cediranib 45 mg/m2
*Reduced to 30 mg/m2 due to toxicities 5.2 months 16.3 months 30% [35]
Hirte et al. (2015) II 74 Cediranib 45 mg/m2
*Reduced to 30 mg/m2 due to toxicities 4.9 months
Platinum sensitive: 7.2 months Platinum resistant: 3.7 months 18.9months
Platinum sensitive: 27.7months Platinum Resistant: 11.9months [36]
Liu et al (2014) II 90 A: Olaparib 400 mg BD
B: Olaparib 200 mg BD + Cediranib 30 mg daily 8.2 months
16.5 months
HR 0.50, 95% CI 0.30-0.83, p=0.007 33.3 months
44.4 months
HR 0.64, 95% CI 0.36-1.11, p=0.11 47.8 %
79.6 % [47, 48]
BRCA mutation carrier (n=48) A (n=25): Olaparib 400 mg BD
B (n=23): Olaparib 200 mg BD + Cediranib 30 mg daily
5.7 months
23.7 months
HR 0.32, p=0.002
23 months
37.8 months
HR 0.48, p=0.074
BRCA wild type/unknown (n=42)
16.5 months
40.1 months
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A: Olaparib 400 mg BD
B: Olaparib 200 mg BD + Cediranib 30 mg daily 16.4 months
(HR 0.75, p=0.42) 44.2 months
(HR 0.79, p=0.55)
Ledermann et al (2016) ICON6 III 486 A: Carboplatin combination + placebo + maintenance placebo 8.7 months 19.9 months NR [37, 39]
B: Carboplatin combination + Cediranib 20 mg+ maintenance placebo
10.1 months
HR 0.67 (0-53-0.87, p 0.0022)
C: Carboplatin combination + Cediranib 20 mg daily + maintenance Cediranib 20 mg
11.1 months
HR 0.57 (0.44-0.74, p 0.00001)
27.3 months
HR 0.85 (0.66-1.10, p=0.21)
Table 3: Cediranib grade 3 and grade 4 toxicities reported on the phase II and III trials
Study Phase N Grade 3-4 adverse events Drug discontinuation/reduction due to toxicity Ref.
Matulonis et al II 47 Cediranib 45mg OD (n=11) Hypertension (46%)
Fatigue (24%)
Diarrhoea (13%)
*grade 4 adverse events: 1 hypercholesterolemia, elevated lipase, and hypertriglyceridemia, 1 dehydration, 1 creatinine increase, 1 CNS haemorrhage in the setting of grade 2 hypertension. Dose reduction: 63% of patients had a dose reduction.
Cediranib 45mg OD (n=11): 72% had at least one dose reduction. Cediranib 30mg OD (n=35): 60% required a dose reduction.
Most common reasons for a dose reduction were: fatigue (52%), diarrhoea (31%), proteinuria (14%), hypertension (10%), and mucositis (10%). [35]
(2009)
Hirte et al. II 74 Cediranib 45mg OD (n=23)
Hypertension (35%) 19 patients discontinued due to adverse events.
Most common grade 3 or higher adverse events leading to discontinuation were: [36]
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(2015) Fatigue (30%)
*grade 4 adverse events: 1 ALT increase, 1 AST increase, 1 abdominal pain, 2 episodes of myocardial ischaemia, 2 grade 2 hypertension and 1 fatal CNS haemorrhage.
Cediranib 30mg OD (n=51) Hypertension (27%)
Fatigue (20%)
Diarrhoea (14%) diarrhoea (n=1), fatigue (n=2), PPE (n=1), headache (n=2), obstruction (n=2), hypertension (n=5), myocardial ischaemia (n=1), thrombosis (n=2) and intracranial haemorrhage (n=1).
Liu et al (2014) II 90 Cediranib (C) 30mg OD olaparib (O) 200mg BD combination versus olaparib (O) 400mg BD
Hypertension (41% vs. 0%)
Fatigue (27% vs. 11%)
Diarrhoea (23% vs. 0%)
*grade 4 events: one hypertensive crisis on cycle 1 and one myelodysplastic syndrome on cycle 14. Dose reduction: 77% in the C-O arm vs 24% in the O arm.
All patients on the C-O combination had at least one reduction of cediranib and 23% also a reduction of olaparib.
Discontinuation: 4 pts were withdrawn due to toxicity (all in the C-O arm): 1 myelodysplastic syndrome, 1 persistent weight loss, 1 recurrent avascular necrosis of the hips, and 1 new rectovaginal fistula. [47]
Ledermann et al (2016) ICON6 III 486 Cediranib plus chemotherapy phase Neutropenia (26%)
Fatigue (16%)
Hypertension (12%)
Diarrhoea (10%)
Cediranib maintenance phase Diarrhoea (12%)
Fatigue (6%) Discontinuation of cediranib/placebo before progression: 33% Overall discontinuation rate due to toxicity: 28%
Arm A: 12%, Arm B 27%, Arm C 39%
Discontinuation rate during chemotherapy phase: 21% Arm A: 7%, Arm B: 23%, Arm C 27%
Discontinuation rate during maintenance phase: 11% Arm A: 5%, Arm B: 7%, Arm C 20% [37]
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Neutropenia (6%)
Hypertension (5%)
*Seven grade 5 serious adverse events were reported:
Arm A: pneumonia and somnolence; Arm B: pneumonia, gastrointestinal perforation and cardiac ischaemia; Arm C: pancreatitis and hypoxia.
ICON6 trial: Arm A: Carboplatin combination + placebo + maintenance placebo, Arm B: Carboplatin combination + Cediranib 20 mg+ maintenance placebo, Arm C: Carboplatin combination + Cediranib 20 mg daily + maintenance Cediranib 20 mg.
OD: once-daily, BD: tice daily, PPE: Palmar-Plantar Erythrodysesthesia
Table 4: Cediranib phase II-III clinical trials in gynaecological tumours
Study N Tumour Drug & Schedule PFS OS ORR Ref.
Symonds et al. (2015) 69 Cervical cancer A: Carboplatin AUC 5 Pacitaxel 175mg/m2 6 cycles + cediranib 20mg OD 8.1 months 13.6 months 64% [40]
Phase II B: Carboplatin AUC 5 Pacitaxel 175mg/m2 6 cycles + pacebo 20mg OD 6.7 months 14.8 months
45%
(HR 0.58 p=0.032) (HR 0.94 p=0.42)
Bender et a (2015)
Phase II 53 Endometrial cancer Cediranib 30mg orally daily 3.65 months 12.5 months PR 12.5%
EFS 29% [64]
OD: once daily, PR: partial response, EFS: event free survival