Effect of renal function (RF) on outcomes in the adjuvant treatment of older women with breast cancer (>65 years): CALGB/CTSU 49907 (CC) ancillary data study.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 9515-9515
Author(s):  
Stuart M. Lichtman ◽  
Constance Cirrincione ◽  
Arti Hurria ◽  
Aminah Jatoi ◽  
Maria Theodoulou ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Renal Function ◽  
Renal Insufficiency ◽  
Continuous Variable ◽  
Hematologic Toxicity ◽  
Logrank Test ◽  
Dose Modification ◽  
Increased Risk ◽  
Therapy Completion ◽  
The Relationship

9515 Background: CC 49907 showed superiority of standard therapy (cyclophosphamide/doxorubicin [AC] or cyclophosphamide/methotrexate/5-fluorouracil [CMF]) over capecitabine[C]. Dose adjustments made for renal insufficiency (RI) for methotrexate and C; ideal body weight used. Purpose was to analyze the relationship between RF at baseline and 5 endpoints: toxicity, dose modification, therapy completion, relapse-free survival [RFS] and overall survival [OS]. Methods: Pre-treatment RF was calculated (Cockcroft-Gault). Endpoints assessed by regimen. RF was tested as a dichotomous and continuous variable of stages 1,2 vs. 3,4 kidney disease (National Kidney Foundation). Logistic regression modeled the relationship between renal stage and the first three endpoints of toxicity, dose modification and therapy completion. Toxicity divided by hematologic or not. The relationship of RFS and OS with RF was assessed with the logrank test and as a continuous variable with Wald chi square. Results: 619 patients; incidence of stage 3/4 RI(<60 ml/min) was: CMF=72%; AC=64%; C=75%. With AC the incidence of toxicity differed by renal function. 31% of patients with poorer function >grade 3 non-hematologic toxicity vs. 14% with better function(p=0.011). There was a suggestion of effect of RF on OS and RFS for C-treated patients. RF was not associated with dose modification, premature therapy termination, RFS or OS for the CMF-treated patients. Conclusions: 1) AC: declining RF was associated with increased non-hematologic toxicity. 2)Patients with RI who received dose modifications were not at increased risk for complications in comparison to those who did not have renal insufficiency and received full dose. 3)Declining RF did not affect therapy completion. 4)C: suggestion that worse RF was related to poorer RFS or OS. 5)Exclusion of patients from clinical trials with RI based on concern of excessive hematologic toxicity may not be justified with appropriate modification. 6)Results should be considered in the design of clinical trials for older patients.

scholarly journals Effect of Pretreatment Renal Function on Treatment and Clinical Outcomes in the Adjuvant Treatment of Older Women With Breast Cancer: Alliance A171201, an Ancillary Study of CALGB/CTSU 49907

2016 ◽  
Vol 34 (7) ◽  
pp. 699-705 ◽  
Author(s):  
Stuart M. Lichtman ◽  
Constance T. Cirrincione ◽  
Arti Hurria ◽  
Aminah Jatoi ◽  
Maria Theodoulou ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Trials ◽  
Renal Function ◽  
Renal Insufficiency ◽  
Early Stage ◽  
Single Agent ◽  
Hematologic Toxicity ◽  
End Points ◽  
Increased Risk ◽  
The Relationship

