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Sumithra J Mandrekar

Publications and source records attributed to Sumithra J Mandrekar.

11 recordsLinked to original sources
PubMed2007

An adaptive phase I design for identifying a biologically optimal dose for dual agent drug combinations.

Historically, designs for dose seeking trials using chemotherapeutic drug combinations have been geared towards finding the maximum tolerated dose, with safety as the primary outcome. With target based agents whose dose-efficacy curves are unknown and dose-toxicity relationships may be minimal, alternative designs are needed. In this paper, we propose an extension to an adaptive single agent dose-finding design previously reported. A generalization of the continuation ratio model allowing separate toxicity and efficacy curves for each agent in a dual agent combination, generating a dose success surface for the combination, is proposed. A continual reassessment approach with a straightforward dose selection criterion using the accumulated data from all patients treated to that point is employed. Our simulation studies demonstrate favourable operating characteristics in terms of experimentation and recommendation rates, and the average sample size, under a variety of scenarios. The proposed approach allowing the incorporation of both the toxicity and efficacy of each agent into the identification of an optimal dosing region for a combination is novel and warrants further consideration.

Algorithms↗
PubMed2007

A pooled analysis of quality of life measures and adverse events data in north central cancer treatment group lung cancer clinical trials.

BACKGROUND: In this pooled analysis, the authors examined correlations between single-item and multiple-item quality of life (QOL) measures and assessed the agreement between clinically significant changes in QOL and patient-reported adverse events (AE). METHODS: Data from 6 lung cancer clinical trials that involved 358 patients were pooled. All trials incorporated the Uniscale and 1 of 3 multiple-item assessments: the Functional Assessment for Cancer Therapy-Lung, the Lung Cancer Symptom Scale, or the Symptom Distress Scale. Spearman rank correlations and a Bland-Altman approach were used to assess agreement. Time-to-event analysis was performed using the Kaplan-Meier method. RESULTS: Correlations between the Uniscale and multiple-item assessments were substantial (correlation coefficient = 0.49-0.66). At least 1 10-point decline was reported in the Uniscale and multiple-item assessments by 58% of patients and 39% of patients, respectively. At least 1 severe AE (grade >or=3) was reported in 35% of patients postbaseline. The percent agreement between experiencing a severe AE and a decline in QOL was 48% and 59% for the Uniscale and multiple-item assessments, respectively. The median time to the first 10-point decline in QOL for the Uniscale and multiple-item assessments was 67 days and 142 days, respectively, and the median time to the first occurrence of a severe AE was 304 days. CONCLUSIONS: Information gleaned from the single-item Uniscale assessment was comparable to that gleaned from multiple-item global measures. There was moderate agreement between QOL and AE. A 10-point decline in QOL occurred earlier than Common Toxicity Criteria AE reporting. This suggests the need for inclusion of a QOL instrument in lung cancer clinical trials.

Activities of Daily Living↗
PubMed2006

A phase I trial of twice-weekly 17-allylamino-demethoxy-geldanamycin in patients with advanced cancer.

PURPOSE: To determine the maximum tolerated dose (MTD), dose-limiting toxicity, and pharmacokinetics of 17-allylamino-demethoxy-geldanamycin (17-AAG) administered on days 1, 4, 8, and 11 every 21 days and to examine the effect of 17-AAG on the levels of chaperone and client proteins. EXPERIMENTAL DESIGN: A phase I dose escalating trial in patients with advanced solid tumors was done. Toxicity and tumor responses were evaluated by standard criteria. Pharmacokinetics were done and level of target proteins was measured at various points during cycle one. RESULTS: Thirteen patients were enrolled in the study. MTD was defined as 220 mg/m2. Dose-limiting toxicities were as follows: dehydration, diarrhea, hyperglycemia, and liver toxicity. At the MTD, the mean clearance of 17-AAG was 18.7 L/h/m2. There was a significant decrease in integrin-linked kinase at 6 hours after infusion on day 1 but not at 25 hours in peripheral blood mononuclear cells. Treatment with 17-AAG on day 1 significantly increased pretreatment levels of heat shock protein (HSP) 70 on day 4, which is consistent with the induction of a stress response. In vitro induction of a stress response and up-regulation of HSP70 resulted in an increased resistance to HSP90-targeted therapy in A549 cells. CONCLUSIONS: The MTD of 17-AAG on a twice-weekly schedule was 220 mg/m2. Treatment at this dose level resulted in significant changes of target proteins and also resulted in a prolonged increase in HSP70. This raises the possibility that HSP70 induction as part of the stress response may contribute to resistance to 17-AAG.

Adult↗
PubMed2006

A prognostic model for advanced stage nonsmall cell lung cancer. Pooled analysis of North Central Cancer Treatment Group trials.

