Lillian L Siu

University Health Network, Toronto, Ontario, Canada

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Publications (319)2328.15 Total impact

  • Jeremy Lewin · Lillian L Siu
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    ABSTRACT: Although significant strides have been made in genome sequencing technology, target-drug matching remains challenging. This article highlights the difficulties associated with patients accessing targeted drugs based on genomic information, and some proposed solutions. Although cancers are increasingly stratified according to molecular subgroups, challenges remain in improving patient outcome based on drug-target matching. Before a drug-target match is even proposed, significant expertise is required of the clinician to interpret genomic information. Once a potential match is made, barriers remain for patients to access treatment via clinical trials, as approved agents on-label or off-label, or through expanded access programs. Solutions to improve drug accessibility are actively being investigated. Several prospective trials using molecular characterization as an entry to access target-drug matching are underway. For those unable to access target-drug matching on trial, proposals for a facilitated access program and registry have been suggested. Although improvements have been made in the drug development and approval timelines, drug accessibility based on molecular characterization remains problematic. However, with the emergence of novel trial designs, and efforts to enhance drug access outside of clinical trial settings, opportunities for drug-target matching are improving.
    No preview · Article · Mar 2015 · Current Opinion in Oncology
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    ABSTRACT: Abstract This phase I trial evaluates 2 schedules of escalating vorinostat in combination with decitabine (20 mg/m(2)/d IV Days 1-5) every 28 days: (a) sequential or (b) concurrent. There were 3 DLTs: grade 3 fatigue and generalized muscle weakness on the sequential schedule (n=1) and grade 3 fatigue on the concurrent schedule (n=2). MTD was not reached on both planned schedules. The ORR was 23% (3 CR, 2 CRi, 1 PR, and 2 MLS). The ORR for all and previously untreated patients in the sequential arm was 13% (1 CRi; 1 MLFS) and 0% compared to 30% (3 CR; 1 CRi; 1 PR; 1 MLFS) and 36% in the concurrent arm (P = 0.26 for both), respectively. Decitabine and vorinostat was safe and has clinical activity in patients with previously untreated AML. Responses appear higher with the concurrent dose schedule. Cumulative toxicities may limit long-term usage on the current dose/schedules.
    No preview · Article · Feb 2015 · Leukemia and Lymphoma
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    ABSTRACT: Purpose: To refine stage and prognostic group for human papillomavirus (HPV) -related nonmetastatic (M0) oropharyngeal cancer (OPC). Methods: All patients with nonmetastatic (M0) p16-confirmed OPC treated with radiotherapy with or without chemotherapy from 2000 to 2010 were included. Overall survival (OS) was compared among TNM stages for patients with HPV-related and HPV-unrelated OPC separately. For HPV-related OPC, recursive partitioning analysis (RPA) derived new RPA stages objectively. Cox regression was used to calculate adjusted hazard ratios (AHRs) to derive AHR stages. The performance of survival prediction of RPA stage and AHR stage was assessed against the current seventh edition TNM stages. Prognostic groups were derived by RPA, combining RPA stage and nonanatomic factors. Results: The cohort comprised 573 patients with HPV-related OPC and 237 patients with HPV-unrelated OPC, with a median follow-up of 5.1 years. Lower 5-year OS with higher TNM stage was evident for patients with HPV-unrelated OPC (stage I, II, III, and IV 5-year OS: 70%, 58%, 50%, and 30%, respectively; P = .004) but not for patients with HPV-related OPC (stage I, II, III, and IV 5-year OS: 88%, 78%, 71%, and 74%, respectively; P = .56). RPA divided HPV-related