Purpose CALGB 49907 showed the superiority of standard therapy, which included either cyclophosphamide/doxorubicin (AC) or cyclophosphamide/methotrexate/fluorouracil over single-agent capecitabine in the treatment of patients age ≥ 65 with early-stage breast cancer. The treatment allowed dosing adjustments of methotrexate and capecitabine for pretreatment renal function. The purpose of the current analysis was to assess the relationship between pretreatment renal function and five end points: toxicity, dose modification, therapy completion, relapse-free survival, and overall survival. Methods Pretreatment renal function was defined as creatinine clearance (CrCl) using the Cockcroft-Gault equation. Multivariable logistic and proportional hazards regression were used to model separately for each regimen the relationship between CrCl and the first three binary end points and the last two time-to-event end points, respectively, after adjusting for variables of prognostic importance. Results Six hundred nineteen assessable patients were analyzed. The incidence of stage III (moderate) or stage IV (severe) renal dysfunction was 72%, 64%, and 75% for treatment with cyclophosphamide/methotrexate/fluorouracil, AC, and capecitabine, respectively. There was no relationship for any regimen between pretreatment renal function and the five end points. For AC, as CrCl increased, the odds of nonhematologic toxicity decreased (P = .008), whereas for capecitabine, as CrCl increased, the odds of experiencing toxicity of any type also increased (P = .035). Patients with renal insufficiency who received dose modifications were not at increased risk for complications compared with those who did not have renal insufficiency and received a full dose. Conclusion Excluding from clinical trials patients with renal insufficiency but good performance status on the basis of concern of excessive hematologic toxicity or poor outcomes may not be justified with appropriate dosing modifications. Results should be considered in the design of clinical trials for older patients.

Renal Function Measures Improve on Lenalidomide and Dexamethasone and Compete with Patient Characteristics to Predict Lenalidomide Dose Density and Hematologic Toxicity: An E4A03 Analysis

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1882-1882 ◽  
Author(s):  
R. Donald Harvey ◽  
Susanna Joan Jacobus ◽  
S. Vincent Rajkumar ◽  
Philip R. Greipp ◽  
Sagar Lonial
Keyword(s):  
Renal Function ◽  
Product Information ◽  
Performance Status ◽  
Patient Characteristics ◽  
Hematologic Toxicity ◽  
Ecog Performance Status ◽  
Logistic Regression Models ◽  
Dose Modification ◽  
Increased Risk ◽  
The Impact

Abstract Abstract 1882 Introduction: Lenalidomide (L) with dexamethasone (D) has demonstrated activity in untreated symptomatic multiple myeloma (MM) (Rajkumar et al. Lancet Oncol 2010; 11: 29–37). Neutropenia may occur, requiring dose reductions, interruptions, or G-CSF support in up to 20% of patients. Renal clearance accounts for 67% of L elimination, and renal insufficiency is associated with an increased risk of cytopenias. Product information recommends the use of the Cockcroft-Gault (C-G) equation for creatinine clearance (CrCL) estimation for initial dosing; however, other estimates including the Modification of Diet in Renal Disease (MDRD) method may be more accurate. We evaluated the impact of renal function on L dosing, cytopenias, and response in patients on the Eastern Cooperative Group (ECOG) E4A03 study. Methods: All patients (n=445) enrolled on E4A03 were included in this analysis. Clinical data at baseline and after 4 cycles was reviewed. Renal function over the first 4 treatment cycles was estimated using both last reported on cycle 4 and last ever reported serum creatinine (SCr) as the former method resulted in a loss of 70 more patients. Patients were classified by CrCL (mL/min) stage: (1) ≥90 (2) 60–89 (3) 30–59 (4) 15–29 (5) <15. Patients were further categorized into CrCL groups collapsing stages 3–5 while maintaining division of normal status. Demographic and disease data of age, ECOG performance status (PS), sex, race, ISS stage, and complete blood counts were included. Percent of planned L dose and dose interruptions were calculated. Descriptive statistics were used to assess measures at each timepoint. Associations between baseline MDRD, C-G, SCr and patient characteristics were assessed by chi-square testing, and logistic regression models of L dose modification, cytopenias, and response status with renal function measures were created. Results: Mean SCr improved in 361/445 (81%) by 0.23 mg/dL following treatment initiation. Mean MDRD CrCL improved in 264/445 (59%) by 24.3 mL/min. Because only initial weight was captured, C-G estimates over time were not available. ISS stage II/III was associated with baseline elevated SCr (> 1.5 mg/dL) and low CrCL (p<0.001). Dose modification of L occurred in 44% of patients over 4 cycles (Table 1). In adjusted analyses, C-G predicted L dose modifications, p<0.001 [stage 3–5 vs 1 OR 2.09 (1.23-3.55)] along with ECOG PS. Similarly, in adjusted analyses, grade 2–5 cytopenias were better predicted by C-G stage, p<0.001 [stage 3–5 vs 1 OR 5.08 (2.18-11.84)], over MDRD stage, p=0.025 [stage 3–5 vs 1 OR 2.66 (1.07-6.61)]. No association between baseline or change in renal function and ≥ VGPR after 4 cycles was noted. Conclusion: Renal function improvement in patients receiving LD warrants regular CrCL monitoring and L dose increases in patients on reduced doses without cytopenias. Baseline MDRD is not superior to C-G for CrCL estimation for predicting L dosing and cytopenia development. Optimizing L exposure through pharmacokinetic modeling or other methods may further refine dosing. Disclosures: Lonial: Millenium: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Bristol Myers Squibb: Consultancy; Onyx: Consultancy; Merck: Consultancy.

