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The study was conducted to evaluate a regional, prospective database of information on mothers of low birth weight (LBW) infants. The database informs on unidentified or under-reported modifiable risk factors from which evidence-based, targeted community intervention strategies could be designed to lower the rate of low birth weight in the region. The LBW Registry is based on informed consent, a semi-structured face-to-face (FTF) interview with the mother of the newborn LBW infant, medical record review, and birth certificate worksheet data collection. Descriptive statistics were used to summarize data from the registry. High rates of modifiable risk factors among mothers of low birth weight infants (October 2007-October 2008) include smoking (44%), alcohol consumption (16%), and drug abuse (14%). Preconception vitamin use was low (34%). The reported use of fertility drugs in FTF interviews was notably higher than information reported on the birth certificate worksheets by the same set of interviewed mothers (5.4 vs. 1.5%), as was alcohol use during pregnancy (16 vs. 1.3%). More than half (52%) of the mothers of low birth weight infants reported a vaginal or urinary tract infection during pregnancy. Additionally there were higher than average rates of unmarried mothers (62%), unintended pregnancies (67%), and Medicaid beneficiaries (57%). Mothers repeatedly expressed excessive demands in their lives, straining their coping abilities and resources. The LBW Registry provides expanded local data on potentially modifiable risk factors to aid in designing targeted prevention and intervention strategies. Keywords Low birth weight * Registry * Risk factors * Birth certificate * Stress management, Introduction Low birth weight (LBW) is defined as a live born infant weighing less than five and a half pounds or 2,500 g regardless of gestational age. Over the past [...]

Byline: Susan Burdette-Radoux (1), Richard G. Tozer (2), Reinhard C. Lohmann (3), Ian Quirt (4), D. Scott Ernst (5), Wendy Walsh (6), Nancy Wainman (6), A. Dimitrios Colevas (7), Elizabeth A. Eisenhauer (6) Keywords: melanoma; flavopiridol; cyclin; cyclin-dependent kinase Abstract: Purpose: To test the activity of the cyclin dependent kinase (cdk) inhibitor flavopiridol in malignant melanoma, a disease with frequent abnormalities of the cyclin dependent kinase system. Patients and methods: Patients had histologically proven, unidimensionally measurable malignant melanoma, incurable by standard therapy. Prior adjuvant immunotherapy was allowed, but patients were otherwise untreated for advanced disease. Flavopiridol was administered at a dose of 50 mg/m.sup.2 IV over 1 hour daily x 3 days every 3 weeks. Patients were assessed for response every 2 cycles. Results: 17 patients were accrued over 5 months. No objective responses were documented in the 16 patients evaluable for response. Seven patients (44%) had stable disease after 2 cycles, with a median of 2.8 months (range 1.8--9.2). The most common treatment-related non-hematologic toxicities were diarrhea (82%), nausea (47%), fatigue (41%), anorexia (35%) and vomiting (29%). Most treatment-related toxicities were mild, except for diarrhea (grade 3 in 3 patients, grade 4 in 1 patient), nausea (grade 3 in 1 patient) and tumor pain (grade 3 in 1 patient). Hematologic toxicities were minimal, none worse than grade 2. Eighty-eight percent of patients received aY=90% planned dose intensity; 2 patients had dose reductions for gastrointestinal (GI) toxicity. Conclusions: Flavopiridol is well tolerated at the dose regimen used in this study, with an acceptable (primarily GI) toxicity profile. Although 7 of the 16 patients had stable disease ranging from 1.8 to 9.2 months in duration, there was no evidence of significant clinical activity in malignant melanoma by objective response criteria. Author Affiliation: (1) McGill University, Montreal, Quebec, Canada (2) Hamilton Regional Cancer Centre, Hamilton, Ontario, Canada (3) London Regional Cancer Centre, London, Ontario, Canada (4) Princess Margaret Hospital, Toronto, Ontario, Canada (5) Tom Baker Cancer Centre, Calgary, Alberta, Canada (6) NCIC Clinical Trials Group, Kingston, Ontario, Canada (7) NCI/CTEP, Rockville, MD, USA Article History: Registration Date: 21/10/2004

