Validating the use of brain volume cutoffs to identify clinically relevant atrophy in RRMS

2017 ◽  
Vol 25 (2) ◽  
pp. 217-223 ◽  
Author(s):  
Francesca Bovis ◽  
Nicola De Stefano ◽  
Joshua R Steinerman ◽  
Volker Knappertz ◽  
Maria Pia Sormani
Keyword(s):  
Brain Volume ◽  
Phase Iii ◽  
Prognostic Impact ◽  
Two Phase ◽  
Data Set ◽  
Phase Iii Clinical Trials ◽  
Hazard Ratios ◽  
Baseline Variable ◽  
The Difference ◽  
Relapsing Remitting Multiple Sclerosis

Background: Baseline brain volume (BV) is predictive at a group level but is difficult to interpret at the single patient level. Objective: To validate BV cutoffs able to identify clinically relevant atrophy in relapsing–remitting multiple sclerosis (RRMS) patients. Methods: The expected normalized brain volume (NBV) for each patient was calculated using RRMS patients from two phase III clinical trials, applying a linear formula developed on the baseline variable of an independent data set. The difference between these expected NBV values and those actually observed was calculated and used to categorize the patients in the low-NBV, medium-NBV, and high-NBV groups. Results: The 2-year probability of 3-month confirmed disability worsening was significantly associated with the NBV categorization ( p = 0.006), after adjusting for treatment effect. Taking the high-NBV group as a reference, the hazard ratios for the medium-NBV and low-NBV groups were 1.22 (95% confidence interval (CI): 0.85–1.76, p = 0.27) and 1.69 (95% CI: 1.11–2.57, p = 0.01), respectively. Conclusion: This study validates the use of BV cutoffs to identify clinically relevant atrophy in RRMS study by showing that the three groups classified according to the baseline NBV adjusted for the other prognostic variables have a significant prognostic impact on the risk of disability progression.

SNP Associations with Event Free Survival in Myeloma from Two Phase III Clinical Trials Using the Bank On A Cure Chip.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 131-131
Author(s):  
Brian G. Van Ness ◽  
John C. Crowley ◽  
Christine Ramos ◽  
Suzanne M. Grindle ◽  
Antje Hoering ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Genetic Variations ◽  
Gene Set Enrichment Analysis ◽  
Phase Iii ◽  
Survival Outcomes ◽  
Cellular Functions ◽  
Two Phase ◽  
Data Set ◽  
Phase Iii Clinical Trials ◽  
Statistical Approaches

Abstract While there are certain common clinical features in myeloma, the disease shows significant heterogeneity with regard to disease progression, and responses to therapy, affecting both survival and toxicities. Heritable variations in a wide variety of genes and pathways affecting cellular functions and drug responses likely impact patient outcomes. In the Bank On A Cure (BOAC) program we have developed a custom chip that assesses 3,404 SNPs representing variations in cellular functions and pathways that may be involved in myeloma progression and response. The chip has gone through rigorous quality controls checks for high call rates, accuracy, and reproducibility that will be presented. Using the BOAC chip, we have conducted studies to look for SNPs that may identify biologic variations that are associated with good or poor response across a variety of treatments. In this study we looked for SNPs that may distinguish short term and long term survivors in two phase III clinical trials: ECOG E9486 and intergroup trial S9321. E9487 patients were treated with VBMCP followed by randomization to no further treatment, IFN-alpha, or cylcophosphamide; and, although there was variation in survival, no significant differences in survival were noted among the 3 arms of the trial. Patients included in this SNP study from S9321 received VAD induction followed by randomization to VBMCP or high dose melphalan + TBI. SNP profiles were obtained for patients with less than 1 year EFS (n=20 in E9487; n=50 in S9321) and patients showing greater than 3 years EFS (n=32 in E9486; n=41 in S9321). Statistical approaches were performed to identify single and groups of SNPs that best discriminated the survival groups. Previous studies have suggested genetic variations in drug metabolism genes, p-glycoprotein transport, and DNA repair genes may influence survival outcomes. Our results show significant survival associations of genetic variations in genes within these functional categories (eg. GST, XRCC, ABCB, and CYP genes). Although genetic variations were found that were uniquely associated with each clinical trial, several of these genetic variations show survival associations that increase in significance when the two trials were examined as a conglomerate data set. Grouping genetic variations through common pathway approaches using gene set enrichment analysis, as well as clustering or partitioning algorithms, further improve the value of the SNPs as potential prognostic markers of survival outcomes. These results and statistical approaches will be presented, and represent steps toward identifying patient variations in biologic mechanisms important in predicting therapeutic outcomes.

