Evaluating longitudinal toxicity of cetuximab in patients with metastatic colorectal cancer (mCRC): A pooled analysis from 1,302 patients in the ARCAD database.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3610-3610
Author(s):  
Guilherme Lopes ◽  
Jane Yeojeong So ◽  
Katrin Marie Sjoquist ◽  
Curtis L. Olswold ◽  
Eric Van Cutsem ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Adverse Events ◽  
Onset Time ◽  
Pooled Analysis ◽  
Lower Grade ◽  
Site Location ◽  
Increased Risk ◽  
Ecog Ps ◽  
Reporting Method ◽  
Entire Treatment

3610 Background: Chronic lower grade adverse events (AE) can negatively affect a patient’s quality of life but it is difficult to capture using a traditional toxicity reporting approach. A novel AE reporting method was recently developed to describe, summarize, and present longitudinal AE profiles(Lopes et al, 2021). We leveraged this method to describe and compare the AE profiles of doublet chemotherapy (DC) + Cetuximab and DC alone in mCRC patients. Methods: This AE reporting method utilizes two additional AE metrics to complement the maximum (max) toxicity grade usually reported in clinical trials. Onset time indicates the time period in which max grade for an AE occurred for the first time, defined here as “early” (i.e. within first 42 days) and “late” (i.e. after the 42nd day). AE Load (AEL) indicates the overall severity of an AE in the entire treatment. AEL varies from 0 to 1. Higher AEL indicates a worse overall severity of that AE over time. AEL is the key metric for describing chronic AE. We included patients receiving DC + cetuximab (n = 738) and DC alone (n = 564 [ref group]) from two randomized first-line trials in the ARCAD database. Diarrhea, rash, hand-foot syndrome (HFS), fatigue, anorexia, and mucositis were examined and adjusted for backbone (FOLFOX vs. FOLFIRI), ECOG PS, sex, site location, dose reduction, and treatment length. Results: For rash, DC + cetuximab had a higher risk of G3+ (21% vs. 0.5%; odds ratio {OR} [95% confidence interval {CI}] = 50 [16,157], p < 0.001), increased overall severity over the entire treatment (AEL = 0.257 vs. 0.069; Adjusted difference in means–Mdiff [95% CI] = 0.22 [0.21,0.23], p < 0.001), and increased risk of early onset (67% vs. 33%; OR [95% CI] = 4.3 [2.7,6.7], p < 0.001). DC + cetuximab also had higher AEL for rash across max grades (p < 0.001 within G1, G2, and G3+). For HFS, DC + cetuximab had a higher risk of G3+ (OR [95% CI] = 6.0 [2.5,14], p < 0.001), increased overall severity (AEL = 0.139 vs. 0.087; Mdiff [95% CI] = 0.03 [0.03,0.04], p < 0.001), and slightly earlier onset (12.4 vs. 13.9 weeks; Mdiff, weeks [95% CI] = -4.9 [-0.80,-9.0], p = 0.021). Within each max grade, DC + cetuximab did not have higher AEL of HFS. No associations were found for diarrhea, fatigue, anorexia, or mucositis. Conclusions: The addition of cetuximab is associated with higher grade, more persistent, and more immediate rash. The higher severity in HFS with the addition of cetuximab appears to be related to higher grade but not chronic HFS. This method may be useful to describe different strategies, e.g. intermittent cetuximab. It provided a comprehensive view of acute and chronic toxicity profiles supporting its potential interest as new metrics in clinical trials. Lopes GS, Tournigand C, Olswold CL, et al. Adverse event load, onset, and maximum grade: A novel method of reporting adverse events in cancer clinical trials. Clinical Trials. 2021;18(1):51-60

