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Joyce F Liu - One of the best experts on this subject based on the ideXlab platform.
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a phase iii study comparing single agent olaparib or the combination of Cediranib and olaparib to standard platinum based chemotherapy in recurrent platinum sensitive ovarian cancer
Journal of Clinical Oncology, 2020Co-Authors: Joyce F Liu, Ursula A Matulonis, Elise C Kohn, Elizabeth M Swisher, Mark F Brady, Austin Miller, William P Tew, Noelle Gillette Cloven, Carolyn Y Muller, David P BenderAbstract:6003Background: Combination Cediranib (C) and olaparib (O) improved progression-free survival (PFS) in patients (pts) with relapsed platinum (plat)-sensitive high-grade ovarian cancer (ovca) compar...
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Overall survival and updated progression-free survival outcomes in a randomized phase II study of combination Cediranib and olaparib versus olaparib in relapsed platinum-sensitive ovarian cancer.
Annals of oncology : official journal of the European Society for Medical Oncology, 2019Co-Authors: Joyce F Liu, Michael J. Birrer, William T Barry, J M Lee, Ronald J. Buckanovich, Gini F. Fleming, Bobbie J. Rimel, Mary K. Buss, Sreenivasa Nattam, Jean A. HurteauAbstract:Abstract Background Olaparib is a poly(ADP-ribose) polymerase inhibitor and Cediranib is an oral anti-angiogenic. In the primary analysis of this phase II study, combination Cediranib/olaparib improved progression-free survival (PFS) compared with olaparib alone in relapsed platinum-sensitive ovarian cancer. This updated analysis was conducted to characterize overall survival (OS) and update PFS outcomes. Patients and methods Ninety patients were enrolled to this randomized, open-label, phase II study between October 2011 and June 2013 across nine United States-based academic centers. Data cut-off was 21 December 2016, with a median follow-up of 46months. Participants had relapsed platinum-sensitive ovarian cancer of high-grade serous or endometrioid histology or had a deleterious germline BRCA1/2 mutation (gBRCAm). Participants were randomized to receive olaparib capsules 400mg twice daily or Cediranib 30mg daily and olaparib capsules 200mg twice daily until disease progression. Results In this updated analysis, median PFS remained significantly longer with Cediranib/olaparib compared with olaparib alone (16.5 versus 8.2months, hazard ratio 0.50; P=0.007). Subset analyses within stratum defined by BRCA status demonstrated statistically significant improvement in PFS (23.7 versus 5.7months, P=0.002) and OS (37.8 versus 23.0months, P=0.047) in gBRCA wild-type/unknown patients, although OS was not statistically different in the overall study population (44.2 versus 33.3months, hazard ratio 0.64; P=0.11). PFS and OS appeared similar between the two arms in gBRCAm patients. The most common CTCAE grade 3/4 adverse events with Cediranib/olaparib remained fatigue, diarrhea, and hypertension. Conclusions Combination Cediranib/olaparib significantly extends PFS compared with olaparib alone in relapsed platinum-sensitive ovarian cancer. Subset analyses suggest this margin of benefit is driven by PFS prolongation in patients without gBRCAm. OS was also significantly increased by the Cediranib/olaparib combination in this subset of patients. Additional studies of this combination are ongoing and should incorporate analyses based upon BRCA status. Trial Registration Clinicaltrials.gov Identifier NCT0111648
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a phase 2 biomarker trial of combination Cediranib and olaparib in relapsed platinum plat sensitive and plat resistant ovarian cancer ovca
Journal of Clinical Oncology, 2018Co-Authors: Joyce F Liu, William T Barry, Jungmin Lee, Robert M Wenham, Andrea Wahner E Hendrickson, Deborah K Armstrong, Nancy Chan, David E Cohn, Richard T Penson, Mihaela C CristeaAbstract:5519Background: The combination of Cediranib (ced) and olaparib (olap) improves progression-free survival and overall response rates (ORR) in women with recurrent plat sensitive high-grade serous (...
