Amit M Oza

University Health Network, Toronto, Ontario, Canada

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Publications (152)1104.99 Total impact

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    ABSTRACT: Purpose: Veliparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, demonstrated clinical activity in combination with oral cyclophosphamide in patients with BRCA-mutant solid tumors in a phase 1 trial. To define the relative contribution of PARP inhibition to the observed clinical activity, we conducted a randomized phase 2 trial to determine the response rate of veliparib in combination with cyclophosphamide compared to cyclophosphamide alone in patients with pretreated BRCA-mutant ovarian cancer or in patients with pretreated primary peritoneal, fallopian tube, or high-grade serous ovarian cancers (HGSOC). Experimental Design: Adult patients were randomized to receive cyclophosphamide alone (50 mg orally once daily) or with veliparib (60 mg orally once daily) in 21-day cycles. Crossover to the combination was allowed at disease progression. Results: Seventy-five patients were enrolled and 72 were evaluable for response; 38 received cyclophosphamide alone and 37 the combination as their initial treatment regimen. Treatment was well tolerated. One complete response was observed in each arm, with three partial responses (PR) in the combination arm and six PRs in the cyclophosphamide alone arm. Genetic sequence and expression analyses were performed for 211 genes involved in DNA repair; none of the detected genetic alterations were significantly associated with treatment benefit. Conclusions: This is the first trial that evaluated single agent, low dose cyclophosphamide in HGSOC, peritoneal, fallopian tube, and BRCA-mutant ovarian cancers. It was well tolerated and clinical activity was observed; the addition of veliparib at 60 mg daily did not improve either the response rate or the median progression free survival. Copyright © 2015, American Association for Cancer Research.
    Clinical cancer research : an official journal of the American Association for Cancer Research. 01/2015;
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    ABSTRACT: Cancer is not one disease. Outcomes and endpoints in trials should incorporate the therapeutic modality and cancer type because these factors affect clinician and patient expectations. In this Review, we discuss how to: define the importance of endpoints; make endpoints understandable to patients; improve the use of patient-reported outcomes; advance endpoints to parallel changes in trial design and therapeutic interventions; and integrate these improvements into trials and practice. Endpoints need to reflect benefit to patients, and show that changes in tumour size either in absolute terms (response and progression) or relative to control (progression) are clinically relevant. Improvements in trial design should be accompanied by improvements in available endpoints. Stakeholders need to come together to determine the best approach for research that ensures accountability and optimises the use of available resources. Copyright © 2015 Elsevier Ltd. All rights reserved.
    The Lancet Oncology 01/2015; 16(1):e43-e52. · 25.12 Impact Factor
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    ABSTRACT: Cancer treatment should allow patients to live better or longer lives, and ideally, both. Trial endpoints should show clinically meaningful improvements in patient survival or quality of life. Alternative endpoints such as progression-free survival, disease-free survival, and objective response rate have been used to identify benefit earlier, but their true validity as surrogate endpoints is controversial. In this Review we discuss the measurement, assessment, and benefits and limitations of trial endpoints in use for cancer treatment. Many stakeholders are affected, including regulatory agencies, industry partners, clinicians, and most importantly, patients. In an accompanying Review, reflections from individual stakeholders are incorporated into a discussion of what the future holds for clinical trial endpoints and design. Copyright © 2015 Elsevier Ltd. All rights reserved.