scholarly journals Carotid Plaque Morphology is Similar in Patients with Reduced and Normal Renal Function

2020 ◽  
Vol 14 ◽  
pp. 117954682095179
Author(s):  
Caroline Heijl ◽  
Fredrik Kahn ◽  
Andreas Edsfeldt ◽  
Christoffer Tengryd ◽  
Jan Nilsson ◽  
...  
Keyword(s):  
Renal Function ◽  
Carotid Plaque ◽  
Continuous Variable ◽  
Intraplaque Hemorrhage ◽  
Plaque Morphology ◽  
Plaque Vulnerability ◽  
Vulnerable Atherosclerotic Plaque ◽  
Increased Risk ◽  
Plaque Phenotype ◽  
Tissue Calcium

Background: Chronic Kidney Disease (CKD) is associated with an increased risk for cardiovascular events such as stroke. However, it is still unclear if decreased kidney function is associated with a vulnerable atherosclerotic plaque phenotype. To explore if renal function was associated with carotid plaque vulnerability we analyzed carotid plaques obtained at surgery from the Carotid Plaque Imaging Project (CPIP). Methods: Patients were enrolled through the CPIP cohort. The indication for surgery was plaques with stenosis >70%, associated with ipsilateral symptoms or plaques with stenosis >80% not associated with symptoms. Transversal sections from the most stenotic plaque region were analyzed for connective tissue, calcium, lipids, macrophages, intraplaque hemorrhage, and smooth muscle cells. Homogenates were analyzed for collagen and elastin. Results: Carotid endarterectomy specimens from 379 patients were obtained. The median GFR was 73 ml/min/1.73 m2. Plaque characteristics showed no significant association with eGFR, neither when eGFR was divided in CKD groups nor when eGFR was handled as a continuous variable and adjusting for other known risk factors (ie, age, diabetes, hypertension, and smoking). Conclusions: The higher risk of cardiovascular disease such as stroke in CKD is not associated with increased plaque vulnerability and other factors have to be sought.

High-dose cytarabine dose modification reduces the incidence of neurotoxicity in patients with renal insufficiency.

1997 ◽  
Vol 15 (2) ◽  
pp. 833-839 ◽  
Author(s):  
G A Smith ◽  
L E Damon ◽  
H S Rugo ◽  
C A Ries ◽  
C A Linker
Keyword(s):  
Renal Function ◽  
Renal Insufficiency ◽  
Univariate Analysis ◽  
Myelogenous Leukemia ◽  
High Dose ◽  
Once Daily ◽  
Dose Modification ◽  
Daily Schedule ◽  
High Dose Cytarabine ◽  
The Impact