Byline: Lyly H. Le (1), Charles Erlichman (1,2), Linda Pillon (3), Jake J. Thiessen (3), Andrew Day (4), Nancy Wainman (4), Elizabeth A. Eisenhauer (4), Malcolm J. Moore (1) Keywords: protein phosphatase inhibitor; topoisomerase II inhibitor; CI-920 Abstract: Fostriecin (CI-920) is a potent inhibitor of protein phosphatase 2A (PP2A) and protein phosphatase 4(PP4) found to have anticancer activity in preclinical testing. A phase I study was conducted to evaluate the maximum-tolerated dose (MTD), toxicity profile, and pharmacokinetics (PK) of this drug. Forty-six patients were treated with escalating doses of fostriecin (2--47mg/m.sup.2) administered as a daily bolus infusion for five consecutive days. PK studies were performed at different time points following administration of fostriecin. Dose-limiting toxicities included: elevation of creatinine, bilirubin, and hepatic transaminases; nausea, anorexia, lethargy, and hypotension. PK studies were compatible with a two-compartment model. Regression analysis revealed a significant relationship between dose and clearance; however, the r .sup.2 value was only 0.168 indicating a low predictive value for the model. No significant difference was seen in PK parameters with repeated dosing during the same cycle. Although no tumor responses were seen, 16 patients had stable disease with a median duration response of 2.6 months. The study was closed before reaching MTD due to problems with the supply of fostriecin from the National Cancer Institute of the United States (NCI US). New methods for synthesizing fostriecin have recently been described and therefore further development of this unique anticancer agent may be warranted. Author Affiliation: (1) Princess Margaret Hospital, Toronto, ON, Canada (2) Mayo Clinic, Rochester, MN, U.S.A (3) Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada (4) Clinical Trials Group of the National Cancer Institute of Canada, Kingston, ON, Canada Article History: Registration Date: 21/10/2004

Byline: Karl Belanger (1), David MacDonald (2), Gregory Cairncross (2), Stan Gertler (3), Peter Forsyth (4), Susan Burdette-Radoux (5), Julie Bergeron (1), Denis Soulieres (1), Samuel Ludwin (6), Nancy Wainman (7), Elizabeth Eisenhauer (7) Keywords: topotecan; oligodendroglioma; phase II Abstract: To determine the efficacy and toxicity of a novel chemotherapeutic approach with topotecan, a camptothecin analog, for progressive or recurring anaplastic oligodendroglioma or mixed oligoastrocytoma. Patients from seven centers with recurrent or progressive disease were treated with topotecan, 1.5mg/m.sup.2 intravenously (i.v.), 30min dailyx5 days every 3 weeks. Efficacy and toxicity were assessed clinically and radiologically. The study was planned to accrue up to 30 evaluable patients if there was at least one response among the first 15 patients treated. Sixteen eligible patients entered the study. No response was documented in 14 evaluable patients. Eleven patients had stable disease of a median of 3.8 months and three had progressive disease. Sixteen patients were evaluable for toxicity. The most significant toxic effect was myelosuppression. Grade 3 or 4 granulocytopenia was experienced by 15 of 16 patients and led to dose reduction in nearly half of the cycles delivered. Other adverse effects were fatigue, nausea, stomatitis, alopecia, and vomiting. Topotecan, delivered in the dailyx5 regimen, is relatively well tolerated. We could not demonstrate significant activity among the population studied to justify completing accrual to 30 patients. Topotecan did not demonstrate, with this small sample size, efficacy as a salvage chemotherapy monotherapy after exposure to procarbazine, CCNU and vincristine. Further trials with different agents in this indication are certainly warranted. Author Affiliation: (1) CHUM-Hopital Notre-Dame, Department of Hematology, Montreal, Quebec, Canada (2) London Regional Cancer Centre, London, Ontario, Canada (3) Ottawa Regional Cancer Centre, Ottawa, Ontario, Canada (4) Tom Baker Cancer Centre, Calgary, Alberta, Canada (5) Department of Oncology, McGill University, Montreal, Quebec, Canada (6) Department of Pathology, Queen's University, Kingston, Ontario, Canada (7) NCIC Clinical Trials Group, Queen's University, Kingston, ON, Canada Article History: Registration Date: 06/10/2004