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Cediranib a pan vegfr inhibitor and olaparib a parp inhibitor in combination therapy for high grade serous ovarian cancer
Expert Opinion on Investigational Drugs, 2016Co-Authors: S P Ivy, Joyce F Liu, Ursula A Matulonis, J M Lee, Elise C KohnAbstract:ABSTRACTIntroduction: An estimated 22,000 women are diagnosed annually with ovarian cancer in the United States. Initially chemo-sensitive, recurrent disease ultimately becomes chemoresistant and may kill ~14,000 women annually. Molecularly targeted therapy with Cediranib (AZD2171), a vascular endothelial growth factor receptor (VEGFR)-1, 2, and 3 signaling blocker, and olaparib (AZD2281), a poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor, administered orally in combination has shown anti-tumor activity in the treatment of high grade serous ovarian cancer (HGSOC). This combination has the potential to change the treatment of HGSOC.Areas covered: Preclinical and clinical studies of single agent Cediranib and olaparib or their combination are reviewed. Data are presented from peer-reviewed published manuscripts, completed and ongoing early phase clinical trials registered in ClinicalTrials.gov, National Cancer Institute-sponsored clinical trials, and related recent abstracts.Expert opin...
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combination Cediranib and olaparib versus olaparib alone for women with recurrent platinum sensitive ovarian cancer a randomised phase 2 study
Lancet Oncology, 2014Co-Authors: Joyce F Liu, Michael J. Birrer, William T Barry, Ronald J. Buckanovich, Gini F. Fleming, Bobbie J. Rimel, Mary K. Buss, Sreenivasa Nattam, Jungmin Lee, Jean A. HurteauAbstract:Summary Background Olaparib is a poly(ADP-ribose) polymerase inhibitor and Cediranib is an anti-angiogenic agent with activity against VEGF receptor (VEGFR) 1, VEGFR2, and VEGFR3. Both oral agents have antitumour activity in women with recurrent ovarian cancer, and their combination was active and had manageable toxicities in a phase 1 trial. We investigated whether this combination could improve progression-free survival (PFS) compared with olaparib monotherapy in women with recurrent platinum-sensitive ovarian cancer. Methods In our randomised, open-label, phase 2 study, we recruited women (aged ≥18 years) who had measurable platinum-sensitive, relapsed, high-grade serous or endometrioid ovarian, fallopian tube, or primary peritoneal cancer, or those with deleterious germline BRCA1 /2 mutations from nine participating US academic medical centres. We randomly allocated participants (1:1) according to permuted blocks, stratified by germline BRCA status and previous anti-angiogenic therapy, to receive olaparib capsules 400 mg twice daily or the combination at the recommended phase 2 dose of Cediranib 30 mg daily and olaparib capsules 200 mg twice daily. The primary endpoint was progression-free survival analysed in the intention-to-treat population. The phase 2 trial is no longer accruing patients. An interim analysis was conducted in November, 2013, after 50% of expected events had occurred and efficacy results were unmasked. The primary analysis was performed on March 31, 2014, after 47 events (66% of those expected). The trial is registered with ClinicalTrials.gov, number NCT01116648. Findings Between Oct 26, 2011, and June 3, 2013, we randomly allocated 46 women to receive olaparib alone and 44 to receive the combination of olaparib and Cediranib. Median PFS was 17·7 months (95% CI 14·7–not reached) for the women treated with Cediranib plus olaparib compared with 9·0 months (95% CI 5·7–16·5) for those treated with olaparib monotherapy (hazard ratio 0·42, 95% CI 0·23–0·76; p=0·005). Grade 3 and 4 adverse events were more common with combination therapy than with monotherapy, including fatigue (12 patients in the Cediranib plus olaparib group vs five patients in the olaparib monotherapy group), diarrhoea (ten vs none), and hypertension (18 vs none). Interpretation Cediranib plus olaparib seems to improve PFS in women with recurrent platinum-sensitive high-grade serous or endometrioid ovarian cancer, and warrants study in a phase 3 trial. The side-effect profile suggests such investigations should include assessments of quality of life and patient-reported outcomes to understand the effects of a continuing oral regimen with that of intermittent chemotherapy. Funding American Recovery and Reinvestment Act grant from the National Institutes of Health (NIH) (3 U01 CA062490-16S2); Intramural Program of the Center for Cancer Research; and the Division of Cancer Treatment and Diagnosis, National Cancer Institute, NIH.
Tracy T Batchelor - One of the best experts on this subject based on the ideXlab platform.