    The Lancet Oncology 01/2015; 16(1):e32-e42. · 25.12 Impact Factor
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    ABSTRACT: The Brief Family History Questionnaire (bFHQ) was developed to identify endometrial cancer patients whose family histories suggest Lynch syndrome (LS). We compared the bFHQ, Extended Family History Questionnaire (eFHQ) and dictated medical records (DMR) to determine which family history screening strategy is superior in identifying LS in unselected women with newly diagnosed endometrial cancer that have undergone universal germline testing. Prospective cohort study recruiting women with newly diagnosed endometrial cancer to evaluate screening strategies to identify LS. Participants completed bFHQ and eFHQ, had tumor assessed with immunohistochemistry (IHC) for mismatch repair proteins (MMR) and micro-satellite instability testing and underwent universal germline testing for LS. The sensitivity, specificity, positive and negative predictive values (PPV, NPV) were compared between the family history screening strategies as well as IHC. 118 of 182 eligible patients (65%) consented; 87 patients (74%) were evaluable with both family history and germline mutation status. Median age was 61years (range 26 - 91). All 7 patients with confirmed LS were correctly identified by bFHQ, compared to 5 and 4 by eFHQ and DMR, respectively. The sensitivity, specificity, PPV and NPV values of bFHQ were 100%, 76.5%, 25.9% and 100%, respectively, performing similar to IHC testing. While eFHQ was more specific than bFHQ (86.7% vs. 76.5%, p=0.007), 2 cases of LS were missed. The patient-administered bFHQ effectively identified women with confirmed LS and is a good screening tool to triage women with endometrial cancer for further genetic assessment. Copyright © 2014. Published by Elsevier Inc.
    Gynecologic Oncology 12/2014; 136(2). · 3.69 Impact Factor
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    ABSTRACT: The poly(ADP-ribose) polymerase inhibitor olaparib has shown antitumour activity in patients with platinum-sensitive, recurrent, high-grade serous ovarian cancer with or without BRCA1 or BRCA2 mutations. The aim of this study was to assess the efficacy and tolerability of olaparib in combination with chemotherapy, followed by olaparib maintenance monotherapy, versus chemotherapy alone in patients with platinum-sensitive, recurrent, high-grade serous ovarian cancer. In this randomised, open-label, phase 2 study, adult patients with platinum-sensitive, recurrent, high-grade serous ovarian cancer who had received up to three previous courses of platinum-based chemotherapy and who were progression free for at least 6 months before randomisation received either olaparib (200 mg capsules twice daily, administered orally on days 1-10 of each 21-day cycle) plus paclitaxel (175 mg/m(2), administered intravenously on day 1) and carboplatin (area under the curve [AUC] 4 mg/mL per min, according to the Calvert formula, administered intravenously on day 1), then olaparib monotherapy (400 mg capsules twice daily, given continuously) until progression (the olaparib plus chemotherapy group), or paclitaxel (175 mg/m(2) on day 1) and carboplatin (AUC 6 mg/mL per min on day 1) then no further treatment (the chemotherapy alone group). Randomisation was done by an interactive voice response system, stratified by number of previous platinum-containing regimens received and time to disease progression after the previous platinum regimen. The primary endpoint was progression-free survival according to Response Evaluation Criteria in Solid Tumors version 1.1, analysed by intention to treat. Prespecified exploratory analyses included efficacy by BRCA mutation status, assessed retrospectively. This study is registered with ClinicalTrials.gov, number NCT01081951, and has been completed. Between Feb 12 and July 30, 2010, 173 patients at 43 investigational sites in 12 countries were enrolled into the study, of whom 162 were eligible and were randomly assigned to the two treatment groups (81 to the olaparib plus chemotherapy group and 81 to the chemotherapy alone group). Of these randomised patients, 156 were treated in the combination phase (81 in the olaparib plus chemotherapy group and 75 in the chemotherapy alone group) and 121 continued to the maintenance or no further treatment phase (66 in the olaparib plus chemotherapy group and 55 in the chemotherapy alone group). BRCA mutation status was known for 107 patients (either at baseline or determined retrospectively): 41 (38%) of 107 had a BRCA mutation (20 in the olaparib plus chemotherapy group and 21 in the chemotherapy alone group). Progression-free survival was significantly longer in the olaparib plus chemotherapy group (median 12·2 months [95% CI 9·7-15·0]) than in the chemotherapy alone group (median 9·6 months [95% CI 9·1-9·7) (HR 0·51 [95% CI 0·34-0·77]; p=0·0012), especially in patients with BRCA mutations (HR 0·21 [0·08-0·55]; p=0·0015). In the combination phase, adverse events that were reported at least 10% more frequently with olaparib plus chemotherapy than with chemotherapy alone were alopecia (60 [74%] of 81 vs 44 [59%] of 75), nausea (56 [69%] vs 43 [57%]), neutropenia (40 [49%] vs 29 [39%]), diarrhoea (34 [42%] vs 20 [27%]), headache (27 [33%] vs seven [9%]), peripheral neuropathy (25 [31%] vs 14 [19%]), and dyspepsia (21 [26%] vs 9 [12%]); most were of mild-to-moderate intensity. The most common grade 3 or higher adverse events during the combination phase were neutropenia (in 35 [43%] of 81 patients in the olaparib plus chemotherapy group vs 26 [35%] of 75 in the chemotherapy alone group) and anaemia (seven [9%] vs five [7%]). Serious adverse events were reported in 12 (15%) of 81 patients in the olaparib plus chemotherapy group and 16 of 75 (21%) patients in the chemotherapy alone group. Olaparib plus paclitaxel or carboplatin followed by maintenance monotherapy significantly improved progression-free survival versus paclitaxel plus carboplatin alone, with the greatest clinical benefit in BRCA-mutated patients, and had an acceptable and manageable tolerability profile. AstraZeneca. Copyright © 2014 Elsevier Ltd. All rights reserved.