OPC into RPA-I (T1-3N0-2b), RPA-II (T1-3N2c), and RPA-III (T4 or N3; 5-year OS: 82%, 76%, and 54%, respectively; P < .001). AHR also yielded a valid classification, but RPA stage demonstrated better survival prediction. A further RPA (including RPA stage, age, and smoking pack-years [PYs]) derived the following four valid prognostic groups for survival: group I (T1-3N0-N2c_≤ 20 PY), group II (T1-3N0-N2c_> 20 PY), group III (T4 or N3_age ≤ 70), and group IVA (T4 or N3_age > 70; 5-year OS: 89%, 64%, 57%, and 40%, respectively; P < .001). Conclusion: An RPA-based TNM stage grouping (stage I/II/III: T1-3N0-N2b/T1-3N2c/T4 or N3, with M1 as stage IV) is proposed for HPV-related OPC as a result of significantly improved survival prediction compared with the seventh edition TNM, and prognostication is further improved by an RPA-based prognostic grouping within the American Joint Committee on Cancer/Union for International Cancer Control TNM framework for HPV-related OPC.
    Full-text · Article · Feb 2015 · Journal of Clinical Oncology
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    ABSTRACT: Understanding the influence or impact of epidemiological factors on cancer outcomes in clinical trials can broaden our knowledge of disease, trial populations and therapeutic effects thus leading to improved patient care. However, there is a lack of data on cancer patients' compliance with an epidemiology questionnaire in the context of a clinical trial. Cancer patients were provided with a hypothetical scenario and surveyed regarding their willingness and preferences to complete an epidemiology questionnaire if incorporated into a cancer therapy trial. Patient compliance with completing a voluntary epidemiology questionnaire and trial coordinators perceptions therein were separately determined in the NCIC Clinical Trials Group HN.6 clinical trial, an ongoing randomized phase III trial comparing two first-line treatment regimens in patients with locoregionally advanced head and neck cancer. Of 617 cancer patients from community, academic and tertiary cancer centres, the majority were willing to complete an epidemiology questionnaire either unconditionally (45%), or provided it did not inconvenience them (31%); 4% would refuse. Patients preferred shorter questionnaires of 30-50 questions requiring 10-20 min to complete, administered over 1-3 sessions. Patients were less willing, but still compliant, to answer questions relating to sexual history (71%) and annual household income (66%) relative to other questions (>90%). Eighteen percent thought that the questionnaire should be mandatory, with 31% believing that they may benefit personally from such research. In the HN.6 trial, compliance averaged 94.8% per question. Cancer patients are very willing to complete epidemiology questions in clinical trials. © The Author(s) 2015.
    No preview · Article · Jan 2015 · Clinical Trials
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    ABSTRACT: Background: Heat-shock protein 990 (HSP990) is a potent and selective synthetic small-molecule HSP90 inhibitor. The primary objectives of this phase I first-in-human study were to determine dose-limiting toxicities (DLTs), maximum-tolerated dose (MTD) and recommended phase II dose (RP2D). Secondary objectives included characterisation of the safety profile, pharmacokinetics (PKs) and pharmacodynamics (PDs). Methods: Heat-shock protein 990 was administered orally once or two times weekly on a 28-day cycle schedule in patients with advanced solid tumours. Dose escalation was guided by a Bayesian logistic regression model with overdose control. Results: A total of 64 patients were enrolled. Fifty-three patients received HSP990 once weekly at 2.5, 5, 10, 20, 30, 50 or 60 mg, whereas 11 patients received HSP990 two times weekly at 25 mg. Median duration of exposure was 8 weeks (range 1-116 weeks) and 12 patients remained on treatment for >16 weeks. Dose-limiting toxicities occurred in seven patients and included diarrhoea, QTc prolongation, ALT/AST elevations and