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improved tumor oxygenation and survival in glioblastoma patients who show increased blood perfusion after Cediranib and chemoradiation
Proceedings of the National Academy of Sciences of the United States of America, 2013Co-Authors: Elizabeth R. Gerstner, Tracy T Batchelor, Dan G Duda, Jayashree Kalpathycramer, Kyrre E Emblem, Matija Snuderl, Marek AncukiewiczAbstract:Antiangiogenic therapy has shown clear activity and improved survival benefit for certain tumor types. However, an incomplete understanding of the mechanisms of action of antiangiogenic agents has hindered optimization and broader application of this new therapeutic modality. In particular, the impact of antiangiogenic therapy on tumor blood flow and oxygenation status (i.e., the role of vessel pruning versus normalization) remains controversial. This controversy has become critical as multiple phase III trials of anti-VEGF agents combined with cytotoxics failed to show overall survival benefit in newly diagnosed glioblastoma (nGBM) patients and several other cancers. Here, we shed light on mechanisms of nGBM response to Cediranib, a pan-VEGF receptor tyrosine kinase inhibitor, using MRI techniques and blood biomarkers in prospective phase II clinical trials of Cediranib with chemoradiation vs. chemoradiation alone in nGBM patients. We demonstrate that improved perfusion occurs only in a subset of patients in Cediranib-containing regimens, and is associated with improved overall survival in these nGBM patients. Moreover, an increase in perfusion is associated with improved tumor oxygenation status as well as with pharmacodynamic biomarkers, such as changes in plasma placenta growth factor and sVEGFR2. Finally, treatment resistance was associated with elevated plasma IL-8 and sVEGFR1 posttherapy. In conclusion, tumor perfusion changes after antiangiogenic therapy may distinguish responders vs. nonresponders early in the course of this expensive and potentially toxic form of therapy, and these results may provide new insight into the selection of glioblastoma patients most likely to benefit from anti-VEGF treatments.
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phase iii randomized trial comparing the efficacy of Cediranib as monotherapy and in combination with lomustine versus lomustine alone in patients with recurrent glioblastoma
Journal of Clinical Oncology, 2013Co-Authors: Tracy T Batchelor, Antje Wick, Burton L Nabors, Paul Mulholland, Surasak Phuphanich, Mario Campone, Tom Mikkelsen, Warren P Mason, Bart Neyns, Lynn S AshbyAbstract:Purpose A randomized, phase III, placebo-controlled, partially blinded clinical trial (REGAL [Recentin in Glioblastoma Alone and With Lomustine]) was conducted to determine the efficacy of Cediranib, an oral pan–vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor, either as monotherapy or in combination with lomustine versus lomustine in patients with recurrent glioblastoma. Patients and Methods Patients (N = 325) with recurrent glioblastoma who previously received radiation and temozolomide were randomly assigned 2:2:1 to receive (1) Cediranib (30 mg) monotherapy; (2) Cediranib (20 mg) plus lomustine (110 mg/m2); (3) lomustine (110 mg/m2) plus a placebo. The primary end point was progression-free survival based on blinded, independent radiographic assessment of postcontrast T1-weighted and noncontrast T2-weighted magnetic resonance imaging (MRI) brain scans. Results The primary end point of progression-free survival (PFS) was not significantly different for either Cediranib alone...
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effects of Cediranib vegf signaling inhibitor on edema in newly diagnosed glioblastoma patients during initial chemoradiation
Journal of Clinical Oncology, 2012Co-Authors: Pavlina Polaskova, Tracy T Batchelor, Rakesh K. Jain, Gregory A. Sorensen, Marco C Pinho, Jayashree Kalpathycramer, Alexander R Guimaraes, Patrick Y Wen, Elizabeth R. GerstnerAbstract:2012 Background: A significant benefit of antiangiogenic therapy is control of brain edema. We evaluated the impact of adding Cediranib to standard chemoradiation (CRT) on peritumoral edema in patients with newly diagnosed glioblastoma(GBM) during the initial 6 weeks of CRT. Methods: Two cohorts of patients were enrolled in two clinical trials. The control group (N=13) received radiation for 6 weeks plus temozolomide. The Cediranib (CED) group received standard CRT plus daily Cediranib (N=34). MRIs were performed at baseline and weekly during CRT. Volumes of interest (VOIs) were drawn outlining the enhancing tumor on T1-weighted post contrast images and the abnormal FLAIR hyperintensity. ADC (apparent diffusion coefficient) maps were calculated from diffusion-weighted images and histograms of the distribution of ADC values created for each visit using the baseline FLAIR VOI to characterize the peritumoraledema. Patients were on stable or decreasing doses of steroids. Results: In the CED group, T1 and FLAI...