    The Lancet Oncology 12/2014; · 25.12 Impact Factor
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    European journal of cancer (Oxford, England: 1990) 12/2014; 50(18):3271-2. · 4.12 Impact Factor
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    ABSTRACT: Objective The phosphatidylinositol-3 kinase/serine-threonine kinase PI3K/AKT pathway is postulated to be central to cancer cell development. Activation of this pathway is believed to promote angiogenesis, protein translation and cell cycle progression. A large percentage of endometrial carcinomas have demonstrated mutations within this regulation pathway which result in constitutional activation. The downstream effector protein mammalian target of rapamycin (mTOR) acts as a critical checkpoint in cancer cell cycling and is a logical target for drug development. The efficacy and tolerability of the oral mTOR inhibitor Ridaforolimus was evaluated in this study. Methods This phase II study evaluated the single agent tolerability and activity of oral ridaforolimus administered at a dose of 40 mg for 5 consecutive days followed by a 2 day break, in women with recurrent or metastatic endometrial carcinoma who had received no chemotherapy in the metastatic setting. Results 31 of 34 patients were evaluable. Three partial responses (8.8%) were observed with response duration ranging between 7.9-26.5 months. An additional 18 patients showed disease stabilisation (52.9%) for a median duration of 6.6 months. Response rates were not affected by previous chemotherapy exposure. No correlation was found between response and mutation status. Conclusion Oral Ridaforolimus was reasonably tolerated and demonstrated modest activity in women with recurrent or metastatic endometrial cancers. Potential synergy between mTOR inhibition, angiogenesis and hormonal pathways warrants ongoing evaluation.
    Gynecologic Oncology 11/2014; · 3.69 Impact Factor
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    ABSTRACT: Mucinous carcinomas of the ovary can be primary or metastatic in origin. Improvements in the pathological diagnosis have increased the ability to distinguish between primary and metastatic ovarian cancers and shown that primary mucinous carcinomas are a rare subtype of ovarian cancer. Most tumors are diagnosed at an early stage, and the prognosis after surgery is good. Advanced or recurrent mucinous carcinoma of the ovary responds poorly to current cytotoxic treatments, and the prognosis is poor. Here, we review the guidelines for surgery and the results of treatment of advanced and recurrent disease. Chemotherapy with platinum and paclitaxel is currently used to treat advanced disease, but the effect of these drugs is modest, and new treatments are needed.
    International Journal of Gynecological Cancer 11/2014; 24(9 Suppl 3):S14-9. · 1.95 Impact Factor
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    ABSTRACT: Clear cell carcinoma of the ovary (CCC) is a histologic subtype of epithelial ovarian cancer with a distinct clinical behavior. There are marked geographic differences in the prevalence of CCC. The CCC is more likely to be detected at an early stage than high-grade serous cancers, and when confined within the ovary, the prognosis is good. However, advanced disease is associated with a very poor prognosis and resistance to standard treatment. Cytoreductive surgery should be performed for patients with stage II, III, or IV disease. An international phase III study to compare irinotecan/cisplatin and paclitaxel/carboplatin as adjuvant chemotherapy for stage IIV CCC has completed enrollment (GCIG/JGOG3017). Considering the frequent PIK3CA mutation in CCC, dual inhibitors targeting PI3K, AKT in the mTOR pathway, are promising. Performing these trials and generating the evidence will require considerable international collaboration.