central neurological toxicities. The most common drug-related adverse events were diarrhoea, fatigue and decreased appetite. Further dose escalation beyond 60 mg once weekly was not possible owing to neurological toxicity. Rapid absorption, no drug accumulation and large interpatient variability in PK exposures were observed. No objective responses were seen; 25 patients had a best overall response of stable disease. Conclusions: Heat-shock protein 990 is relatively well tolerated, with neurological toxicity being the most relevant DLT. The single agent MTD/RP2D of HSP990 was declared at 50 mg once weekly.
    No preview · Article · Jan 2015 · British Journal of Cancer
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    ABSTRACT: Background: AT7519 is a small-molecular inhibitor of multiple cyclin-dependent kinases (CDKs). It shows encouraging anti-cancer activity against multiple cell lines and in tumour xenografts. This phase I study was conducted to evaluate the safety and tolerability of AT7519 given as 1-h intravenous infusion on days 1, 4, 8 and 11 every 3 weeks. Methods: Patients with advanced refractory solid tumours or non-Hodgkin's lymphoma were enroled. Dose escalation occurred in a 3+3 manner based on toxicity assessment. Pharmacokinetic samples were collected after first AT7519 infusion, whereas pharmacodynamics (PD) samples were obtained in selected patients. Results: Thirty-four patients were enroled, and 32 received study treatments over 4 dose levels. Dose-limiting toxicities included mucositis, febrile neutropenia, rash, fatigue and hypokalemia. The recommended phase II dose (RP2D) was 27.0 mg m(-2). Ten of 19 patients evaluable for efficacy had stable disease as the best response (median duration: 3.3 months; range: 2.5 to 11.1 months). There was no clinically significant QTc prolongation. There was an apparent dose proportional increase in AT7519 exposure. The PD studies showed reduction in markers of CDK activity in selected patients' skin biopsies post treatment. Conclusions: AT7519, when administered as an intravenous infusion on days 1, 4, 8 and 11, was well tolerated. The RP2D is 27.0 mg m(-2). At this dose level, plasma AT7519 concentrations were above the biologically active concentrations, and preliminary anti-cancer activity was observed in patients. This dosing schedule is being further evaluated in multiple phase II studies.
    Full-text · Article · Nov 2014 · British Journal of Cancer
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    ABSTRACT: Purpose Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) and fibroblast growth factor-inducible molecule 14 (Fn14) are a ligand-receptor pair frequently overexpressed in solid tumors. TWEAK:Fn14 signaling regulates multiple oncogenic processes through MAPK, AKT, and NFκB pathway activation. A phase I study of RG7212, a humanized anti-TWEAK IgG1κ monoclonal antibody, was conducted in patients with advanced solid tumors expressing Fn14. Methods Dose escalations, over a 200- to 7200-mg range, were performed with patients enrolled in weekly (QW), bi-weekly (Q2W), or every-three-week (Q3W) schedules. Primary objectives included determination of dose and safety profile. Secondary endpoints included assessments related to inhibition of TWEAK:Fn14 signaling, tumor proliferation, tumor immune cell infiltration, and pharmacokinetics. Results In 192 treatment cycles administered to 54 patients, RG7212 was well-tolerated with no dose-limiting toxicities observed. More than 95% of related adverse events were limited to grade 1/2. Pharmacokinetics were dose proportional for all cohorts, with a t1/2 of 11-12 days. Pharmacodynamic changes included clearance of free and total TWEAK ligand and reductions in tumor Ki-67 and TRAF1. A patient with BRAF wild-type melanoma who received 36 weeks of RG7212 therapy had tumor regression and pharmacodynamic changes consistent with antitumor effects. Fifteen patients (28%) received 16 or more weeks of RG7212 treatment.
    No preview · Article · Nov 2014 · Clinical Cancer Research