How to improve toxicity evaluation in clinical trials? Testing new metrics from irinotecan or oxaliplatin-based treatments in metastatic colorectal cancer (mCRC): A pooled analysis from 2,349 patients in ARCAD database.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 89-89 ◽  
Author(s):  
Christophe Tournigand ◽  
Guilherme Lopes ◽  
Curtis L. Olswold ◽  
Richard Adams ◽  
John Raymond Zalcberg ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Adverse Events ◽  
Logistic Model ◽  
Onset Time ◽  
Pooled Analysis ◽  
Toxicity Assessment ◽  
Lower Grade ◽  
Persistent Diarrhea ◽  
Toxicity Evaluation ◽  
Entire Treatment

89 Background: Monitoring of adverse events (AE) is crucial in clinical trials. Maximum grade per patient (pt) is commonly used but better metrics are needed to aid describing and comparing AE profiles. Methods: We developed and evaluated 2 longitudinal AE summary metrics. 1) Onset time of max grade refers to whether a pt has max grade within pre-specified timeframes for an AE, e.g. onset can be defined as “early” (max grade before the 6th cy) or “late” (≥ 6th cy). 2) Adverse effect load (AEL) is a longitudinal score of worst grade possible excluding death over the entire treatment for an AE. Higher AEL means worst overall experience of AE. We applied these metrics to real trial data. Pts were from 6 mCRC trials included in ARCAD database and received Irinotecan-based (n = 1,119) or Oxaliplatin-based (n = 1,230) treatments that did not include biologicals. AEs were diarrhea, nausea/vomiting, neutropenia/leukopenia, and neuropathy. We used linear model to AEL and logistic model to the other metrics, adjusting for age, sex, and number of metastases. Results: For nausea/vomiting, pts in Oxali-based chemo showed a higher AEL compared to patients in Iri-based (mean (M) [standard deviation (SD)] = 0.04 [0.06] vs. 0.02 [0.04]; p < 0.001) even though less pts had gr ≥ 3 (10.4% vs. 16.2%, resp.; p < 0.001), suggesting a lower-grade but persistent nausea/vomiting for Oxali-based. Among pts with diarrhea max gr 2, pts in Iri-based had higher AEL than with Oxali-based (M [SD] = 0.11 [0.11] vs. 0.08 [0.09]; p = 0.008), indicating more persistent diarrhea for Iri-based trts even among pts with same max grade. For neutropenia/leukopenia, pts in Oxali-based trts experienced higher AEL (M [SD] = 0.09 [0.13] vs. 0.05 [0.11], p < 0.001), and more pts in Oxali-based trts had gr ≥ 3 (70.1% vs. 64.4%; p = 0.002), suggesting that pts in Oxali-based trts experienced worst overall and max grade neutropenia/leukopenia compared to pts in Iri-based. Conclusions: To improve toxicity assessment in clinical trials, AEL and onset time of max grade are new measures that describe the evolution of adverse events over time. Further validation is warranted.

scholarly journals 32 Quantifying the Prevalence of Frailty in Drug Trials and the Relationship with Serious Adverse Events

2021 ◽  
Vol 50 (Supplement_1) ◽  
pp. i7-i11
Author(s):  
P Hanlon ◽  
E Butterly ◽  
J Lewsey ◽  
S Siebert ◽  
F S Mair ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Adverse Events ◽  
Disease Severity ◽  
Negative Binomial ◽  
Frailty Index ◽  
Chronic Obstructive ◽  
Drug Trials ◽  
Phase 3 ◽  
Serious Adverse Events ◽  
Increased Risk

