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Thiessen B.,BC Cancer Agency | Stewart C.,St Judes Childrens Research Hospital | Tsao M.,Princess Margaret Hospital | Kamel-Reid S.,Princess Margaret Hospital | And 7 more authors.
Cancer Chemotherapy and Pharmacology | Year: 2010

Purpose: We undertook a phase I/II study of the EGFR/erbB2 inhibitor lapatinib in patients with recurrent glioblastoma multiforme (GBM) to determine response rate, pharmacokinetics (PK) and recommended dose in patients taking enzyme-inducing anti-epileptic drugs (EIAEDs) and to explore relationships of molecular genetics to outcome. Methods: Recurrent GBM patients taking EIAEDs were enrolled on the phase I portion (starting dose of lapatinib 1,000 mg po bid). In the absence of dose-limiting toxicity (DLT), escalation continued in cohorts of three patients. Patients not on EIAEDs enrolled in the phase II arm (lapatinib 750 mg bid po). Immunohistochemical and quantitative RT PCR studies were performed on tumor to determine PTEN and EGFRvIII status, respectively. Lapatinib PK was analyzed using HPLC with tandem mass spectrometry. Results: Phase II: Of 17 patients, 4 had stable disease and 13 progressed. Accrual ceased because of no responses. Phase I: Four patients received 1,000 mg bid and three, 1,500 mg bid. No DLT occurred, but escalation stopped because of lack of phase II efficacy. Lapatinib apparent oral clearance in patients taking EIAEDs was 106.9 L h-1 m-2 in comparison to 12.1 L h-1 m-2 in those not on EIAEDs. In 16 phase II patients, PTEN loss was seen in 6 and EGFRvIII expression in 4. No correlation was seen with outcome and molecular results. Conclusions: Lapatinib apparent oral clearance increased by approximately tenfold when given with EIAEDs. In this small sample, EGFRvIII expression and PTEN loss did not predict a favorable subtype. Overall, lapatinib did not show significant activity in GBM patients. © 2009 Springer-Verlag.

Goss P.E.,Massachusetts General Hospital | Ingle J.N.,Mayo Medical School | Martino S.,Los Angeles Clinic and Research Institute | Robert N.J.,Inova Fairfax Hospital | And 10 more authors.
Annals of Oncology | Year: 2013

Background: MA17 showed improved outcomes in postmenopausal women given extended letrozole (LET) after completing 5 years of adjuvant tamoxifen. Patients and methods: Exploratory subgroup analyses of disease-free survival (DFS), distant DFS (DDFS), overall survival (OS), toxic effects and of life (QOL) in MA17 were performed based on menopausal status atquality breast cancer diagnosis. Results: At diagnosis, 877 women were premenopausal and 4289 were postmenopausal. Extended LET was significantly better than placebo (PLAC) in DFS for premenopausal [hazard ratio (HR) = 0.26, 95% confidence interval (CI) 0.13-0.55; P = 0.0003] and postmenopausal women (HR = 0.67; 95% CI 0.51-0.89; P = 0.006), with greater DFS benefit in those premenopausal (interaction P = 0.03). In adjusted post-unblinding analysis, those who switched from PLAC to LET improved DDFS in premenopausal (HR = 0.15; 95% CI 0.03-0.79; P = 0.02) and postmenopausal women (HR = 0.45; 95% CI 0.22-0.94; P = 0.03). Conclusions: Extended LET after 5 years of tamoxifen was effective in pre- and postmenopausal women at diagnosis, and significantly better in those premenopausal. Women premenopausal at diagnosis should be considered for extended adjuvant therapy with LET if menopausal after completing tamoxifen. © The Author 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

MacKay H.J.,University of Toronto | Eisenhauer E.A.,National Cancer Institute of Canada | Kamel-Reid S.,University of Toronto | Tsao M.,University of Toronto | And 9 more authors.
Cancer | Year: 2014