    International Journal of Gynecological Cancer 11/2014; 24(9 Suppl 3):S20-5. · 1.95 Impact Factor
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    ABSTRACT: Background:Folate receptor 1 (FOLR1) is expressed in the majority of ovarian carcinomas (OvCa), making it an attractive target for therapy. However, clinical trials testing anti-FOLR1 therapies in OvCa show mixed results and require better understanding of the prognostic relevance of FOLR1 expression. We conducted a large study evaluating FOLR1 expression with survival in different histological types of OvCa.Methods:Tissue microarrays composed of tumour samples from 2801 patients in the Ovarian Tumour Tissue Analysis (OTTA) consortium were assessed for FOLR1 expression by centralised immunohistochemistry. We estimated associations for overall (OS) and progression-free (PFS) survival using adjusted Cox regression models. High-grade serous ovarian carcinomas (HGSC) from The Cancer Genome Atlas (TCGA) were evaluated independently for association between FOLR1 mRNA upregulation and survival.Results:FOLR1 expression ranged from 76% in HGSC to 11% in mucinous carcinomas in OTTA. For HGSC, the association between FOLR1 expression and OS changed significantly during the years following diagnosis in OTTA (Pinteraction=0.01, N=1422) and TCGA (Pinteraction=0.01, N=485). In OTTA, particularly for FIGO stage I/II tumours, patients with FOLR1-positive HGSC showed increased OS during the first 2 years only (hazard ratio=0.44, 95% confidence interval=0.20-0.96) and patients with FOLR1-positive clear cell carcinomas (CCC) showed decreased PFS independent of follow-up time (HR=1.89, 95% CI=1.10-3.25, N=259). In TCGA, FOLR1 mRNA upregulation in HGSC was also associated with increased OS during the first 2 years following diagnosis irrespective of tumour stage (HR: 0.48, 95% CI: 0.25-0.94).Conclusions:FOLR1-positive HGSC tumours were associated with an increased OS in the first 2 years following diagnosis. Patients with FOLR1-negative, poor prognosis HGSC would be unlikely to benefit from anti-FOLR1 therapies. In contrast, a decreased PFS interval was observed for FOLR1-positive CCC. The clinical efficacy of FOLR1-targeted interventions should therefore be evaluated according to histology, stage and time following diagnosis.British Journal of Cancer advance online publication, 30 October 2014; doi:10.1038/bjc.2014.567 www.bjcancer.com.
    British journal of cancer. 10/2014;
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    ABSTRACT: Ovarian cancer patients are usually diagnosed at an advanced stage, experience recurrence after platinum-based chemotherapy, and eventually develop resistance to chemotherapy. Overall survival (OS), which has improved in recent years as more active treatments have been incorporated into patient care, is regarded as the most clinically relevant endpoint in ovarian cancer trials. However, although there remains a significant need for new treatments that prolong OS further without compromising quality of life, it has become increasingly difficult to detect an OS benefit for investigational treatments because of the use of multiple lines of chemotherapy to treat ovarian cancer. Progression-free survival (PFS), which measures the time to disease progression or death, is unaffected by postprogression therapies but does not evaluate the long-term impact of investigational treatments on tumor biology and responses to future therapies. Recent clinical trials of targeted agents in relapsed ovarian cancer have shown improvements in PFS but not OS, and this is possibly reflective of the long postprogression survival (PPS) period associated with this disease. Intermediate endpoints such as the time to second disease progression or death and the time to second subsequent therapy or death may provide supportive evidence for clinically meaningful PFS improvements and may be used to determine whether these improvements persist beyond the first disease progression and throughout subsequent lines of therapy. For clinical trials that have settings with a long PPS duration and/or involve multiple rounds of postprogression therapy, a primary endpoint of PFS supported by intermediate clinical endpoints and OS may provide a more comprehensive approach for evaluating efficacy. Cancer 2014. © 2014 American Cancer Society.