scholarly journals Defining brain volume cutoffs to identify clinically relevant atrophy in RRMS

2016 ◽  
Vol 23 (5) ◽  
pp. 656-664 ◽  
Author(s):  
Maria Pia Sormani ◽  
Ludwig Kappos ◽  
Ernst-Wilhelm Radue ◽  
Jeffrey Cohen ◽  
Frederik Barkhof ◽  
...  
Keyword(s):  
Treatment Effect ◽  
Brain Volume ◽  
Risk Groups ◽  
Multiple Regression Model ◽  
Lesion Volume ◽  
Hazard Ratios ◽  
Disability Status ◽  
Relapsing Remitting ◽  
The Difference ◽  
Relapsing Remitting Multiple Sclerosis

Objective: To define values of normalized brain volume (NBV) that can be categorized as low, medium, or high, according to baseline characteristics of relapsing-remitting multiple sclerosis (RRMS) patients. Methods: Expected NBV (eNBV) was calculated for each patient based on age, disease duration, sex, baseline Expanded Disability Status Scale (EDSS), and T2-lesion volume, entering these variables into a multiple regression model run on 2342 RRMS patients (pooled FREEDOMS/FREEDOMS-II population). According to the difference between their observed NBV and their eNBV, patients were classified as having low NBV, medium NBV, or high NBV. We evaluated whether these NBV categories were clinically meaningful by assessing correlation with disability worsening. Results: The distribution of differences between observed NBV and eNBV was used to categorize patients as having low NBV, medium NBV or high NBV. Taking the high-NBV group as reference, the hazard ratios (HRs) for 2-year disability worsening, adjusted for treatment effect, were 1.23 (95% confidence interval (CI): 0.92–1.63, p = 0.16) for the medium NBV and 1.75 (95% CI: 1.26–2.44, p = 0.001) for the low NBV. The predictive value of NBV groups was preserved over 4 years. Treatment effect appeared more evident in low-NBV patients (HR = 0.58) than in medium-NBV (HR = 0.72) and in high-NBV (HR = 0.80) patients; however, the difference was not significant ( p = 0.57). Conclusion: RRMS patients can be categorized into disability risk groups based on individual eNBV values according to baseline demographics and clinical characteristics.

scholarly journals Characterisation of MS phenotypes across the age span using a novel data set integrating 34 clinical trials (NO.MS cohort): Age is a key contributor to presentation

2021 ◽  
pp. 135245852098863
Author(s):  
Frank Dahlke ◽  
Douglas L Arnold ◽  
Piet Aarden ◽  
Habib Ganjgahi ◽  
Dieter A Häring ◽  
...  
Keyword(s):  
Disease Activity ◽  
Brain Volume ◽  
Young Patients ◽  
Clinical Trial Data ◽  
Study Data ◽  
Phase Iii ◽  
Brain Images ◽  
Data Set ◽  
Brain Volume Loss ◽  
Phase Iii Study

Background: The Oxford Big Data Institute, multiple sclerosis (MS) physicians and Novartis aim to address unresolved questions in MS with a novel comprehensive clinical trial data set. Objective: The objective of this study is to describe the Novartis–Oxford MS (NO.MS) data set and to explore the relationships between age, disease activity and disease worsening across MS phenotypes. Methods: We report key characteristics of NO.MS. We modelled MS lesion formation, relapse frequency, brain volume change and disability worsening cross-sectionally, as a function of patients’ baseline age, using phase III study data (≈8000 patients). Results: NO.MS contains data of ≈35,000 patients (>200,000 brain images from ≈10,000 patients), with >10 years follow-up. (1) Focal disease activity is highest in paediatric patients and decreases with age, (2) brain volume loss is similar across age and phenotypes and (3) the youngest patients have the lowest likelihood (<25%) of disability worsening over 2 years while risk is higher (25%–75%) in older, disabled or progressive MS patients. Young patients benefit most from treatment. Conclusion: NO.MS will illuminate questions related to MS characterisation, progression and prognosis. Age modulates relapse frequency and, thus, the phenotypic presentation of MS. Disease worsening across all phenotypes is mediated by age and appears to some extent be independent from new focal inflammatory activity.

scholarly journals Impact of elagolix on work loss due to endometriosis-associated pain: estimates based on the results of two phase III clinical trials

2019 ◽  
Vol 112 (3) ◽  
pp. 545-551 ◽  
Author(s):  
Robin M. Pokrzywinski ◽  
Ahmed M. Soliman ◽  
Jun Chen ◽  
Michael Snabes ◽  
Michael P. Diamond ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Phase Iii ◽  
Work Loss ◽  
Two Phase ◽  
Phase Iii Clinical Trials