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phase ii study of Cediranib an oral pan vascular endothelial growth factor receptor tyrosine kinase inhibitor in patients with recurrent glioblastoma
Journal of Clinical Oncology, 2010Co-Authors: Tracy T Batchelor, Emmanuelle Di Tomaso, Scott R Plotkin, April F Eichler, Elizabeth R. Gerstner, Fred H Hochberg, Marek Ancukiewicz, Jan Drappatz, Dan G Duda, Thomas BennerAbstract:Purpose Glioblastoma is an incurable solid tumor characterized by increased expression of vascular endothelial growth factor (VEGF). We performed a phase II study of Cediranib in patients with recurrent glioblastoma. Methods Cediranib, an oral pan-VEGF receptor tyrosine kinase inhibitor, was administered (45 mg/d) until progression or unacceptable toxicity to patients with recurrent glioblastoma. The primary end point was the proportion of patients alive and progression free at 6 months (APF6). We performed magnetic resonance imaging (MRI) and plasma and urinary biomarker evaluations at multiple time points. Results Thirty-one patients with recurrent glioblastoma were accrued. APF6 after Cediranib was 25.8%. Radiographic partial responses were observed by MRI in 17 (56.7%) of 30 evaluable patients using three-dimensional measurements and in eight (27%) of 30 evaluable patients using two-dimensional measurements. For the 15 patients who entered the study taking corticosteroids, the dose was reduced (n = 10...
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a vascular normalization index as potential mechanistic biomarker to predict survival after a single dose of Cediranib in recurrent glioblastoma patients
Cancer Research, 2009Co-Authors: Gregory A. Sorensen, Tracy T Batchelor, Johanna Lahdenranta, Patrick Y Wen, Weiting Zhang, Poejou Chen, Priscilla Yeo, Meiyun Wang, Dominique Jennings, Marek AncukiewiczAbstract:Early imaging or blood biomarkers of tumor response are desperately needed to customize antiangiogenic therapy for cancer patients. Anti–vascular endothelial growth factor (VEGF) therapy can “normalize” brain tumor vasculature by decreasing vessel diameter and permeability, and thinning the abnormally thick basement membrane. We hypothesized that the extent of vascular normalization will be predictive of outcome of anti-VEGF therapy in glioblastoma. We used advanced magnetic resonance imaging methods to monitor vascular parameters and treatment response in 31 recurrent glioblastoma patients enrolled in a phase II trial of Cediranib, an oral pan-VEGF receptor tyrosine kinase inhibitor. We evaluated the correlation between clinical outcome and magnetic resonance imaging–measured changes in vascular permeability/flow (i.e., K trans ) and in microvessel volume, and the change of circulating collagen IV levels, all after a single dose of Cediranib. Here, we show that evaluation of biomarkers as early as after one day of anti-VEGF therapy with Cediranib is predictive of response in patients with recurrent glioblastoma. Changes in K trans , microvessel volume, and circulating collagen IV correlated with duration of overall survival and/or progression-free survival ( P P = 0.004) and progression-free survival (ρ = 0.6; P = 0.001). The vascular normalization index described here should be validated in randomized clinical trials. [Cancer Res 2009;69(13):5296–300]
Jungmin Lee - One of the best experts on this subject based on the ideXlab platform.
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Cediranib in combination with olaparib in patients without a germline brca1 2 mutation with recurrent platinum resistant ovarian cancer phase iib concerto trial
Journal of Clinical Oncology, 2020Co-Authors: Jungmin Lee, Richard G Moore, Sharad A Ghamande, Min S Park, John P Diaz, Julia Chapman, James E Kendrick, Brian M Slomovitz, Krishnansu S Tewari, Elizabeth S LoweAbstract:6056Background: A Phase I trial (NCT01116648) of Cediranib (cedi) in combination with olaparib (ola) (cedi + ola) demonstrated an overall response rate of 44% in patients (pts) with recurrent ovari...
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a phase 2 biomarker trial of combination Cediranib and olaparib in relapsed platinum plat sensitive and plat resistant ovarian cancer ovca
Journal of Clinical Oncology, 2018Co-Authors: Joyce F Liu, William T Barry, Jungmin Lee, Robert M Wenham, Andrea Wahner E Hendrickson, Deborah K Armstrong, Nancy Chan, David E Cohn, Richard T Penson, Mihaela C CristeaAbstract:5519Background: The combination of Cediranib (ced) and olaparib (olap) improves progression-free survival and overall response rates (ORR) in women with recurrent plat sensitive high-grade serous (...