    Cancer 10/2014; · 5.20 Impact Factor
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    ABSTRACT: BACKGROUND The anticipated clinical outcome of the standard/control arm is an important parameter in the design of randomized phase 3 (RP3) trials to properly calculate sample size, power, and study duration. Changing patterns of care or variation in the study population enrolled may lead to a deviation from the initially anticipated outcome. The authors hypothesized that recent changes in patterns of care in epithelial ovarian cancer (EOC) have led to challenges in correctly estimating the outcome of control groups.METHODSA systematic review of the literature was conducted for RP3 trials of EOC published between January 2000 and December 2010. The expected outcome of the control arm as well as the actual outcome achieved by this cohort was collected and a ratio (actual-over-expected ratio) was calculated. The estimation of outcome was deemed accurate if the outcome of the control arm was between 0.75 to 1.25 times the anticipated outcome.RESULTSA total of 35 trials were eligible for analysis. Fifteen trials had survival as the primary endpoint whereas 20 had a progression-based primary endpoint. In total, 12 of 15 trials with a survival-based endpoint significantly underestimated the outcome of the control arm, whereas only 4 of 20 trials with a progression-based endpoint did. Studies with a survival endpoint underestimated outcome more frequently than those with a progression endpoint (P<.001).CONCLUSIONS Survival of the control arm has frequently been underestimated in recent EOC RP3 trials. This underestimation means that the initial statistical assumptions of these trials may have been inaccurate. Underestimating the outcome of the control arm may result in trials being underpowered to demonstrate the absolute benefit they were designed to show. Cancer 2014. © 2014 American Cancer Society.
    Cancer 10/2014; · 5.20 Impact Factor
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    ABSTRACT: BACKGROUND Immunohistochemistry (IHC) for mismatch repair protein expression, microsatellite instability (MSI) testing, tumor morphology, and family history were compared to determine which screening strategy is superior in identifying Lynch syndrome (LS) in unselected women with newly diagnosed endometrial cancer (EC) who have undergone universal germline mutation testing.METHODSA prospective cohort study was performed that recruited women with newly diagnosed EC. Participants completed a family history assessment with molecular characterization of EC with IHC and MSI testing and EC assessment for LS-associated morphologic features and underwent universal germline mutation testing for mutations in the mismatch repair pathway. The sensitivity, specificity, and positive and negative predictive values were compared between the screening strategies.RESULTSA total of 118 (65%) of 182 consecutive women with EC participated. Of these, 34 women (29%) had tumors that were IHC deficient and 27 women (23%; N = 117) had tumors that were positive for MSI. Twenty women (17%) met IHC criteria and 16 women (15.2%, N = 105) met family history criteria based on Ontario Ministry of Health Criteria for the genetic assessment for LS. Seven women (5.9%) had a germline mutation: 4 had MLH1 (mutL homolog 1), 2 had MSH6 (mutS homolog 6), and 1 had MSH2 (mutS homolog 2). IHC in women aged <60 years had the best performance characteristics, with a sensitivity of 100%, a specificity of 86.1%, a positive predictive value of 58.3%, and a negative predictive value of 100%. Family history and tumor morphology both had the lowest sensitivity at 71.4%. Overall tumor morphology had the poorest performance, with a specificity of 42.1%.CONCLUSIONS The mutation rate of 5.9% was higher than expected in this unselected cohort of women with EC. The superior screening strategy to identify women presenting with EC is universal IHC screening in women aged <60 years. Cancer 2014. © 2014 American Cancer Society.