BACKGROUND: A pooled analysis was performed to examine the impact of pretreatment factors on overall survival (OS) and time to progression (TTP) in patients with advanced-stage nonsmall cell lung cancer (NSCLC) and to construct a prediction equation for OS using pretreatment factors. METHODS: A pooled data set of 1053 patients from 9 North Central Cancer Treatment Group trials was used. Age, gender, Eastern Cooperative Oncology Group performance status (PS), tumor stage (Stage IIIB vs. Stage IV), body mass index (BMI), creatinine level, hemoglobin (Hgb) level, white blood cell (WBC) count, and platelet count were evaluated for their prognostic significance in both univariate and multivariate analyses by using a Cox proportional-hazards model. RESULTS: Patients who had high WBC counts, low Hgb levels, PS >0, BMI < 18.5 kg/m2, and TNM Stage IV disease had significantly worse TTP and OS. Patients who had Stage IV disease with a high WBC count had a particularly poor prognosis. An equation to predict the OS of patients with Stage IV NSCLC based on pretreatment PS, BMI, Hgb level, and WBC count was constructed. CONCLUSIONS: In addition to the widely accepted prognostic factors of PS, BMI, and disease stage, both of the readily available laboratory parameters of Hgb level and WBC count were found to be significant prognostic factors for OS and TTP in patients with advanced-stage NSCLC. The authors' prediction equation can be used to evaluate the benefit of a treatment in Phase II trials by comparing the observed survival of a cohort with its expected survival by using the patients' own prognostic factors in place of comparisons with historic data that may have substantially different baseline patient characteristics.

Aged↗
PubMed2006

A phase I and pharmacologic study of sequences of the proteasome inhibitor, bortezomib (PS-341, Velcade), in combination with paclitaxel and carboplatin in patients with advanced malignancies.

PURPOSE: Bortezomib, a selective inhibitor of the 20S proteasome with activity in a variety of cancers, exhibits sequence-dependent synergistic cytotoxicity with taxanes and platinum agents. Two different treatment schedules of bortezomib in combination with paclitaxel and carboplatin were tested in this phase I study to evaluate the effects of scheduling on toxicities, pharmacodynamics and clinical activity. METHODS: Patients with advanced malignancies were alternately assigned to receive (schedule A) paclitaxel and carboplatin (IV d1) followed by bortezomib (IV d2, d5, d8) or (schedule B) bortezomib (IV d1, d4, d8) followed by paclitaxel and carboplatin (IV d2) on a 21-day cycle. RESULTS: Fifty-three patients (A 25, B 28) were treated with a median of 3 cycles (range 1-8) for schedule A and 3.5 cycles (range 1-10) for schedule B. Grade 3 or higher treatment related hematologic adverse events in all cycles of treatment included neutropenia (A 52%, B 50%), anemia (A 12%, B 7.1%) and thrombocytopenia (A 16%, B 17.9%). Non-hematologic treatment related adverse events were fairly mild (primarily grades 1 and 2). The maximum tolerated dose and the recommended doses for future phase II trials are bortezomib 1.2 mg/m2, paclitaxel 135 mg/m2 and carboplatin AUC = 6 for schedule A and bortezomib 1.2 mg/m2, paclitaxel 175 mg/m2 and carboplatin AUC = 6 for schedule B. Six (21.4%) partial responses (PR) were seen with schedule B. In contrast, only 1 (4%) PR was achieved with schedule A. Similar proteasome inhibition was achieved at MTD for both schedules. CONCLUSION: Administration of sequential bortezomib followed by chemotherapy (schedule B) was well tolerated and associated with an encouraging number of objective responses in this small group of patients. Further studies with this administration schedule are warranted.

Adult↗
PubMed2005

Randomized phase II trial of three schedules of pemetrexed and gemcitabine as front-line therapy for advanced non-small-cell lung cancer.

PURPOSE: A randomized three-arm phase II study was undertaken to evaluate the optimum administration schedule of pemetrexed and gemcitabine in chemotherapy-naïve patients with non-small-cell lung cancer. PATIENTS AND METHODS: Patients were randomly assigned to three schedules of pemetrexed 500 mg/m2 plus gemcitabine 1,250 mg/m2, separated by a 90-minute interval, on a 21-day cycle as follows: schedule A, pemetrexed followed by gemcitabine on day 1 and gemcitabine on day 8; schedule B, gemcitabine followed by pemetrexed on day 1 and gemcitabine on day 8; and schedule C, gemcitabine on day 1 and pemetrexed followed by gemcitabine on day 8. RESULTS: One hundred fifty-two eligible patients (schedule A, n = 59; schedule B, n = 31, and schedule C, n = 62) received a median of five (schedule A), two (schedule B), and four (schedule C) treatment cycles. Overall, 66% of patients experienced grade 3 or 4 neutropenia. Common grade 3 and 4 nonhematologic toxicities were dyspnea (11%), fatigue (16%), and transaminase elevation (9%). Schedule A seemed less toxic compared with schedule C (grade 3 or 4 events: 86% v 94%, respectively; P = .19; grade 4 events: 39% v 48%, respectively; P = .30). Schedule B was closed at interim analysis for inferior efficacy. Schedule A, with a confirmed response rate of 31% (95% CI, 20% to 45%), met the protocol-defined efficacy criteria, whereas schedule C, with a confirmed response rate of 16.1% (95% CI, 11% to 34%), did not. Median survival time and time to progression were 11.4 and 4.4 months, respectively, with no observable difference between the arms. CONCLUSION: Pemetrexed and gemcitabine administered as outlined for schedule A met the protocol-defined efficacy criteria, was less toxic compared with the other treatment schedules, and should be further evaluated.