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safety and clinical activity of the programmed death ligand 1 inhibitor durvalumab in combination with poly adp ribose polymerase inhibitor olaparib or vascular endothelial growth factor receptor 1 3 inhibitor Cediranib in women s cancers a dose esca
Journal of Clinical Oncology, 2017Co-Authors: Jungmin Lee, Ashley Ciminomathews, Cody J Peer, Alexandra S Zimmer, Stanley Lipkowitz, Christina M Annunziata, Liang Cao, Maria I Harrell, Elizabeth M Swisher, Nicole D HoustonAbstract:Purpose Data suggest that DNA damage by poly (ADP-ribose) polymerase inhibition and/or reduced vascular endothelial growth factor signaling by vascular endothelial growth factor receptor inhibition may complement antitumor activity of immune checkpoint blockade. We hypothesize the programmed death-ligand 1 (PD-L1) inhibitor, durvalumab, olaparib, or Cediranib combinations are tolerable and active in recurrent women's cancers. Patients and Methods This phase I study tested durvalumab doublets in parallel 3 + 3 dose escalations. Durvalumab was administered at 10 mg/kg every 2 weeks or 1,500 mg every 4 weeks with either olaparib tablets twice daily or Cediranib on two schedules. The primary end point was the recommended phase II dose (RP2D). Response rate and pharmacokinetic analysis were secondary end points. Results Between June 2015 and May 2016, 26 women were enrolled. The RP2D was durvalumab 1,500 mg every 4 weeks with olaparib 300 mg twice a day, or Cediranib 20 mg, 5 days on/2 days off. No dose-limiting toxicity was recorded with durvalumab plus olaparib. The Cediranib intermittent schedule (n = 6) was examined because of recurrent grade 2 and non-dose-limiting toxicity grade 3 and 4 adverse events (AEs) on the daily schedule (n = 8). Treatment-emergent AEs included hypertension (two of eight), diarrhea (two of eight), pulmonary embolism (two of eight), pulmonary hypertension (one of eight), and lymphopenia (one of eight). Durvalumab plus intermittent Cediranib grade 3 and 4 AEs were hypertension (one of six) and fatigue (one of six). Exposure to durvalumab increased Cediranib area under the curve and maximum plasma concentration on the daily, but not intermittent, schedules. Two partial responses (≥15 months and ≥ 11 months) and eight stable diseases ≥ 4 months (median, 8 months [4 to 14.5 months]) were seen in patients who received durvalumab plus olaparib, yielding an 83% disease control rate. Six partial responses (≥ 5 to ≥ 8 months) and three stable diseases ≥ 4 months (4 to ≥ 8 months) were seen in 12 evaluable patients who received durvalumab plus Cediranib, for a 50% response rate and a 75% disease control rate. Response to therapy was independent of PD-L1 expression. Conclusion To our knowledge, this is the first reported anti-PD-L1 plus olaparib or Cediranib combination therapy. The RP2Ds of durvalumab plus olaparib and durvalumab plus intermittent Cediranib are tolerable and active. Phase II studies with biomarker evaluation are ongoing.
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combination Cediranib and olaparib versus olaparib alone for women with recurrent platinum sensitive ovarian cancer a randomised phase 2 study
Lancet Oncology, 2014Co-Authors: Joyce F Liu, Michael J. Birrer, William T Barry, Ronald J. Buckanovich, Gini F. Fleming, Bobbie J. Rimel, Mary K. Buss, Sreenivasa Nattam, Jungmin Lee, Jean A. HurteauAbstract:Summary Background Olaparib is a poly(ADP-ribose) polymerase inhibitor and Cediranib is an anti-angiogenic agent with activity against VEGF receptor (VEGFR) 1, VEGFR2, and VEGFR3. Both oral agents have antitumour activity in women with recurrent ovarian cancer, and their combination was active and had manageable toxicities in a phase 1 trial. We investigated whether this combination could improve progression-free survival (PFS) compared with olaparib monotherapy in women with recurrent platinum-sensitive ovarian cancer. Methods In our randomised, open-label, phase 2 study, we recruited women (aged ≥18 years) who had measurable platinum-sensitive, relapsed, high-grade serous or endometrioid ovarian, fallopian tube, or primary peritoneal cancer, or those with deleterious germline BRCA1 /2 mutations from nine participating US academic medical centres. We randomly allocated participants (1:1) according to permuted blocks, stratified by germline BRCA status and previous anti-angiogenic therapy, to receive olaparib capsules 400 mg twice daily or the combination at the recommended phase 2 dose of Cediranib 30 mg daily and olaparib capsules 200 mg twice daily. The primary endpoint was progression-free survival analysed in the intention-to-treat population. The phase 2 trial is no longer accruing patients. An interim analysis was conducted in November, 2013, after 50% of expected events had occurred and efficacy results were unmasked. The primary analysis was performed on March 31, 2014, after 47 events (66% of those expected). The trial is registered with ClinicalTrials.gov, number NCT01116648. Findings Between Oct 26, 2011, and June 3, 2013, we randomly allocated 46 women to receive olaparib alone and 44 to receive the combination of olaparib and Cediranib. Median PFS was 17·7 months (95% CI 14·7–not reached) for the women treated with Cediranib plus olaparib compared with 9·0 months (95% CI 5·7–16·5) for those treated with olaparib monotherapy (hazard ratio 0·42, 95% CI 0·23–0·76; p=0·005). Grade 3 and 4 adverse events were more common with combination therapy than with monotherapy, including fatigue (12 patients in the Cediranib plus olaparib group vs five patients in the olaparib monotherapy group), diarrhoea (ten vs none), and hypertension (18 vs none). Interpretation Cediranib plus olaparib seems to improve PFS in women with recurrent platinum-sensitive high-grade serous or endometrioid ovarian cancer, and warrants study in a phase 3 trial. The side-effect profile suggests such investigations should include assessments of quality of life and patient-reported outcomes to understand the effects of a continuing oral regimen with that of intermittent chemotherapy. Funding American Recovery and Reinvestment Act grant from the National Institutes of Health (NIH) (3 U01 CA062490-16S2); Intramural Program of the Center for Cancer Research; and the Division of Cancer Treatment and Diagnosis, National Cancer Institute, NIH.