BACKGROUND Targeting the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway is of increasing interest as a therapeutic strategy in many tumors. The aim of this study was to identify molecular markers associated with mTOR inhibitor activity in women with metastatic endometrial cancer. METHODS Archival tumor samples were collected from 94 women with recurrent or metastatic endometrial cancer who participated in 3 National Cancer Insitute of Canada Clinical Trials Group phase 2 trials investigating single-agent mTOR inhibitors: IND160A and IND160B (temsirolimus) and IND192 (ridaforolimus). Analyses included mutational profiling using the OncoCarta Panel version 1.0 and immunohistochemical expression of the tumor suppressor gene PTEN (phosphatase and tensin homologue) and stathmin, a marker of PI3K activation. Associations between biomarker results and clinical outcomes were assessed. RESULTS Mutations were found in 32 of 73 analyzed tumors, PIK3CA (21 patients) was the most common mutated gene. Co-mutations were seen in 8 tumors, most frequently KRAS and PIK3CA (4 cases). PTEN loss was observed in 46 of 85 samples analyzed and increased stathmin expression was observed in 15 of 65 analyzed samples. No correlation was observed between biomarkers and response or progression. In patients taking concurrent metformin, there was a trend toward lower progression, of 11.8% versus 32.5% (P =.14). CONCLUSIONS No predictive biomarker or combination of biomarkers for mTOR inhibitor activity were identified in this study. Restriction and enrichment of study entry, especially based on archival tumor tissue, should be undertaken with caution in trials using these agents. Cancer 2014;120:603-610. © 2013 American Cancer Society. Despite extensive molecular profiling, no predictive biomarker for inhibition of mammalian target of rapamycin was identified. Restriction and enrichment of study entry, especially based on archival tumor tissue, should be undertaken with caution. © 2013 American Cancer Society.

Mackay H.J.,Princess Margaret Hospital | Provencheur D.,Center Hospitalier Of Luniversite Of Montreal | Heywood M.,BC Cancer Agency | Tu D.,National Cancer Institute of Canada | And 3 more authors.
Current Oncology | Year: 2011

Three large randomized clinical trials have shown a survival benefit in women with stage iii epithelial ovarian cancer (EOC) who receive intraperitoneal (IP) chemotherapy after optimal primary debulking surgery. The most recent Gynecologic Oncology Group study, GOG 172, showed an improvement in median overall survival of approximately 17 months. That result led to a U.S. National Cancer Institute (NCI) clinical announcement recommending that IP chemotherapy be considered for this group of women with EOC. However, IP chemotherapy is associated with increased toxicity, and rates for completion of treatment are low (42% in GOG 172). The optimal IP regimen and duration of treatment has yet to be defined. Women undergoing chemotherapy before optimal debulking surgery were not included in the studies or in the NCI clinical announcement. The National Cancer Institute of Canada Clinical Trials Group has developed a protocol for a randomized phase II/III study which will examine whether IP platinum-taxane-based chemotherapy benefits women who have received neoadjuvant chemotherapy before optimal surgical debulking. To address whether the less systemically toxic carboplatin can be substituted for cisplatin IP, the first phase of the study will have 3 arms: 1 intravenous-only, and 2 IP-containing regimens. At the end of the first stage, and provided that IP therapy is feasible to administer in this patient population, one of the IP regimens, either IP carboplatin or IP cisplatin, will proceed into a phase III comparison with the intravenous arm. This exciting new study has gathered international support.

Harbison C.T.,Bristol Myers Squibb | Horak C.E.,Bristol Myers Squibb | Ledeine J.-M.,Bristol Myers Squibb | Mukhopadhyay P.,Bristol Myers Squibb | And 12 more authors.
Archives of Pathology and Laboratory Medicine | Year: 2013

Context.-The therascreen KRAS RGQ polymerase chain reaction kit is being developed as a companion diagnostic to aid clinicians, through detection of KRAS mutations, in the identification of patients with metastatic colorectal cancer (mCRC) who are more likely to benefit from cetuximab. Objective.-To assess whether KRAS mutation status, determined by using the therascreen KRAS kit, is a predictive marker of cetuximab efficacy. Design.-Tissue samples were obtained from patients with mCRC treated on the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) CO.17 phase 3 study of cetuximab plus best supportive care (BSC) versus BSC alone. Tumor DNA samples were assessed for the presence of KRAS mutations by using the therascreen KRAS kit. Efficacy and safety were assessed to determine whether mutation status was predictive of outcomes. Results.-Evaluable samples were available from 453 patients (79.2%) enrolled in the NCIC CTG CO.17 trial. The KRAS wild-type subset represented 54.1% (245 of 453) of the evaluated population. Median overall survival of patients with KRAS wild-type tumors was 8.6 months among those who received cetuximab plus BSC and 5.0 months among patients who received BSC alone (hazard ratio [HR], 0.63; P.002). Among patients with KRAS mutant mCRC, no meaningful difference in overall survival was observed between arms (HR, 0.91; P.55). These results are consistent with a previous report that analyzed patient tumor samples by using bidirectional sequencing. Conclusions.-These data support the utility of the therascreen KRAS kit as a means of selecting patients who may benefit from cetuximab therapy.