Adult↗
PubMed2005

Statistical modelling of the differences between successive R-R intervals.

Understanding the behaviour of R-R interval data and its successive differences is critical to the dynamics of cardiac control. Several time domain measures that quantify R-R interval variability have important clinical significance in terms of risk stratification and evaluating the effectiveness of treatment procedures. The present approach at examining the distributions of successive beat-to-beat differences of R-R interval data from different populations and under different conditions (baseline and reaction times) provides a valuable insight into their previously unexplored distributional properties. In particular, our analysis reveals that the successive differences have non-normal statistical distributions (a contradiction to the commonly used assumption of normality), and the absolute successive R-R interval differences approximately follows a Weibull distribution. As an illustration of the utility of this approach, we explore the statistical properties of the time domain measure: root mean square successive difference, study the association between the Weibull scale parameter estimate and respiratory sinus arrhythmia, and propose improvements in artifact detection algorithms.

Adult↗
PubMed2005

CT screening for lung cancer: five-year prospective experience.

PURPOSE: To report results of a 5-year prospective low-dose helical chest computed tomographic (CT) study of a cohort at high risk for lung cancer. MATERIALS AND METHODS: After informed written consent was obtained, 1520 individuals were enrolled. Protocol was approved by institutional review board and National Cancer Institute and was compliant with Health Insurance Portability and Accountability Act, or HIPAA. Participants were aged 50 years and older and had smoked for more than 20 pack-years. Participants underwent five annual (one initial and four subsequent) CT examinations. A significant downward shift was evaluated in non-small cell lung cancers detected initially from advanced stage down to stage I by using a one-sided binomial test of proportions. Poisson regression and Fisher exact tests were used for comparisons with Mayo Lung Project. RESULTS: In 788 (52%) men and 732 (48%) women, 61% (927 of 1520) were current smokers, and 39% were former smokers. After five annual CT examinations, 3356 uncalcified lung nodules were identified in 1118 (74%) participants. Sixty-eight lung cancers were diagnosed (31 initial, 34 subsequent, three interval cancers) in 66 participants. Twenty-eight subsequent cases of non-small cell cancers were detected, of which 17 (61%; 95% confidence interval: 41%, 79%) were stage I tumors. Diameter of cancers detected subsequently was 5-50 mm (mean, 14.4 mm; median, 10.0 mm). Analysis for a more than 50% shift in proportion of stage I non-small cell cancer detection did not show statistical significance. Forty-eight participants died of various causes since enrollment. Lung cancer mortality rate for incidence portion of trial was 1.6 per 1000 person-years. There was no significant difference in lung cancer mortality rates of cancers detected in subsequent examinations between this trial and Mayo Lung Project after separation of participants into subsets (2.8 vs 2.0 per 1000 person-years, P = .43). CONCLUSION: CT allows detection of early-stage lung cancers. Benign nodule detection rate is high. Results suggest no stage shift.

Aged↗
PubMed2005

Clinical trial designs for prospective validation of biomarkers.

Traditionally, anatomic staging systems have been used to determine predictions of individual patient outcome and, to a lesser extent, guide the choice of treatment in patients with cancer. With new targeted therapies, the role of biomarkers is increasingly promising, suggesting an integrated approach using the genetic make-up of the tumor and the genotype of the patient for treatment selection and patient management. Specifically, biomarkers can aid in patient stratification (risk assessment), treatment response identification (surrogate markers), or in differential diagnosis (identifying individuals who are likely to respond to specific drugs). To be clinically useful, a marker must favorably affect clinical outcomes such as decreased toxicity, increased overall and/or disease-free survival, or improved quality of life. This paper focuses on possible clinical trial designs for assessing the utility of a predictive marker(s) for toxicity or clinical efficacy. We consider the scenario of single and multiple markers as well as present alternative solutions based on the prevalence of a marker. Our designs rest on the assumption that the methods for assessment of the biomarker are established and the initial results show promise with regard to the predictive ability of a marker. Additional research is clearly warranted to achieve the goal of 'predictive oncology'.

Biomarkers, Tumor↗
PubMed2003

Are our data symmetric?

Skewness indicates a lack of symmetry in a distribution. Knowing the symmetry of the underlying data is essential for parametric analysis, fitting distributions or doing transformations to the data. The coefficient of skewness is the commonly used measure to identify a lack of symmetry in the underlying data, although graphical procedures can also be effective. We discuss three different methods to assess skewness: traditional coefficient of skewness index, skewness index based on the L-moments discussed by Hosking and the asymptotic test of symmetry developed by Randles et al. With this work, we provide easy-to-implement S-PLUS functions as well as discuss the advantages and shortcomings of each technique.

Biometry↗