Ashley Ciminomathews - One of the best experts on this subject based on the ideXlab platform.
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a phase i study of the pd l1 inhibitor durvalumab in combination with a parp inhibitor olaparib and a vegfr1 3 inhibitor Cediranib in recurrent women s cancers with biomarker analyses
Journal for ImmunoTherapy of Cancer, 2019Co-Authors: Alexandra S Zimmer, Elise C Kohn, Ashley Ciminomathews, Cody J Peer, Stanley Lipkowitz, Christina M Annunziata, Liang Cao, Erin Nichols, Minjung Lee, Jane B TrepelAbstract:Strategies to improve activity of immune checkpoint inhibitors are needed. We hypothesized enhanced DNA damage by olaparib, a PARP inhibitor, and reduced VEGF signaling by Cediranib, a VEGFR1–3 inhibitor, would complement anti-tumor activity of durvalumab, a PD-L1 inhibitor, and the 3-drug combination would be tolerable. This phase 1 study tested the 3-drug combination in a 3 + 3 dose escalation. Cediranib was taken intermittently (5 days on/2 days off) at 15 or 20 mg (dose levels 1 and 2, respectively) with durvalumab 1500 mg IV every 4 weeks, and olaparib tablets 300 mg twice daily. The primary end point was the recommended phase 2 dose (RP2D). Response rate, pharmacokinetic (PK), and correlative analyses were secondary endpoints. Nine patients (7 ovarian/1 endometrial/1 triple negative breast cancers, median 3 prior therapies [2–6]) were treated. Grade 3/4 adverse events include hypertension (1/9), anemia (1/9) and lymphopenia (3/9). No patients experienced dose limiting toxicities. The RP2D is Cediranib, 20 mg (5 days on/2 days off) with full doses of durvalumab and olaparib. Four patients had partial responses (44%) and 3 had stable disease lasting ≥6 months, yielding a 67% clinical benefit rate. No significant effects on olaparib or Cediranib PK parameters from the presence of durvalumab, or the co-administration of Cediranib or olaparib were identified. Tumoral PD-L1 expression correlated with clinical benefit but cytokines and peripheral immune subsets did not. The RP2D is tolerable and has preliminary activity in recurrent women’s cancers. A phase 2 expansion study is now enrolling for recurrent ovarian cancer patients. ClinicalTrials.gov identifier: NCT02484404. Registered June 29, 2015.