  • No preview · Article · Nov 2014 · European Journal of Cancer

  • No preview · Article · Nov 2014 · European Journal of Cancer

  • No preview · Article · Nov 2014 · European Journal of Cancer
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    ABSTRACT: Purpose: The combination of low-dose radiotherapy with PARP inhibition has been shown to enhance antitumor efficacy through potentiating DNA damage. We combined low-dose fractionated whole abdominal radiation (LDFWAR) with escalating doses of veliparib (ABT-888), a small-molecule PARP inhibitor, in patients with peritoneal carcinomatosis from advanced solid tumor malignancies. Experimental design: Patients were treated with veliparib (80-320 mg daily) for a total of 3 cycles. LDFWAR consisted of 21.6 Gy in 36 fractions, 0.6 Gy twice daily on days 1 and 5 for weeks 1-3 of each cycle. Circulating tumor cells (CTC) were collected and evaluated for γ-H2AX. Quality of life (QoL) was assessed using the EORTC-QLQ-C30 questionnaire. Results: Twenty-two patients were treated. Treatment-related grade 3 and 4 toxicities included lymphopenia (68%), anemia (9%), thrombocytopenia (14%), neutropenia (4%), leukopenia (9%), ascites (4%), vomiting (4%), and dyspnea (4%). No objective responses were observed. Disease stabilization (≥24 weeks) was observed in 7 patients (33%). Median progression-free survival (mPFS) was 4.47 months and median overall survival (mOS) was 13.04 months. In the subset of 8 ovarian and fallopian cancers, mPFS was 6.77 months and mOS was 17.54 months compared with mPFS 2.71 months and mOS 13.01 months in others. Patients with ovarian and fallopian cancers had better QoL over time than those with other cancers. An increased percentage of γ-H2AX-positive CTCs was observed in a subset of patients (3/6 with >2 CTCs at baseline). Conclusions: Combined veliparib and LDFWAR is a well-tolerated regimen that resulted in prolonged disease stability for some patients with advanced solid tumors and carcinomatosis, particularly in the ovarian and fallopian cancer subpopulation.
    No preview · Article · Oct 2014 · Clinical Cancer Research
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    ABSTRACT: The implementation of cancer genomic testing into the clinical setting has brought major opportunities. However, as our understanding of cancer initiation, maintenance and progression improves through detailed cancer genomic studies, the challenges associated with driver identification and target classification in the clinical setting become clearer. Here, we review recent insights into cancer genomic testing in the clinical setting, and suggest a target classification approach that considers the levels of evidence supporting the prioritization of tumour drivers for therapeutic targeting in light of complex cancer clonal and sub-clonal structures and clinical successes and failures in the field. We argue that such classification approaches, together with transparent reporting of both positive and negative clinical data and continued research to identify the sub-clonal dynamics of driver events during the disease course, will facilitate inter-trial comparisons, optimize patient informed consent and provide a critically balanced evaluation of genomic testing in clinical practice.
    Preview · Article · Oct 2014 · Annals of Oncology