Efficacy of Daratumumab Based Regimens Compared to Standard of Care for Transplant Ineligible Newly Diagnosed Multiple Myeloma in Phase III Clinical Trials: A Meta-Analysis

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 32-33
Author(s):  
Zahoor Ahmed ◽  
Karun Neupane ◽  
Rabia Ashraf ◽  
Amna Khan ◽  
Moazzam Shahzad ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
Standard Care ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Control Group ◽  
Two Phase ◽  
Phase Iii Trial ◽  
Free Survival ◽  
Phase Iii Clinical Trials

Introduction: Daratumumab (Dara) is a human anti-CD38 monoclonal antibody approved for multiple myeloma (MM) treatment. Dara has a promising efficacy and a favorable safety profile in newly diagnosed MM (NDMM) patients. This study is focused on the efficacy and safety of Dara when added to the standard care regimen in transplant ineligible NDMM in phase III clinical trials. Methods: We performed a comprehensive database search on four major databases (PubMed, Embase, Cochrane, and Clinicaltrials.gov). Our search strategy included MeSH (Medical Subject Headings) terms and key words for multiple myeloma and Dara including trade names and generic names from date of inception to May 2020. Initial search revealed 587 articles. After excluding review articles, duplicates, and non-relevant articles, two phase III clinical trials were included which reported overall response rate (ORR), and progression free survival (PFS) of transplant ineligible NDMM patients with Dara addition to standard care regimen. Odds ratios (OR) of ORR were computed and hazard ratios (HR) of PFS (along with 95% confidence intervals; CI) were extracted to compute a pooled HR using a fixed effect model in RevMan v.5.4. Results: A total of 1453 transplant ineligible NDMM patients were enrolled and evaluated in two phase III randomized clinical trials. Seven hundred and eighteen patients were in Dara group and 735 patients were in control group. Bahlis et al. (2019) studied Dara + lenolidamide (R) and dexamethasone (d) vs Rd in NDMM pts (n=737) in MAIA phase III trial. Similarly, Mateos et al. (2018) reported the role of Dara + bortezomib (V) + melphalan (M), and prednisone (P) vs VMP in NDMM pts (n=706) in a phase III trial (Alcyone). A pooled analysis of these phase III trials showed ORR (OR: 3.26, 95% CI 2.36-4.49; p &lt; 0.00001, I2 = 0%), and progression free survival (PFS) (HR: 0.53, 95% CI 0.43-0.65; p &lt; 0.00001, I2 = 0%). Achievement of minimal residual disease (MRD) negative status was significant in Dara based regimen as compared to control group (OR: 4.49, 95% CI 3.31-6.37; p &lt; 0.00001, I2 = 0%). Dara addition to standard care regimen (Rd and VMP) decreased the risk of progression/death to 42% (HR: 0.58, 95% CI 0.48-0.70; p &lt; 0.00001, I2 = 0%). The addition of Dara increased the risk of neutropenia (OR: 1.41, 95% CI 1.07-1.85; p &lt; 0.02, I2 = 44%), and pneumonia (OR: 2.25, 95% CI 1.54-3.29; p &lt; 0.0001, I2 = 37%) vs control group. However, decreased risk of anemia (OR: 0.64, 95% CI 0.49-0.85: p &lt; 0.002, I2=30%) was observed in Dara group vs control group (Figure 1). Conclusion: Addition of Dara to the standard care regimen for transplant ineligible NDMM achieved the surrogate end points with improved efficacy and MRD negative status with manageable toxicity. However, data from more randomized controlled trials is needed. Table Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.

Impact of Different Chemotherapy Regimen in Comorbid Patients with Advanced Chronic Lymphocytic Leukemia: Metaanalysis of Two Phase-III-Trials of the German CLL Study Group.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2840-2840 ◽  
Author(s):  
Paula Cramer ◽  
Valentin Goede ◽  
Petra Jenke ◽  
Raymonde Busch ◽  
Michael Hallek ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Chemotherapy Regimen ◽  
Lymphocytic Leukemia ◽  
Phase Iii ◽  
Prognostic Impact ◽  
Concomitant Disease ◽  
Two Phase ◽  
Phase Iii Trials ◽  
The Impact ◽  
Dose Reductions