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safety and clinical activity of the programmed death ligand 1 inhibitor durvalumab in combination with poly adp ribose polymerase inhibitor olaparib or vascular endothelial growth factor receptor 1 3 inhibitor Cediranib in women s cancers a dose esca
Journal of Clinical Oncology, 2017Co-Authors: Jungmin Lee, Ashley Ciminomathews, Cody J Peer, Alexandra S Zimmer, Stanley Lipkowitz, Christina M Annunziata, Liang Cao, Maria I Harrell, Elizabeth M Swisher, Nicole D HoustonAbstract:Purpose Data suggest that DNA damage by poly (ADP-ribose) polymerase inhibition and/or reduced vascular endothelial growth factor signaling by vascular endothelial growth factor receptor inhibition may complement antitumor activity of immune checkpoint blockade. We hypothesize the programmed death-ligand 1 (PD-L1) inhibitor, durvalumab, olaparib, or Cediranib combinations are tolerable and active in recurrent women's cancers. Patients and Methods This phase I study tested durvalumab doublets in parallel 3 + 3 dose escalations. Durvalumab was administered at 10 mg/kg every 2 weeks or 1,500 mg every 4 weeks with either olaparib tablets twice daily or Cediranib on two schedules. The primary end point was the recommended phase II dose (RP2D). Response rate and pharmacokinetic analysis were secondary end points. Results Between June 2015 and May 2016, 26 women were enrolled. The RP2D was durvalumab 1,500 mg every 4 weeks with olaparib 300 mg twice a day, or Cediranib 20 mg, 5 days on/2 days off. No dose-limiting toxicity was recorded with durvalumab plus olaparib. The Cediranib intermittent schedule (n = 6) was examined because of recurrent grade 2 and non-dose-limiting toxicity grade 3 and 4 adverse events (AEs) on the daily schedule (n = 8). Treatment-emergent AEs included hypertension (two of eight), diarrhea (two of eight), pulmonary embolism (two of eight), pulmonary hypertension (one of eight), and lymphopenia (one of eight). Durvalumab plus intermittent Cediranib grade 3 and 4 AEs were hypertension (one of six) and fatigue (one of six). Exposure to durvalumab increased Cediranib area under the curve and maximum plasma concentration on the daily, but not intermittent, schedules. Two partial responses (≥15 months and ≥ 11 months) and eight stable diseases ≥ 4 months (median, 8 months [4 to 14.5 months]) were seen in patients who received durvalumab plus olaparib, yielding an 83% disease control rate. Six partial responses (≥ 5 to ≥ 8 months) and three stable diseases ≥ 4 months (4 to ≥ 8 months) were seen in 12 evaluable patients who received durvalumab plus Cediranib, for a 50% response rate and a 75% disease control rate. Response to therapy was independent of PD-L1 expression. Conclusion To our knowledge, this is the first reported anti-PD-L1 plus olaparib or Cediranib combination therapy. The RP2Ds of durvalumab plus olaparib and durvalumab plus intermittent Cediranib are tolerable and active. Phase II studies with biomarker evaluation are ongoing.
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safety and clinical activity of the programmed death ligand 1 inhibitor durvalumab in combination with poly adp ribose polymerase inhibitor olaparib or vascular endothelial growth factor receptor 1 3 inhibitor Cediranib in women s cancers a dose esca
Journal of Clinical Oncology, 2017Co-Authors: Ashley Ciminomathews, Cody J Peer, Alexandra S Zimmer, Stanley Lipkowitz, Christina M Annunziata, Maria I Harrell, Elizabeth M Swisher, Nicole Houston, Dana Adriana Botesteanu, Janis M TaubeAbstract:PurposeData suggest that DNA damage by poly (ADP-ribose) polymerase inhibition and/or reduced vascular endothelial growth factor signaling by vascular endothelial growth factor receptor inhibition may complement antitumor activity of immune checkpoint blockade. We hypothesize the programmed death-ligand 1 (PD-L1) inhibitor, durvalumab, olaparib, or Cediranib combinations are tolerable and active in recurrent women’s cancers.Patients and MethodsThis phase I study tested durvalumab doublets in parallel 3 + 3 dose escalations. Durvalumab was administered at 10 mg/kg every 2 weeks or 1,500 mg every 4 weeks with either olaparib tablets twice daily or Cediranib on two schedules. The primary end point was the recommended phase II dose (RP2D). Response rate and pharmacokinetic analysis were secondary end points.ResultsBetween June 2015 and May 2016, 26 women were enrolled. The RP2D was durvalumab 1,500 mg every 4 weeks with olaparib 300 mg twice a day, or Cediranib 20 mg, 5 days on/2 days off. No dose-limiting to...
Glenwood D Goss - One of the best experts on this subject based on the ideXlab platform.