    Cancer 07/2014; · 5.20 Impact Factor
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    ABSTRACT: Purpose: Randomized ovarian cancer trials, including ICON7, have reported improved progression-free survival (PFS) when bevacizumab was added to conventional cytotoxic therapy. The improvement was modest prompting the search for predictive biomarkers for bevacizumab. Experimental Design: Pre-treatment training (n = 91) and validation (n = 114) blood samples were provided by ICON7 patients. Plasma concentrations of 15 angio-associated factors were determined using validated multiplex ELISAs. Results: The combined values of circulating Ang1 and Tie2 concentrations predicted improved PFS in bevacizumab-treated patients in the training set. Using median concentrations as cut-offs, high Ang1/low Tie2 values were associated with significantly improved PFS for bevacizumab-treated patients (median: 23.0 months versus 16.2, log rank test, p=0.006). High Ang1/high Tie2 values were associated with a poor outcome for bevacizumab-treated patients (median: 12.8 months versus 28.5 months, log rank test p=0.007). Ang1 and Tie2 jointly interacted with the effect of bevacizumab on PFS (pinteraction=0.003). The prognostic indices derived from the training set differentiated classes of high and low probability for progression in the validation set (p = 0.008). Conclusions: The combined values of Ang1 and Tie2 are predictive biomarkers for improved PFS in bevacizumab-treated patients with ovarian cancer.
    Clinical Cancer Research 06/2014; · 8.19 Impact Factor
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    ABSTRACT: Angiogenesis is a valid target in the treatment of epithelial ovarian cancer. Trebananib inhibits the binding of angiopoietins 1 and 2 to the Tie2 receptor, and thereby inhibits angiogenesis. We aimed to assess whether the addition of trebananib to single-agent weekly paclitaxel in patients with recurrent epithelial ovarian cancer improved progression-free survival.
    The Lancet Oncology 06/2014; · 25.12 Impact Factor
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    ABSTRACT: The aim of this study was to determine the optimal patient-reported outcome measure (PROM) for assessing symptom benefit in trials of palliative chemotherapy for women with symptomatic ovarian cancer.
    International journal of gynecological cancer : official journal of the International Gynecological Cancer Society. 06/2014; 24(5):865-73.
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    ABSTRACT: Background: Low-grade serous (LGS) carcinomas of the ovary, fallopian tube and primary peritoneum are rare and unique tumors for which current therapies (chemotherapy, hormonal) have demonstrated limited efficacy. As LGS carcinoma is characterized by mutations in genes of the RAS/RAF/MEK/ERK signaling pathway, such as BRAF and KRAS, evaluating therapies that target this pathway is warranted. This study will evaluate the efficacy of the MEK1/2 inhibitor binimetinib (MEK162) vs physician’s choice chemotherapy in patients with LGS carcinoma. This study will enroll patients regardless of RAS/RAF mutational status; however, tumor tissue will be retrospectively analyzed for mutations in RAS/RAF and other genes (NCT01849874 ). Methods: This is a 2-arm, open-label, 2:1 randomized Phase 3 study of binimetinib vs physician’s choice chemotherapy (pegylated liposomal doxorubicin, paclitaxel or topotecan). Eligible patients must have LGS carcinoma that is recurrent or persistent following at least 1 prior platinum-based chemotherapy and no more than 3 prior lines of chemotherapy, and must have RECIST v1.1-defined measurable disease confirmed by independent central review. Prior to randomization, independent central review of a patient’s tumor specimen is required to confirm LGS diagnosis. Prior treatment with a MEK or BRAF inhibitor is prohibited. Randomization is stratified by last platinum-free interval and number of prior systemic therapy regimens. The primary endpoint is progression-free survival as determined by blinded independent central review; secondary endpoints include overall survival, overall response, duration of response, disease control rate, safety, quality of life and pharmacokinetics of binimetinib. Binimetinib is administered 45 mg BID orally. Patients receive therapy until disease progression or unacceptable toxicity. This study will enroll 300 patients worldwide. Clinical trial information: NCT01849874.
    Journal of Clinical Oncology 05/2014; Vol 32, No 15_suppl (May 20 Supplement),. · 17.88 Impact Factor
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    ABSTRACT: Treatment options remain limited for women with relapsed/metastatic endometrial cancer (EC). Angiogenesis is one of the major components of tumor progression and thus an attractive target. The aim of this phase II trial was to assess the efficacy and tolerability of sunitinib, an oral multitargeted receptor tyrosine-kinase inhibitor with antiangiogenic and antitumor activity in the treatment of recurrent EC.