Abstract Introduction: Since chronic lymphocytic leukemia (CLL) is a disease of elderly patients (pts) comorbidity is a frequent feature which has already been shown to be associated with survival-shortening in lymphoma patients. It has been hypothesized that intensity of chemotherapy may interfere with treatment outcome, but the precise mechanisms underlying the impact of comorbidity are still not understood. Consequently, comorbitity currently keeps away oncologists from administering intense combined (immuno−)chemotherapy to pts with CLL and concomitant diseases. Patients & methods: 554 pts treated in two different phase-III-trials of the GCLLSG were eligible for this analysis: 362 pts (65%) younger than 65 years were treated on the CLL4-protocol with Fludarabine (F) or Fludarabine-Cyclophosphamide (FC) and 192 pts (35%) aged 65 years and older on the CLL5-protocol with F or Chlorambucile (Clb). The mean age for all pts was 61 years; 68% of the pts were male. Results: Comorbidity was present in 53% of the pts, 25% had at least two comorbidities. The most common comorbidities were: hypertension (19%), lipometabolic disorders (16%), diabetes mellitus (10%) and coronary heart disease (7%). Progression free survival (PFS) and overall survival (OS) were significantly shorter in comorbid pts (median OS: 43,5 vs. 51,6 months, p=0,01; median PFS: 20,3 vs. 23,5 months, p=0,03). Survival was also impaired if pts had a higher number of comorbidities (PFS & OS: p=0,0001) or more severe concomitant diseases (PFS: p=0,007, OS: p=0,0000). Whereas this impact of comorbidity on OS was not significant in the FC- and Clb-arm, comorbid pts treated with F had a significantly shorter survival (median OS: 38,29 vs. 51,58 months, p=0,0452). Notably only the younger F-treated comorbid pts were affected by this disadvantage (CLL4: p=0,0221). Although myelotoxicity, infections and all grade III–IV adverse effects were not influenced by comorbidity, pts with concomitant disease had a higher rate of treatment terminations (38% vs. 25%, p=0,002). The higher percentage of dose reductions and treatment terminations for comorbid pts were only significant in the subgroup of F-treated pts (dose reduction: 31% vs. 19,1%, p=0,029; treatment termination in the younger CLL4-pts: 28,2% vs. 18,0%, p=0,023). Administration of more intense chemotherapy-regimen improved the survival of pts with concomitant disease (median OS: FC: not reached, F: 38,29 and Clb: 33,72 months, p=0,0248; median PFS: FC: not reached, F: 18,8 and Clb: 14,1 months, p=0,0000). A multivariate analysis on the prognostic impact of comorbidity and different chemotherapy regimen will be presented. Conclusions: Due to the here presented results the wide impact of comorbidity in CLL pts is apparent. It should be considered when it comes to treatment decisions eventhough this population was selected due to the strict criteria of the clinical trial. The mechanism of survival shortening in comorbid pts with CLL is not yet understood, but seems to be related with dose reductions and treatment terminations. Additional harm to these pts by an insufficient treatment and a poor control of the CLL ought to be avoided. As more intense chemotherapy-regimen, like FC are feasible for pts with comorbidity, more trials surveying these therapies in pts with more severe concomitant disease are needed.

Prognostic value of waterfall plots with the addition of nontarget lesion data.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 11082-11082
Author(s):  
William Leonard Mietlowski ◽  
Andrew Marc Stein ◽  
Weichao Bao ◽  
Roger J. Waltzman ◽  
Patricia Ann Wood
Keyword(s):  
Cell Cancer ◽  
Target Lesion ◽  
Tumor Burden ◽  
Percentage Change ◽  
Phase Iii ◽  
Two Phase ◽  
Data Set ◽  
Cancer Trial ◽  
Best Response ◽  
Anti Tumor Activity

11082 Background: In patients with solid tumors, the use of a waterfall plot displaying the best percentage change in sum of the longest diameters of target lesions per patient is a common way to depict anti-tumor activity for cytostatic agents (Booth 2008, Dhani 2009). This representation assumes that the best percentage change represents the maximum anti-tumor activity for each patient. Information about new lesions and/or changes in non-target lesions is not incorporated in the waterfall plot; yet these additional events were found to be significant prognostic factors for overall survival adjusting for change in the target lesions (Litiere 2012, Suzuki 2012). Methods: We analyzed two phase III lung cancer trials of 1st and 2nd line combination chemotherapy ± ASA404 (ATTRACT-1,n=1299, ATTRACT-2, n= 920). For patients whose best response in the target lesions was shrinkage, we calculated how often this best response was synchronously accompanied by non-target disease progression. Results: See Table. Conclusions: There can be substantial tumor shrinkage in target lesions synchronously with progressive disease outside the target lesions. Therefore, graphical displays of anti-tumor activity should consider incorporating new and non-target lesion information, as well as target lesion tumor burden. We propose an extended waterfall plot presenting a more complete assessment of anti-tumor activity by incorporating non-target lesion information. We illustrate its utility in an additional data set, the RECORD-1 phase III renal cell cancer trial. Clinical trial information: NCT00662597. [Table: see text]

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