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analysis of serum protein levels of angiogenic factors and their soluble receptors as markers of response to Cediranib in the ncic ctg br 24 clinical trial
Lung Cancer, 2015Co-Authors: Christina L Addison, K Ding, Lesley Seymour, Huijun Zhao, Scott A Laurie, Frances A Shepherd, Glenwood D GossAbstract:Abstract Objectives Prognostic and predictive ability of circulating vascular endothelial growth factor (VEGF), stromal derived factor (SDF)-1α and soluble VEGF receptors (sVEGFR) 2 and 3, were evaluated in non-small cell lung cancer (NSCLC) patients enrolled in NCIC Clinical Trials Group BR. 24 comparing chemotherapy with or without Cediranib. Materials and methods Biomarker levels were assessed by ELISA in serum from 149/296 enrolled patients at baseline and 146/149 patients after one treatment cycle. Experimental cut-offs for baseline measures determined using a graphic method were: VEGF-A: 3.5ng/ml, sVEGFR2: Results No baseline biomarker was prognostic for OS, however, high baseline sVEGFR2 was prognostic for better PFS ( p =0.0008) in the chemotherapy alone arm. Low baseline sVEGFR2 or sVEGFR3 were predictive of PFS benefit from Cediranib (interaction p =0.06 and p =0.05, respectively). While on treatment, VEGF-A increases were associated with better PFS ( p =0.02) and OS ( p =0.01) for Cediranib treated patients. Decreases in sVEGFR2 ( p =0.01) or sVEGFR3 ( p =0.02) were also predictive of better OS in Cediranib treated patients. Conclusions 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 patients. Validation of these results is warranted.
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correlation of lactate dehydrogenase isoenzyme profile with outcome in patients with advanced colorectal cancer treated with chemotherapy and bevacizumab or Cediranib retrospective analysis of the horizon i study
Clinical Colorectal Cancer, 2014Co-Authors: Juliane M Jurgensmeier, David Cunningham, Jair Bar, Stuart Spencer, Shethah Morgan, Laura Brooks, Jane Robertson, Glenwood D GossAbstract:Abstract Introduction Bevacizumab improves outcome for patients with advanced colorectal cancer (CRC) when added to chemotherapy. The HORIZON I trial resulted in similar outcome with bevacizumab or Cediranib, a small-molecule tyrosine kinase inhibitor of vascular endothelial growth factor (VEGF) receptor, as treatment of advanced CRC. The spectrum of lactate dehydrogenase (LDH) isoenzyme expression was examined in serum samples of HORIZON I participants to identify biomarkers predictive of efficacy of VEGF pathway inhibitors. Materials and Methods Total LDH levels, as well as LDH isoenzyme levels in frozen baseline serum samples, were retrospectively evaluated. Total LDH serum levels measured during the study, progression-free survival (PFS), and overall survival (OS) were available from the HORIZON I study data. Results Total LDH levels measured in the frozen serum samples correlated with those measured in fresh samples. The expected reciprocal correlation was found between hypoxic and oxic LDH isoenzymes. High total LDH correlated with shorter PFS, and high hypoxia-related LDH isoenzymes correlated with shorter PFS and OS. The difference in outcome of the Cediranib-treated patients vs. those treated with bevacizumab was not substantially different in the various LDH isoform expression subgroups. In patients with a hypoxic LDH pattern of expression, there was a nonsignificant trend of better outcome in Cediranib-treated patients. Conclusion Evaluation of total LDH and its isoforms in frozen serum samples is feasible. High total LDH and high hypoxic LDH isoenzymes were associated with poor prognosis. Further studies are needed to evaluate the predictive value of LDH isoenzyme expression pattern for VEGF-pathway inhibition efficacy.
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randomized double blind trial of carboplatin and paclitaxel with either daily oral Cediranib or placebo in advanced non small cell lung cancer ncic clinical trials group br24 study
Journal of Clinical Oncology, 2010Co-Authors: Glenwood D Goss, Frances A Shepherd, F Laberge, Andrew Arnold, Mircea Dediu, T Ciuleanu, David Fenton, Mauro Zukin, David Walde, M VincentAbstract:Purpose This phase II/III double-blind study assessed efficacy and safety of Cediranib with standard chemotherapy as initial therapy for advanced non–small-cell lung cancer (NSCLC). Patients and Methods Paclitaxel (200 mg/m2) and carboplatin (area under the serum concentration-time curve 6) were given every 3 weeks, with daily oral Cediranib or placebo at 30 mg (first 45 patients received 45 mg). Progression-free survival (PFS) was the primary outcome of the phase II interim analysis; phase III would proceed if the hazard ratio (HR) for PFS ≤ 0.77 and toxicity were acceptable. Results A total of 296 patients were enrolled, 251 to the 30-mg cohort. The phase II interim analysis demonstrated a significantly higher response rate (RR) for Cediranib than for placebo, HR of 0.77 for PFS, no excess hemoptysis, and a similar number of deaths in each arm. The study was halted to review imbalances in assigned causes of death. In the primary phase II analysis (30-mg cohort), the adjusted HR for PFS was 0.77 (95% CI,...