    Gynecologic Oncology 05/2014; · 3.69 Impact Factor
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    Stephanie Lheureux, Amit M Oza
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    ABSTRACT: Introduction: Epithelial ovarian cancer (OC) remains the most lethal gynecologic malignancy. Germline mutations in either breast cancer gene 1(BRCA1) or BRCA2 genes are responsible for 15% of all OC, including those in women without a family history of cancer. Despite an initial response to the first line of treatment based on surgery and chemotherapy, most patients will relapse, highlighting the urgent need to develop smarter treatment options. The family of polyadenosine diphosphate-ribose polymerase (PARP) inhibitors is one of the most promising targeted agents. Areas covered: This report reviews the interest to target DNA repair defects with a focus on olaparib, the most investigated PARP inhibitor (PARPi) in OC. The results of the completed Phase I and II studies are analyzed and discussed with an update on translational research presented at major international congresses. Expert opinion: With five disparate histological subtypes, and a complex genomic landscape, OC remains a therapeutic challenge as evidenced by poor overall survival. Maturing data on olaparib provide evidence of efficacy and safety in the specific subgroup of women with high grade serous OC and BRCA mutations, and it seems likely that PARPi will represent an important step in the personalization of OC treatment.
    Expert Opinion on Orphan Drugs. 05/2014; 2(5).
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    ABSTRACT: Early prediction of the expected benefit of treatment in recurrent ovarian cancer (ROC) patients may help in drug development decisions. The actual value of 50% CA-125 decrease is being reconsidered. The main objective of the present study was to quantify the links between longitudinal assessments of CA-125 kinetics and progression-free survival (PFS) in treated recurrent ovarian cancer (ROC) patients. The CALYPSO randomized phase III trial database comparing two platinum-based regimens in ROC patients was randomly split into a "learning dataset" and a "validation dataset". A parametric survival model was developed to associate longitudinal modeled CA-125 changes (ΔCA125), predictive factors, and PFS. The predictive performance of the model was evaluated with simulations. The PFS of 534 ROC patients were properly characterized by a parametric mathematical model. The modeled ΔCA125 from baseline to week 6 was a better predictor of PFS than the modeled fractional change in tumor size. Simulations confirmed the model's predictive performance. We present the first parametric survival model quantifying the relationship between PFS and longitudinal CA-125 kinetics in treated ROC patients. The model enabled calculation of the increase in ΔCA125 required to observe a predetermined benefit in PFS to compare therapeutic strategies in populations. Therefore, ΔCA125 may be a predictive marker of the expected gain in PFS and an early predictive tool in drug development decisions.
    Gynecologic Oncology 04/2014; · 3.69 Impact Factor

Publication Stats

4k Citations
1,104.99 Total Impact Points

Institutions

  • 2003–2014
    • University Health Network
      Toronto, Ontario, Canada
  • 1997–2014
    • University of Toronto
      • • Department of Medicine
      • • Department of Radiation Oncology
      Toronto, Ontario, Canada
    • The Princess Margaret Hospital
      Toronto, Ontario, Canada
  • 2013
    • Hospices Civils de Lyon
      Lyons, Rhône-Alpes, France
  • 2012
    • Harvard Medical School
      Boston, Massachusetts, United States
  • 2011
    • Vancouver Prostate Centre
      Vancouver, British Columbia, Canada
    • St. James University
      Сент-Джеймс, New York, United States
    • BC Cancer Agency
      Vancouver, British Columbia, Canada
  • 2010
    • Peter MacCallum Cancer Centre
      • Department of Medical Oncology
      Melbourne, Victoria, Australia
  • 2008
    • University of Southern California
      Los Angeles, California, United States
    • Hamilton Health Sciences
      Hamilton, Ontario, Canada
  • 2007
    • Regional Integration Cancer Center
      Мендоса, Mendoza, Argentina
  • 2005
    • National Cancer Institute (USA)
      Maryland, United States
  • 2002
    • Ottawa Regional Cancer Foundation
      Ottawa, Ontario, Canada
  • 2000
    • Ontario Institute for Cancer Research
      Toronto, Ontario, Canada