PURPOSE To determine the impact of high-dose cytarabine (ARA-C) (HDAC) dose modification, based on renal function, on the incidence of neurotoxicity (NT). PATIENTS AND METHODS We retrospectively analyzed the records of 256 patients treated with HDAC (> or = 2.0 g/m2 per dose) for acute myelogenous leukemia (AML) at the University of California, San Francisco (UCSF). From 1985 to 1994, a total of 358 cycles of HDAC were administered, using either a twice-daily schedule (n = 208) or a once-daily regimen (n = 48). In 1989, a dose-modification algorithm was initiated at our institution, which reduced ARA-C doses in the setting of renal insufficiency (RI). For patients with a serum creatinine (Cr) level of 1.5 to 1.9 mg/dL during treatment, or an increase in Cr during treatment (deltaCr) of 0.5 to 1.2 mg/dL, ARA-C was decreased to 1 g/m2 per dose. For patients with a Cr > or = 2.0 mg/dL or a deltaCr greater 1.2 mg/dL, the dose was reduced to 0.1 g/m2/d. RESULTS Overall, the incidence of NT was 16% (34 of 208) for patients treated with twice-daily HDAC and 0% (none of 48) for patients treated with daily HDAC (P = .003). NT occurred more often in patients treated on a twice-daily schedule with 3 g/m2 per dose compared with 2 g/m2 per dose (25% v 8%; P = .009). NT occurred in 55% of the twice-daily-treated patients with RI, compared with 7% of those with normal renal function (P = .00001). In patients with RI, NT occurred in none of 11 dose-modified cycles versus five of 11 (45%) total unmodified cycles (P = .01). None of 14 patients treated with once-daily HDAC given during RI developed NT, compared to 55% of patients (23 of 42) receiving twice-daily HDAC during RI (P = .009). By univariate analysis, NT was not associated with patient age or serum alkaline phosphatase, but NT was significantly increased in patients treated with twice-daily HDAC when the serum bilirubin was > or = 2.0 mg/dL compared with twice-daily HDAC given when the total bilirubin was less than 2.0 mg/dL (33% v 14%; P = .017). Multivariate analysis confirmed that RI was the most significant risk factor associated with the development of NT. CONCLUSION HDAC NT is strongly associated with RI. The risk of HDAC NT can be reduced by the following: (1) routinely reducing the ARA-C dose from 3 to 2 g/m2 per dose; (2) modifying the ARA-C dose based on daily Cr values; and (3) administering HDAC on a once-daily rather than twice-daily schedule.

Both low birthweight and high birthweight are associated with cognitive impairment in persons with schizophrenia and their first-degree relatives

2013 ◽  
Vol 43 (11) ◽  
pp. 2361-2367 ◽  
Author(s):  
M. Torniainen ◽  
A. Wegelius ◽  
A. Tuulio-Henriksson ◽  
J. Lönnqvist ◽  
J. Suvisaari
Keyword(s):  
Low Birthweight ◽  
Neuropsychological Test ◽  
Estimating Equation ◽  
Population Based ◽  
Continuous Variable ◽  
First Degree Relatives ◽  
Increased Risk ◽  
Axis I ◽  
Persons With Schizophrenia ◽  
The Relationship

BackgroundBoth low birthweight and high birthweight have been associated with an increased risk for schizophrenia and cognitive impairments in the general population. We assessed the association between birthweight and cognitive performance in persons with schizophrenia and their unaffected first-degree relatives.MethodWe investigated a population-based family sample comprising persons with schizophrenia (n = 142) and their unaffected first-degree relatives (n = 277). Both patients and relatives were interviewed with the Structured Clinical Interview for DSM-IV Axis I Disorders, Clinician Version (SCID-CV) and a comprehensive neuropsychological test battery was administered. Information on birthweight was obtained from obstetric records. We used generalized estimating equation (GEE) models to investigate the effect of birthweight, as a continuous variable, on cognitive functioning, adjusting for within-family correlation and relevant covariates.ResultsBoth low birthweight and high birthweight were associated with lower performance in visuospatial reasoning, processing speed, set-shifting and verbal and visual working memory among persons with schizophrenia and their unaffected first-degree relatives compared to individuals with birthweight in the intermediate range. The group × birthweight interactions were non-significant.ConclusionsBoth low birthweight and high birthweight are associated with deficits in cognition later in life. Schizophrenia does not seem to modify the relationship between birthweight and cognition in families with schizophrenia.