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    ABSTRACT: Background: RO4929097 is an oral inhibitor of γ -secretase that results in Notch signaling inhibition. Prior work has demonstrated that Notch signaling inhibition enhances chemotherapy sensitivity of cancer cells. This phase I study was conducted to determine maximum tolerated dose (MTD), toxicities and efficacy of RO4929097 and capecitabine in advanced solid tumors. Methods: Patients with refractory solid tumors received capecitabine at a fixed dose of 1,000 mg/m(2) twice daily with escalating doses of RO4929097 on a 21-day cycle in a 3 + 3 design. Capecitabine was administered for 14 days and the RO49029097 once daily, 3 days per week, both for a 21 day cycle. Results: Thirty patients were treated on six dose levels (20 to 150 mg). The maximally tolerated dose was not reached. One dose limiting toxicity was observed at each level 3 through 6 (hypophosphatemia, fatigue, and nausea/vomiting). Three confirmed partial responses were observed: two patients with fluoropyrimide-refractory colon cancer and one patient with cervical cancer. Autoinduction of RO4929097 was demonstrated with increasing dose levels and duration. Conclusions: The recommended phase 2 dose is capecitabine 1,000 mg/m(2) orally twice daily on days 1 through 14 with RO4929097 20 mg orally once daily on days 1-3, 8-10 and 15-17 with a 21 day cycle. Clinical benefit was observed in cervical and colon cancer. Autoinduction of RO4929097 was seen both with increasing cycle number and increasing dose. Plasma concentrations of RO4929097 were above those needed for Notch inhibition.
    No preview · Article · Oct 2014 · Investigational New Drugs
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    ABSTRACT: Background: Two strategies to interrogate the insulin growth factor 1 receptor (IGF-1R) pathway were investigated: vertical inhibition with dalotuzumab and MK-2206 or ridaforolimus to potentiate PI3K pathway targeting and horizontal cross-talk inhibition with dalotuzumab and MK-0752 to exert effects against cellular proliferation, angiogenesis, and stem cell propagation. Methods: A phase I, multi-cohort dose escalation study was conducted in patients with advanced solid tumours. Patients received dalotuzumab (10 mg kg(-1)) and escalating doses of MK-2206 (90-200 mg) or escalating doses of dalotuzumab (7.5-10 mg kg(-1)) and MK-0752 (1800 mg) weekly. Upon maximum tolerated dose determination, patients with low-RAS signature, high-IGF1 expression ovarian cancer were randomised to dalotuzumab/MK-2206 versus dalotuzumab/ridaforolimus, whereas patients with high IGF1/low IGF2 expression colorectal cancer received dalotuzumab/MK-0752. Results: A total of 47 patients were enrolled: 29 in part A (18 in the dalotuzumab/MK-2206 arm and 11 in the dalotuzumab/MK-0752 arm) and 18 in part B (6 in each arm). Dose-limiting toxicities (DLTs) for dalotuzumab/MK-2206 included grade 4 neutropenia and grade 3 serum sickness-like reaction, maculopapular rash, and gastrointestinal inflammation. For dalotuzumab/MK-0752, DLTs included grade 3 dehydration, rash, and diarrhoea. Seven patients remained on study for >4 cycles. Conclusions: Dalotuzumab/MK-2206 and dalotuzumab/MK-0752 combinations were tolerable. Further developments of prospectively validated predictive biomarkers to aid in patient selection for anti-IGF-1R therapies are needed.
    Preview · Article · Oct 2014 · British Journal of Cancer