Abstract Introduction Frailty is common in clinical practice, but trials rarely report on participant frailty. Consequently, clinicians and guideline-developers assume frailty is largely absent from trials and have questioned the relevance of trial findings to frail people. Therefore, we examined frailty in phase 3/4 industry-sponsored clinical trials of pharmacological interventions for three exemplar conditions: type 2 diabetes mellitus (T2DM), rheumatoid arthritis (RA), and chronic obstructive pulmonary disease (COPD). Methods We constructed a 40-item frailty index (FI) in 19 clinical trials (7 T2DM, 8 RA, 4 COPD, mean age 42–65 years) using individual-level participant data. Participants with a FI &gt;0.24 were considered “frail”. Baseline disease severity was assessed using HbA1c for T2DM, Disease Activity Score-28 (DAS28) for RA, and % predicted FEV1 for COPD. Using generalised gamma regression, we modelled FI on age, sex and disease severity. In negative binomial regression we modelled serious adverse event rates on FI, and combined results for each index condition in a random-effects meta-analysis. Results All trials included frail participants: prevalence 7–21% in T2DM trials, 33–73% in RA trials, and 15–22% in COPD trials. Increased disease severity and female sex were associated with higher FI in all trials. Frailty was associated with age in T2DM and RA trials, but not in COPD. Across all trials, and after adjusting for age, sex, and disease severity, higher FI predicted increased risk of serious adverse events; the pooled incidence rate ratios (per 0.1-point increase in FI scale) were 1.46 (95% CI 1.21–1.75), 1.45 (1.13–1.87) and 1.99 (1.43–2.76) for T2DM, RA and COPD, respectively. Conclusion Frailty is identifiable and prevalent among middle aged and older participants in phase 3/4 drug trials and has clinically important safety implications. Trial data may be harnessed to better understand chronic disease management in people living with frailty.

Update on Clinical Trials of Tadalafil Demonstrates No Increased Risk of Cardiovascular Adverse Events

2004 ◽  
Vol 1 (2) ◽  
pp. 161-167 ◽  
Author(s):  
Graham Jackson ◽  
Robert A. Kloner ◽  
Timothy M. Costigan ◽  
Margaret R. Warner ◽  
Jeffrey T. Emmick
Keyword(s):  
Clinical Trials ◽  
Adverse Events ◽  
Increased Risk

scholarly journals A pooled analysis of adverse events in 393 adults with Gaucher disease type 1 from four clinical trials of oral eliglustat: Evaluation of frequency, timing, and duration

2018 ◽  
Vol 68 ◽  
pp. 185-191 ◽  
Author(s):  
M. Judith Peterschmitt ◽  
Gerald F. Cox ◽  
Jennifer Ibrahim ◽  
James MacDougall ◽  
Lisa H. Underhill ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Adverse Events ◽  
Gaucher Disease ◽  
Pooled Analysis ◽  
Disease Type ◽  
Gaucher Disease Type 1

scholarly journals Safety and reactogenicity of the adjuvanted recombinant zoster vaccine: experience from clinical trials and post-marketing surveillance

2021 ◽  
Vol 9 ◽  
pp. 251513552110574
Author(s):  
Joseph Fiore ◽  
Maribel Miranda Co-van der Mee ◽  
Andrés Maldonado ◽  
Lisa Glasser ◽  
Phil Watson
Keyword(s):  
Clinical Trials ◽  
Adverse Events ◽  
Pooled Analysis ◽  
Cell Transplant ◽  
Zoster Vaccine ◽  
Phase 3 ◽  
Pivotal Phase ◽  
Post Marketing Surveillance ◽  
Post Marketing ◽  
Recombinant Zoster Vaccine

An adjuvanted recombinant zoster vaccine (RZV) is licensed for the prevention of herpes zoster. This paper reviews its safety and reactogenicity. A pooled analysis of two pivotal randomized Phase-3 trials (NCT01165177, NCT01165229) in adults ⩾50 years found that more solicited adverse events (AEs) were reported with RZV than placebo. Injection site pain was the most common solicited AE (RZV: 78.0% participants; placebo: 10.9%). Grade-3 pain occurred in 6.4% of RZV and 0.3% of placebo recipients. Myalgia, fatigue, and headache were the most commonly reported general solicited AEs (RZV: 44.7%, 44.5%, and 37.7%, respectively; placebo: 11.7%, 16.5%, and 15.5%, respectively). Most symptoms were mild to moderate in intensity with a median duration of 2–3 days. The intensity of reactogenicity symptoms did not differ substantially after the first and second vaccine doses. The pooled analysis of the pivotal Phase-3 trials did not identify any clinically relevant differences in the overall incidence of serious adverse events (SAEs), fatal AEs or potential immune-mediated diseases (pIMDs) between RZV and placebo. Reactogenicity in five studies of immunocompromised patients ⩾18 years (autologous stem cell transplant, human immunodeficiency virus, solid tumors, hematological malignancies, and renal transplant; NCT01610414, NCT01165203, NCT01798056, NCT01767467, and NCT02058589) was consistent with that observed in the pivotal Phase-3 trials. There were no clinically relevant differences between RZV and placebo in the immunocompromised populations with regard to overall incidence of SAEs, fatal AEs, pIMDs, or AEs related to patients’ underlying condition. Post-marketing surveillance found that the most commonly reported AEs were consistent with the reactogenicity profile of the vaccine in clinical trials. Overall, the clinical safety data for RZV are reassuring. [Formula: see text]