scholarly journals Use of Therapeutic Drug Monitoring to Characterize Cefepime-Induced Neurotoxicity

2020 ◽  
Author(s):  
Veena Venugopalan ◽  
Cara Nys ◽  
Natalie Hurst ◽  
Yiqing Chen ◽  
Maria Bruzzone ◽  
...  
Keyword(s):  
Renal Function ◽  
Therapeutic Drug Monitoring ◽  
Trough Concentration ◽  
Drug Monitoring ◽  
Hospitalized Patients ◽  
Therapeutic Drug ◽  
Eeg Abnormalities ◽  
Increased Risk ◽  
Trough Concentrations ◽  
The Relationship

AbstractBackgroundThe incidence of cefepime-induced neurotoxicity (CIN) in hospitalized patients is highly variable. Although greater cefepime exposures incite neurotoxicity, data evaluating trough thresholds associated with CIN remains limited. The objectives of this study were to evaluate the incidence of CIN, assess the relationship between cefepime trough concentrations and CIN, investigate clinical factors associated with CIN, and describe electroencephalogram (EEG) abnormalities in CIN.MethodsThis was a retrospective study of adult patients who had received ≥ 5 days of cefepime with ≥ 1 trough concentration > 25 mg/L. Potential CIN cases were identified utilizing neurological symptoms, neurologist assessments, EEG findings and improvement of neurotoxicity after cefepime discontinuation.ResultsOne-hundred and forty-two patients were included. The incidence of CIN was 13% (18/142). The mean cefepime trough concentration in CIN patients was significantly greater than the non-neurotoxicity group (74.2 mg/L ± 41.1 vs. 46.6 mg/L ± 23, p=0.015). Lower renal function (creatinine clearance < 30 ml/min), greater time to therapeutic drug monitoring (TDM) (≥72 hours), and each 1 mg/mL rise in cefepime trough were independently associated with increased risk of CIN. Moderate generalized slowing of the background rhythm was the most common EEG pattern associated with CIN.ConclusionCefepime should be used cautiously in hospitalized patients due to the risk of neurotoxicity. Patients with greater renal function and those who had early cefepime TDM (≤ 72 hours) had lower risk of CIN.

scholarly journals Epidemiology of Anemia Associated with Chronic Renal Insufficiency among Adults in the United States: Results from the Third National Health and Nutrition Examination Survey

2002 ◽  
Vol 13 (2) ◽  
pp. 504-510 ◽  
Author(s):  
Chi-yuan Hsu ◽  
Charles E. McCulloch ◽  
Gary C. Curhan
Keyword(s):  
Public Health ◽  
Renal Function ◽  
Renal Insufficiency ◽  
Chronic Renal Insufficiency ◽  
Transferrin Saturation ◽  
Hemoglobin Level ◽  
Nutrition Examination Survey ◽  
The Third ◽  
Health And Nutrition ◽  
The Relationship

ABSTRACT. Anemia associated with chronic renal insufficiency (CRI) may have substantial clinical and public health importance, but little is known about its epidemiology. This study aims to quantify the relationship between reduced renal function and hemoglobin level, to assess the iron status of subjects with CRI, and to estimate the burden of anemia associated with CRI. The Third National Health and Nutrition Examination Survey (NHANES III) (1988 to 1994) data on 15,971 adults aged >18 yr with measurements of serum creatinine, hemoglobin, and iron profile were analyzed. General linear models were used to determine the relationship between hemoglobin level and Cockcroft-Gault creatinine clearance (CrCl) and to estimate the likelihood of anemia at different levels of renal function in different demographic subgroups. Sample weights were used to produce weighted regression parameters and population estimates. A statistically significant decrease in hemoglobin was apparent among men starting at CrCl ≤70 ml/min and among women starting at CrCl ≤50 ml/min. At any given level of CrCl, men had a larger decrease in hemoglobin than women. For example, compared with subjects with CrCl >80 ml/min, the decrease in hemoglobin for subjects with CrCl 20 to 30 ml/min was 1.0 g/dl in women and 1.4 g/dl in men. A substantial number of subjects with CRI might not have sufficient iron stores to support erythropoiesis as judged by the NKF-K/DOQI transferrin saturation or serum ferritin targets. Among those with CrCl 20 to 30 ml/min, 46% of women and 19% of men had transferrin saturation <20%, and 47% of women and 44% of men had serum ferritin <100 ng/ml. Results estimate that 13.5 million US adults had CrCl ≤50 ml/min. The overall burden of CRI associated anemia, defined as hemoglobin <11 g/dl, was 800,000 adults. The public health burden of anemia associated with CRI may be substantial, given the large number of people with CRI; and that even a modest reduction in renal function is associated with decreased hemoglobin level.