PubMed | National Cancer Institute of Canada
Type: Journal Article | Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2016

6528 Background: CO.17 study is the first intergroup (Canadian/Australian) trial, that prospectively collected resource utilization and utility data for cetuximab (N=283) vs. best supportive care alone (BSC; N=274) in advanced colorectal cancer patients. A cost-effectiveness analysis was conducted based on the improved survival, higher cost of cetuximab and variable costs across countries from the perspective of the Canadian health care system.The mean difference in trial survival times between cetuximab and BSC was calculated. Direct medical resource utilization data was collected during the trial from the time of randomization until death or study closure. Trial resources included medications physician visits, toxicity management, institutionalization, emergency department visits and hospitalizations. Mean overall incremental cost (2007 $CAN-provincial sources) was determined. Drug acquisition costs (DAC) for cetuximab, based on several countries, were used to determine the incremental cost effectiveness ratio (ICER) in dollars per life-year gained (LYG). Sensitivity analyses for cetuximab DACs were conducted. Bootstrapping (1,000 iterations) provided 95%CI.Mean incremental trial survival was 0.12 years. Preliminary results showed variability in the ICER, where DAC was the cost driver. At the lowest DAC ($2.94/mg), overall incremental costs were $19,361 for cetuximab compared to BSC, with incremental values of $1,086 for toxicity management, $1,016 for hospitalization, and $410 plus $81 for oncologist and family physician visits respectively. The ICER for cetuximab was $183,287/LYG (95%CI: $114,139-$581,027) using a $2.94/mg DAC (Switzerland), $198,467/LYG ($123,509-$558,270; $3.24/mg-Canadian suggested) and $375,047/LYG ($237,139- $1,233,111; $6.73/mg US). Sensitivity analyses produced an ICER of $50,000/LYG at $0.28/mg; $100,000/LYG at $1.30/mg and $200,000/LYG at $3.27/mg. Cost per quality adjusted life year will also be determined.Cetuximab showed high and variable ICERs dependent on a range of DACs in CO.17 advanced colorectal cancer patients. Utility will impact the incremental value. No significant financial relationships to disclose.

PubMed | National Cancer Institute of Canada
Type: Journal Article | Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2016

7200 Background: Cisplatin ACT induced anemia may correlate with adverse events (AEs), poor Quality of Life (QoL), inability to deliver ACT, relapse free survival (RFS) or overall survival (OS).JBR.10 showed improved OS and RFS for pts with resected NSCLC treated with ACT (n=243) compared to observation (obs) (n=239) (Winton, ASCO 2004). Exploratory analyses were performed evaluating the predictive value of baseline (BL, all enrolled pts) and during-treatment (DT, ACT pts only) Hb (median,minimum and % drop) on RFS and OS. Analyses were adjusted for BL prognostic factors (age, gender, PS, disease stage, LDH, surgery type and histology). Hb was also correlated with AEs (lethargy, dizziness, headache, dyspnea, ischemia, venous thromboembolic events (VTE)), QoL, morbidity and ACT dose intensity (DI).BL Hb was significantly lower in female pts, older pts and pts with PS =1. BL Hb was not predictive of RFS or OS (log-rank), although in adjusted Cox model there was a trend to shorter OS (p= 0.1) in pts with BL Hb <12. Lower BL Hb predicted for more frequent hospitalization (ACT pts only, p=0.04) while higher BL Hb predicted for better QoL (obs only, SOB, p=0.03). There was no impact on AEs, or DI. Median DT Hb was associated only with increased fatigue (p=0.02), while lower nadir DT Hb was associated with longer RFS (p=0.08) Maximum DT Hb drop < 10% was associated with shorter OS and RFS (p=0.01) even when DI was included in the model. Maximum DT Hb drop was also associated with worse QoL (fatigue, 0.07), fatigue (0.003) and VTE (0.07) Conclusion: Lower BL and DT Hb levels appear to be associated with fatigue, poorer QoL, increased hospitalization and higher rates of VTE. Lower BL Hb is associated with shorter OS (NS) while smaller falls in Hb during treatment appear to predict for shorter OS and RFS. [Table: see text].