  • No preview · Article · Oct 2014 · Cancer Research
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    ABSTRACT: Background: Genomic testing in cancer (GTC) characterizes genes that play an important role in the development and growth of a patient's cancer. This form of DNA testing is currently being studied for its ability to guide cancer therapy. The objective of the current study was to describe patients' knowledge, attitudes, and expectations toward GTC. Methods: A 42-item self-administered GTC questionnaire was developed by a multidisciplinary group and patient pretesting. The questionnaire was distributed to patients with advanced cancer who were referred to the Princess Margaret Cancer Center for a phase 1 clinical trial or GTC testing. Results: Results were reported from 98 patients with advanced cancer, representing 66% of the patients surveyed. Seventy-six percent of patients were interested in learning more about GTC, and 64% reported that GTC would significantly improve their cancer care. The median score on a 12-item questionnaire to assess knowledge of cancer genomics was 8 of 12 items correct (67%; interquartile range, 7-9 of 12 items correct [58%-75%]). Scores were associated significantly with patients' education level (P < .0001). Sixty-six percent of patients would consent to a needle biopsy, and 39% would consent to an invasive surgical biopsy if required for GTC. Only 48% of patients reported having sufficient knowledge to make an informed decision to pursue GTC whereas 34% of patients indicated a need for formal genetic counseling. Conclusions: Patients with advanced cancer are motivated to participate in GTC. Patients require further education to understand the difference between somatic and germline mutations in the context of GTC. Educational programs are needed to support patients interested in pursuing GTC.
    Full-text · Article · Oct 2014 · Cancer
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    ABSTRACT: Background: In preclinical models, the proton pump inhibitor pantoprazole enhances the antitumor activity of chemotherapeutic agents by improving drug distribution and by inhibiting autophagy. Methods: Patients with advanced solid tumors (n = 24) received doxorubicin 60 mg/m(2) and escalating doses of pantoprazole (80, 160, 240 and 360 mg) administered intravenously prior to doxorubicin. Blood samples were collected for pharmacokinetic studies. An optional biopsy was performed to evaluate doxorubicin concentration and pharmacodynamic markers of drug activity. Results: Twenty-four patients participated in the study (17 in the dose escalation phase and 7 in the dose expansion). Three patients experienced a dose limiting toxicity (grade 3 fatigue in the three cases), one patient at dose level 3 (pantoprazole 240 mg) and two patients at dose level 4 (pantoprazole 360 mg). Dose level 4 was considered to exceed the maximum tolerated dose. The recommended phase II dose was pantoprazole 240 mg and doxorubicin 60 mg/m(2). The most commonly observed toxicities included fatigue, neutropenia and leukopenia. Two patients achieved a confirmed partial response. Median maximum serum concentration of pantoprazole was 84.3 μM at 1-2 h after injection of pantoprazole 240 mg. No drug-drug interaction was observed. A single on-treatment tumor biopsy showed a sharply decreasing gradient in doxorubicin concentration and associated activity markers with increasing distance from tumor blood vessels. Conclusion: Administration of high doses of pantoprazole in combination with doxorubicin is feasible. The recommended phase II dose of pantoprazole, 240 mg, will be evaluated in combination with docetaxel as first line in patients with castration-resistant prostate cancer.
    No preview · Article · Sep 2014 · Investigational New Drugs
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    ABSTRACT: The purpose of early stage clinical trials is to determine the recommended dose and toxicity profile of an investigational agent or multi-drug combination. Molecularly targeted agents (MTAs) and immunotherapies have distinct toxicities from chemotherapies that are often not dose dependent and can lead to chronic and sometimes unpredictable side effects. Therefore utilizing a dose escalation method that has toxicity based endpoints may not be as appropriate for determination of recommended dose, and alternative parameters such as pharmacokinetic or pharmacodynamic outcomes are potentially appealing options. Approaches to enhance safety and optimize dosing include improved preclinical models and assessment, innovative model based design and dose escalation strategies, patient selection, the use of expansion cohorts and extended toxicity assessments. Tailoring the design of phase I trials by adopting new strategies to address the different properties of MTAs is required to enhance the development of these agents. This review will focus on the limitations to safety and dose determination that have occurred in the development of MTAs and immunotherapies. In addition, strategies are proposed to overcome these challenges to develop phase I trials that can more accurately define the recommended dose and identify adverse events.
    Full-text · Article · Aug 2014 · Molecular Oncology
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    ABSTRACT: Could the human papillomavirus (HPV) vaccination be cost-effective in males for the prevention of oropharyngeal squamous cell cancer (OPC)? It could be under certain conditions. Research on HPV vaccine has focused mainly on females. However, within the next decade, it is predicted that OPC will surpass cervical cancer as the most common HPV-related cancer, and it is postulated that HPV vaccination may alter the incidence of OPC. The purpose of this editorial is to comment on the potential cost-effectiveness of HPV vaccination in males for OPC prevention by addressing three elements payers often consider when making a decision to fund an intervention and to provide an overview of recent findings regarding the cost-effectiveness of HPV vaccine in males.
    Full-text · Article · Aug 2014 · Expert Review of Pharmacoeconomics & Outcomes Research
  • Herbert H Loong · Lillian L Siu

    No preview · Chapter · Aug 2014

Publication Stats

11k Citations
2,328.15 Total Impact Points

Institutions

  • 2002-2015
    • University Health Network
      • • Princess Margaret Hospital
      • • Department of Medical Oncology
      Toronto, Ontario, Canada
    • Centre hospitalier de l'Université de Montréal (CHUM)
      Montréal, Quebec, Canada
  • 1998-2015
    • University of Toronto
      • • Department of Medicine
      • • Department of Radiation Oncology
      Toronto, Ontario, Canada
  • 1998-2014
    • The Princess Margaret Hospital
      Toronto, Ontario, Canada
  • 2009
    • University of Texas MD Anderson Cancer Center
      • Department of Biostatistics
      Houston, Texas, United States
  • 2008
    • Memorial Sloan-Kettering Cancer Center
      New York, New York, United States
  • 2007
    • University of Chicago
      Chicago, Illinois, United States
  • 2006-2007
    • National Cancer Institute (USA)
      베서스다, Maryland, United States
    • Hôpital Maisonneuve-Rosemont
      Montréal, Quebec, Canada
  • 2001
    • University of Texas Health Science Center at San Antonio
      • Department of Medicine
      San Antonio, Texas, United States