scholarly journals Pomalidomide Based Regimens for Treatment of Relapsed Multiple Myeloma: A Systematic Review and Meta-Analysis of Clinical Trials

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2022-2022
Author(s):  
Adeela Mushtaq ◽  
Ahmad Iftikhar ◽  
Midhat Lakhani ◽  
Fnu Sagar ◽  
Ahmad Kamal ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
Adverse Events ◽  
Meta Analysis ◽  
Random Effect Model ◽  
Pooled Analysis ◽  
Cochrane Library ◽  
Significant Heterogeneity ◽  
Grade 3 ◽  
Stratified Analysis

Abstract Introduction Bortezomib, a proteasome inhibitor and lenalidomide (Len), an immunomodulatory drug are the backbone of established treatment regimens for newly diagnosed MM. Patients with dual-refractory (refractory to both bortezomib and lenalidomide) disease have a poor prognosis with overall survival estimated to be less than one year. Pomalidomide (Pom) has distinct anticancer, antiangiogenic and immunomodulatory properties and has demonstrated synergistic antiproliferative activity in combination regimens. The aim of our study is to compare different Pom based regimens to identify the most effective regimen for relapsed refractory multiple myeloma (RRMM) patients. Methods A comprehensive literature search was performed on PubMed, Cochrane library, Web of Science, Embase and AdisInsight databases on 03/29/2018 which identified a total of 1374 studies. We included phase II/III clinical trials on pomalidomide based regimens that have clearly documented efficacy outcomes. All statistical analyses were performed using Comprehensive Meta-analysis (CMA) Version 3. We used the Cochrane Q statistics (p<0.05 considered significant) and I2 index to calculate the degree of heterogeneity of the studies. A random effect model was used if there was significant heterogeneity (p>0.05 or I2 >50%). Studies were classified into subgroups according to the therapeutic regimen: dual and triplet combinations. A separate stratified analysis of triplet regimens based on type of regimen was also performed. Results A total of 35 studies (n = 4623 patients) were included. The most commonly studied regimen was Pom + LoDex (Low dose dexamethasone) with a total of 16 studies on this regimen. All patients included in our study had ≥ 2 prior lines of therapy. Mean number of prior lines of therapy was 6. Most patients were lenalidomide refractory, with 10 patient cohorts of 100% refractoriness and 8 cohorts of ≥ 90% refractoriness. Pooled analysis showed an overall response rate (ORR) of 47.1% across all Pom regimens including both doublet and triplet regimens. An I2 value of 87.3 was found, indicating high heterogeneity across all Pom regimens. With Pom-LoDex, pooled ORR was found to be 35.7% and mean OS 14.37 months. With triplet regimens, pooled ORR was found to be 61.9%. In a separate stratified analysis of triplet regimens based on type of regimen, pooled ORRs with few selected regimens were as follows; Bort-Pom-LoDex (pooled ORR 83.5%, mean PFS 15.7 months [mos]), CFZ-Pom-LoDex (pooled ORR 77.1%, mean PFS 15.3 mos), Pom-LoDex-bendamustine (pooled ORR 74.2%), Pom-Dex-daratumumab (pooled ORR 64.5%), Pom-LoDex-cyclophosphamide (pooled ORR 59.4%, mean PFS 9.5 mos), Pom-LoDex-doxorubicin (pooled ORR 32%). Most frequently reported adverse event with Pom based regimens was myelosuppression. Mean incidences of grade ≥3 hematologic adverse events were neutropenia (47.6%), anemia (26.5%), and thrombocytopenia (20.8%). Mean incidences of grade ≥3 non-hematologic adverse events were infections (29.1%), pneumonia (13.8%) and fatigue (10%). Most of the studies used pomalidomide 4mg daily dosing. Lacy et al. suggested no advantage of 4mg pomalidomide over 2 mg daily dosing. Conclusion From results of pooled analysis, we can infer that triplet combinations of Pom yield almost double response rates (pooled ORR 61.9%) when compared to dual combination of Pom-LoDex (pooled ORR 35.7%). Among three drug combinations, Bort-Pom-LoDex (pooled ORR 83.5%) and CFZ-Pom-LoDex (pooled ORR 77.1%) seem to produce better outcomes. Our study provides useful insight into relative efficacy of various Pom regimens for treatment of RRMM patients. Several trials involving various MoAbs like nivolumab, daratumumab, elotuzumab, isatuximab and pembrolizumab in combination with Pom-LoDex are currently ongoing. Pomalidomide has an acceptable safety profile. Most common treatment emergent adverse events were myelotoxicity and infections that can be effectively managed with supportive care and dose modifications. Disclosures No relevant conflicts of interest to declare.