PubMed | National Cancer Institute of Canada
Type: Journal Article | Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2016

7018 Background: In meta-analyses platinum based adjuvant chemotherapy using 2Patients with completely resected stage 1 (T2N0) or stage 2 (excluding T3N0) NSCLC were stratified by nodal status (N0 vs. N1) and ras mutation status (present vs. absent vs. unknown) and randomised to receive 4 cycles of VIN (25mg/m482 patients were randomized between 1994 and 2001.age 61 years, 65% male, 51% PS 1, 53% N1, 24% ras mutation present. 45% of patients had T2N0, 40% T2N1 and 15% T1N1. 53% had adenocarcinoma. Grade 4 neutropenia, was common with febrile neutropenia in 7%, predominantly in patients receiving VIN 30mg/mThis is the first randomized clinical trial demonstrating that a 3

PubMed | National Cancer Institute of Canada
Type: Journal Article | Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2016

5019 Background: EGFR over expression is seen in 60-80% of endometrial cancers(EC) and may have a major role in tumour growth and progression. Erlotinib is an orally active, selective inhibitor of EGFR tyrosine kinase activity.A 2 stage phase II study was performed to evaluate single agent activity of erlotinib in EC. Multinomial endpoints incorporating response and stable disease were used. Women with recurrent or metastatic EC, with measurable disease, chemotherapy nave and up to 1 line of prior hormonal therapy were eligible to participate. Patients (pts) received single agent erlotinib at a daily dose of 150 mg continuously. A cycle was defined as 4 weeks of therapy, with response assessment every 2 cycles.Twenty seven pts have been entered to date, with 25 evaluable for toxicity and 23 for response (1 cancelled before starting, 1 had only 5 days of trial drug, additional 2 pts too early for assessment). Treatment was well tolerated with 60% of pts receiving 90% of planned dose intensity. Seven had dose reductions (3 for skin toxicity; 3 diarrhea and 1 keratitis/conjuctivitis). The most common drug related toxicity was rash (2 grade(gr)3, 10 gr2 and 10 gr1). Drug related severe toxicity was infrequent with the only gr4 toxicity being an elevation of transaminases (SGOT). Grade-3 toxicities included 3 pts with diarrhea, 1 rash and pruritis, 1 non-neutropenic infection and dyspnea, plus single reports of fatigue, arthralgia, keratitis/conjunctivitis, rash, puritis and an elevation of bilirubin. There were no grade 3 or 4 hematologic toxicities. To date there is 1 confirmed partial response (PR) of disease in the mesentery and lungs lasting 10.4 mo. 12 pts have had stable disease (SD), with median duration of 3.4 mo (1.5-7.6). EGFR status using primary archival tumor tissue has been analyzed on 12 pts to date; 7 were positive, 5 were negative. Of the 7 pts who were EGFR positive, 1 had a PR, 3 SD and 3 progressive disease(PD). Of 5 who were EGFR negative, 2 had SD and 3 PD.Erlotinib in endometrial cancer is well tolerated. The study has fulfilled criteria to proceed stage II, with planned accrual of 30 evaluable patients. [Table: see text].

Hirte H.,Juravinski Cancer Center | Swenerton K.,British Columbia Cancer Agency | Ellard S.L.,British Columbia Cancer Agency | Grimshaw R.,Queen Elizabeth Center for Clinical Research | And 2 more authors.
Gynecologic Oncology | Year: 2010

Objectives: Approximately 50% of ovarian cancers have elevated levels of epidermal growth factor receptor (EGFR) which correlates with a poor prognosis. Preclinical evidence suggests that EGFR tyrosine kinase inhibitors (TKIs), such as erlotinib (OSI-774), may potentiate the anti-tumour effects of cytotoxic agents, including carboplatin. Blocking EGFR could thus potentially reverse drug resistance. The primary objective of the study was to assess the response rate to the addition of erlotinib in patients with recurrent ovarian cancer who were receiving carboplatin. Methods: Patients enrolled on this study had either local or advanced recurrent ovarian cancer with measurable disease. They may have had up to 2 prior chemotherapy regimens, one of which must have contained platinum, and they must have responded to prior platinum therapy. Patients were stratified by platinum sensitivity and were treated with erlotinib 150 mg daily on a continuous dosing schedule, and carboplatin at an AUC of 5 every 21 days. Results: Fifty patients with recurrent ovarian cancer entered the study, 33 in the platinum-sensitive arm and 17 in the platinum-resistant arm. Of patients evaluable for response, there were 14 partial responses (PR) of 30 evaluable for response (57% objective response rate (ORR)) in the platinum-sensitive arm, and 1 PR of 14 evaluable for response (7% ORR) in the platinum-resistant arm. Conclusions: The combination of erlotinib and carboplatin was active in patients with platinum-sensitive disease, but not in platinum-resistant disease. The toxicities seen were those expected with carboplatin and erlotinib. © 2010 Elsevier Inc.

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