Byline: Alison J. Davis (1), Karen A. Gelmon (2), Lillian L. Siu (1), Malcolm J. Moore (1), Carolyn D. Britten (2), Nisha Mistry (1), Henry Klamut (1), Susan D'Aloisio (2), Martha MacLean (1), Nancy Wainman (3), Debbie Ayers (2), Patricia Firby (1), Jeffrey M. Besterman (4), Gregory K. Reid (4), Elizabeth A. Eisenhauer (1) Keywords: antisense; DNS; methyltransferase; phase I trial Abstract: Purpose: MG98 is a second generation phosphorothioate antisense oligodeoxynucleotide which is a highly specific inhibitor of translation of the mRNA for human DNA MeTase I (DNMT 1). This phase I study examined the toxicity and pharmacologic profile of MG98 administered as a continuous 21-day intravenous infusion every 4 weeks. Patients and methods: Fourteen patients with solid cancers received a total of 25 cycles of MG98 at doses ranging from 40 to 240 mg/m.sup.2/day. Steady-state concentrations of MG98 were measured as were several pharmacodynamic assessments including mRNA of the target gene, DNMT1, in PBMC. In addition, other potential surrogate markers of drug effects were explored, including hemoglobin F, Vimentin and GADD45. Results: Dose limiting effects were drug-related reversible transaminase elevation and fatigue seen at doses of 240, 200 and 160 mg/m.sup.2/day. The dose level of 80 mg/m.sup.2/day was felt to be safe and tolerable when delivered on this schedule. No evidence of antitumor activity was observed. Although pharmacokinetic analysis revealed that at the higher dose levels, mean Css values of MG98 were approximately 10-fold times the IC.sub.50 values associated with target inhibition in vitro, the extent of MG98 penetration into target tumors in this trial was not determined. No consistent, dose-related changes in correlative markers including DNMT1 mRNA, hemoglobin F, Vimentin and GADD45, were observed. Conclusions: This schedule of MG98 given as a 21-day continuous intravenous infusion every 4 weeks was poorly tolerated in the highest doses therefore, further disease-site specific evaluation of the efficacy of this agent will utilize a more favorable, intermittent dosing schedule. Pharmacodynamic evaluations undertaken in an attempt to explore and validate the biological mechanisms of MG98 did not show dose-related effects. Author Affiliation: (1) National Cancer Institute, Canada (2) British Columbia Cancer Agency, Vancouver, Canada (3) Investigational New Drug Program, National Cancer Institute of Canada Clinical Trials Group, Kingston (4) MethylGene Inc, Montreal, Canada Article History: Registration Date: 05/10/2004