Prognostic significance of patient-physician disagreement about performance status in patients with advanced cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 9021-9021 ◽  
Author(s):  
I. D. Schnadig ◽  
E. K. Fromme ◽  
C. L. Loprinzi ◽  
J. A. Sloan ◽  
M. Mori ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Nutritional Status ◽  
Cox Regression ◽  
Performance Status ◽  
Prognostic Significance ◽  
Risk Of Death ◽  
Increased Risk ◽  
Advanced Malignancies ◽  
The Difference ◽  
Ecog Ps

9021 Background: Physician-reported performance status (PS) is an important prognostic factor in advanced malignancies and is a commonly used stratification variable in cancer clinical trials. However, the extent, predictors, and prognostic importance of disagreement in PS assessment between physicians and patients have not been examined. Methods: Using NCCTG clinical trials from 1987–1990 (J Clin Oncol 19(15):3539–3546, 2001), we analyzed the difference and agreement of PS (ECOG and Karnofsky [KPS]) and nutritional status assessments reported by physicians and patients individually. The degree of disagreement was analyzed using paired t-test. Overall mortality was estimated by Kaplan-Meier method. The effect of disagreement on overall survival was analyzed by Cox regression. Independent predictors of disagreement were identified by logistic regression. Results: 1,636 patients with advanced lung and colorectal cancer had a median survival of 9.8 months (95% CI, 9.4 to 10.4). Percent agreement between patients and physicians about KPS, ECOG PS, and appetite/nutritional status was 32.9%, 43.4% and 42.0% respectively. Physicians were more likely to rate patients better than individual patients were to rate themselves: ECOG (Mean 0.91 vs 1.30, p<.0001), KPS (Mean 83.3 vs. 81.7, p<0.0001), appetite/nutritional status (Mean 1.6 vs. 2.1, p<0.0001). Inability to work, depression and less than a high school education were independently associated with disagreement. An increased risk of death was observed for patient and physician disagreement on KPS (HR=1.15, 95% CI, 1.03 to 1.27 p=0.01) and appetite/nutritional status (HR=1.39, 95% CI, 1.26 to 1.54 p<0.0001). Conclusions: Patients and physicians frequently disagree about patient PS, with physicians tending to rate patients higher than patients do themselves. Baseline patient demographic factors that independently predict disagreement have been identified. Disagreement confers an increased risk of death in the setting of advanced malignancies. These findings illustrate limitations of physician-only assessed PS. No significant financial relationships to disclose.

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