Renal function of MDR-TB patients treated with kanamycin regimens or concomitantly with antiretroviral agents

2017 ◽  
Vol 21 (12) ◽  
pp. 1245-1250 ◽  
Author(s):  
E. L. Sagwa ◽  
N. Ruswa ◽  
F. Mavhunga ◽  
T. Rennie ◽  
A. Mengistu ◽  
...  
Keyword(s):  
Renal Function ◽  
Renal Insufficiency ◽  
Proportional Hazards ◽  
Multidrug Resistant ◽  
Similar Rate ◽  
Cox Proportional Hazards ◽  
Resistant Tuberculosis ◽  
Kaplan Meier ◽  
Increased Risk ◽  
Mdr Tb

SETTING: To compare renal insufficiency among multidrug-resistant tuberculosis (MDR-TB) patients treated with kanamycin (KM) based regimens and those treated concomitantly with tenofovir disoproxil fumarate (TDF) or other antiretroviral therapy (ART) regimens in Namibia.DESIGN: Retrospective review of the treatment records and laboratory tests of patients initiated on MDR-TB treatment (January–December 2014). The glomerular filtration rates (eGFR) estimated pre- and post-treatment were compared using the analysis of variance test. Renal insufficiency was defined as an eGFR of <60 ml/min/1.73 m2. Use of KM or TDF and association with renal insufficiency was assessed using Kaplan-Meier plots and Cox proportional hazards analysis.RESULTS: The baseline mean eGFR for the three groups was similar (P = 0.24): 139.3 ± 25.6 ml/min for the KM group (n = 68), 131.1 ± 25.7 ml/min for the KM+TDF group (n = 44) and 134.2±34.4 ml/min for the KM+Other group (n = 23). After 8 months, the values had declined significantly to respectively 104.8 ± 37.5 ml/min (P < 0.001), 101.5 ± 38.3 ml/min (P < 0.001) and 111.5 ± 41.7 ml/min (P = 0.01). Co-treatment with KM+ART was associated with an increased risk of renal insufficiency (hazard ratio [HR] 1.8, 95%CI 0.7–4.1, P = 0.20 for KM+TDF, and HR 3.5, 95%CI 1.4–8.2, P = 0.005 for KM+Other ART).CONCLUSION: Renal function declined at a similar rate in MDR-TB patients treated with KM-based regimens compared with patients treated concomitantly with TDF-based or other ART. The risk of renal insufficiency was greater for patients on ART.

scholarly journals Both Low and High PAPP-A Concentrations in the First Trimester of Pregnancy Are Associated with Increased Risk of Delivery before 32 Weeks in Twin Gestation

2020 ◽  
Vol 9 (7) ◽  
pp. 2099
Author(s):  
Aleksandra Saletra-Bielińska ◽  
Katarzyna Kosińska-Kaczyńska ◽  
Iwona Szymusik ◽  
Bartosz Kaczyński ◽  
Robert Brawura-Biskupski-Samaha ◽  
...  
Keyword(s):  
High Risk ◽  
Pregnancy Complications ◽  
Perinatal Outcome ◽  
First Trimester ◽  
Continuous Variable ◽  
Increased Risk ◽  
First Trimester Of Pregnancy ◽  
High Concentrations ◽  
The Relationship ◽  
Twin Pregnancies