Byline: Ian Quirt (1), Audley Bodurtha (2,3), Reinhard Lohmann (4), James Rusthoven (5), Karl Belanger (6), Vincent Young (7), Nancy Wainman (8), William Steward (8,9), Elizabeth Eisenhauer (8) Keywords: marimastat; melanoma; phase II; translational study Abstract: Objectives: To determine thetolerability and efficacy of daily oralmarimastat (BB-2516 in patients withmetastatic melanoma and to determine thematrix metalloproteinase (MMP) activity,tumour necrosis, peri- and intra-tumoralfibrosis and tumor inflammation in pre- and post-treatmenttumor biopsies. Patients and methods: Patients withmeasurable metastatic melanoma who hadreceived no more than one priorchemotherapy regimen and lesions accessiblefor biopsy were eligible. The first 18 weretreated with 100 mg p.o. twice daily and thenext 11 received a reduced dose of 10 mgp.o. twice daily because of musculoskeletaltoxicity. Response was assessed accordingto standard criteria. Results: Twenty-nine patients were entered and 28 wereeligible. Five had early progression (&lt 4 weeks oftherapy), 2 experienced a partial responsespersisting for 3.2 months and 3.6 months, 5had stable disease and 16 progressivedisease. Eleven patients had both pre- andpost-treatment biopsies. In 3, no tumortissue was present in one or the otherbiopsy. Two patients showed a clearincrease in peri-tumoral fibrosis and twoothers showed an increase in tumornecrosis, but no consistent pattern inhistologic changes was seen. In onepatient, who later developed a PR,apoptosis was increased. Conclusion: Marimastat has onlylimited activity in patients withmetastatic malignant melanoma. However,the observation of two partial responseswas interesting given that this agent mighthave been expected to cause tumor stasisrather than regression. Additional studieswill be required to determine if thedevelopment of peri-tumoral fibrosis ortumor necrosis antedates a clinicalresponse to marimastat. Author Affiliation: (1) Princess Margaret Hospital, Toronto (2) Ottawa Regional Cancer Centre, Ottawa (3) Nova Scotia Cancer Centre, Halifax, Nova Scotia, Canada (4) London Regional Cancer Centre, London (5) Hamilton Regional Cancer Centre, Hamilton, Ontario (6) CHUM-Hopital Notre Dame, Montreal, Quebec (7) Ottawa Regional Cancer Centre, Ottawa (8) National Cancer Institute of Canada, Clinical Trials Group, Queen's University, Kingston, Ontario (9) Leicester Royal Infirmary, Leicester, England, UK Article History: Registration Date: 10/10/2004

To assess the response rate and toxicity of the kinesin spindle protein (KSP) inhibitor, ispinesib, in malignant melanoma. Seventeen patients were enrolled from April to November 2005. Ispinesib was administered as a 1-hour infusion at a dose of 18 mg/m2 once every 3 weeks until disease progression. No objective responses were seen. Six patients (35%) had a best response of stable disease for a median duration of 2.8 months. Disease progression was documented in 9 (53%) after 1 or 2 cycles. Eighty-eight percent of patients received > or =90% of planned dose intensity. Grade 3 non-hematologic toxicities included dizziness (1) and blurred vision (1). There was one episode of febrile neutropenia, but no grade 3 or 4 biochemical adverse events. Pharmacokinetics was consistent with prior studies. KSP immunoreactivity was seen in 14 of 16 available archival tissue samples (88%). Ispinesib can be safely administered using the dose and schedule employed, with mild hematologic and non-hematologic toxicity. No objective responses were observed, and further development of single-agent ispinesib in malignant melanoma is not recommended. Although KSP expression appears to be common in melanoma, KSP may not be a suitable target for its treatment.

Triapine is a novel small molecule ribonucleotide reductase inhibitor that showed activity in renal cell carcinoma (RCC) cell lines. Evaluating new agents with novel mechanisms remains of interest for patients with incurable RCC. This was a single-arm, multicentre phase II trial where Triapine was given at a schedule of 96 mg/m2 2-h infusion daily x 4 repeated every 2 weeks in patients with recurrent RCC. A median of four cycles of Triapine was administered to 19 eligible patients. One response was seen (7%.) Median time to progression was 3.6 months. Common adverse events (AEs) were grade 1-2, with fatigue in 74%, nausea in 68% and vomiting in 58%. However grade 3/4 neutropenia was seen in 79% and acute reactions of hypoxia, hypotension, methemoglobinemia were seen. Dose reductions/delays due to AEs were common with only 47% of patients receiving > 90% of planned dose intensity. The study closed, at the end of stage 1 as it did not meet the minimal efficacy criteria to proceed. Further evaluation of Triapine at this dose and schedule in patients with advanced kidney cancer is not recommended.