In twin gestation, the relationship between pregnancy associated plasma protein (PAPP-A) and perinatal outcome is unclear. The aim of the study was to determine if low and high concentrations of PAPP-A in the first trimester are related to perinatal outcome in twins. A retrospective study was conducted. Medical data of women in twin pregnancies who delivered between 2013 and 2018 were analyzed. PAPP-A concentrations were measured between 10 + 0 and 13 + 6 weeks. The associations between low (<10th percentile) and high (>90th percentile) values of PAPP-A and pregnancy complications were analyzed. A total of 304 patients were included. PAPP-A <10th percentile was associated with a high risk of preterm delivery (OR 6.14; 95% CI 2.1–18), delivery <34 weeks (OR 2.39; 95% CI 1.1–5.1) or <32 weeks (OR3.06; 95% CI 1.4–6.8). Significant relations between PAPP-A >90th percentile and delivery <34 weeks (OR4.09; 95% CI 1.8–9.1) or <32 weeks (OR 2.83; 95% CI 1.2–6.6) were found. PAPP-A >90th percentile was related to high risk of intrauterine fetal demise (OR 10; 95% CI 2.4–42.5). Both low and high PAPP-A concentrations seem to be related to pregnancy outcome. Further research is needed to investigate evaluation of risk of pregnancy complications according to PAPP-A concentrations as a continuous variable.

Cabozantinib (C) exposure-response (ER) modeling of safety endpoints in patients (pts) with renal cell carcinoma (RCC) in the phase III METEOR study.

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 447-447 ◽  
Author(s):  
Steven Lacy ◽  
Matthew M Hutmacher ◽  
Bei Yang ◽  
Robert J. Motzer ◽  
Bernard J. Escudier ◽  
...  
Keyword(s):  
Dose Reduction ◽  
Objective Response ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Dose Modification ◽  
Steady Stage ◽  
Hazard Ratios ◽  
Increased Risk ◽  
Grade 3 ◽  
The Relationship

447 Background: ER models were previously developed to characterize the relationship between C exposure and efficacy endpoints in RCC pts in the phase III METEOR study (J Clin Oncol 34, 2016 [suppl; abstr 2565]). Higher C exposure correlated with decreased tumor size and improved progression-free survival and objective response rate. Model-based predictions showed that C would be effective at the 60 mg starting dose evaluated in METEOR as well as dose levels of 40 and 20 mg resulting from dose reduction. In the current study, ER models were developed to characterize the relationship between C exposure and safety endpoints in RCC pts. Methods: The ER analysis included 318 RCC pts who had received at least one C dose and had at least one measurable C concentration. Time-to-event Cox proportional hazard ER models were developed to characterize the relationship between various individual predicted C exposure measures and the likelihood of dose modification and 6 specific adverse events (AEs): fatigue/asthenia, palmar-plantar erythrodysesthesia (PPE), nausea/vomiting, diarrhea, hypertension, and stomatitis. Results: A statistically significant relationship was identified between individual predicted C clearance (CL/F) and the rate of dose modification (p <0.0001), with the risk of dose modification decreasing with increasing CL/F. An increase in average C concentration was associated with increased risk of fatigue/asthenia (Grade ≥3), PPE (Grade ≥1), hypertension (systolic blood pressure [BP] >160 mmHg or diastolic BP >100 mmHg), and diarrhea (Grade ≥3). The predicted hazard ratios for these AEs were 2.01, 2.21, 1.85, and 1.78, respectively, based on the predicted steady-stage average C concentration for a 60 mg dose relative to a 20 mg dose. Statistically significant ER relationships were not identified for nausea/vomiting (Grade ≥3) or stomatitis (Grade ≥3). Conclusions: Based on the ER analysis, higher C exposures resulting from lower C CL/F are predicted to increase the dose modification rate. Reduced C exposures resulting from dose reduction are predicted to decrease the risk of fatigue/asthenia, PPE, hypertension, and diarrhea while maintaining clinical benefit. Clinical trial information: NCT01865747.

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