Optimism bias in the design of phase III randomized control trials (RCTs) evaluating PD-1/PD-L1 targeting monoclonal antibodies (mAbs).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e18616-e18616
Author(s):  
Laith Al-Showbaki ◽  
Fahad Almugbel ◽  
Husam Alqaisi ◽  
Eitan Amir ◽  
Eric Xueyu Chen
Keyword(s):  
Monoclonal Antibodies ◽  
Hazard Ratio ◽  
Phase Iii ◽  
Randomized Control Trials ◽  
Optimism Bias ◽  
Number Of Patients ◽  
Cancer Types ◽  
The Mean ◽  
Randomized Control ◽  
Palliative Setting

e18616 Background: PD-1/PD-L1 targeting monoclonal antibodies (mAbs) improve outcomes in multiple cancer types. Multiple mAbs are in clinical development, and many randomized control trials (RCTs) have been completed or are in progress. These RCTs compete for limited clinical trials infrastructure, human resources and patients. Since the hypothesized benefit of an intervention is a critical determinant of the number of patients required for an RCT, it is crucial that the expected benefit be estimated appropriately. We examined the hypothesized hazard ratio (HHR) and the observed hazard ratio (OHR) in RCTs evaluating PD-1/PD-L1 targeting mAbs. Methods: Publications of RCTs evaluating at least one PD-1/PD-L1 targeting mAbs approved by the US Food and Drug Administration were identified through PubMed searches. The primary publication for each RCT and its associated protocol were retrieved. Two investigators independently extracted HHR, OHR for the primary endpoint among other data elements. The differences (∆HR) in HHR and OHR were analyzed statistically. Updated OHRs (uOHR) were extracted from reports with extended follow-ups. Results: 49 RCTs enrolling 36867 patients were included. 45/49 RCTs were in the palliative setting. HHR was met or exceeded in 22 (45%) RCTs. The mean HHR and OHR were 0.672 and 0.738, respectively. The mean ∆HR was 0.067 (range: -0.300 to 0.895, 95% confidence interval = 0.003 – 0.130). A lower magnitude of effect than hypothesized in 12/29 RCTs in non-small cell lung cancer, melanoma and renal cell carcinoma, but in 15/20 RCTs in other cancer types. OHR was ≥ 1.0 in 6 RCTs (12%). In the palliative setting, ∆HR was larger in more heavily pre-treated patients. PD-L1 expression was not associated with magnitude of effect. However, a higher magnitude of effect was observed for RCTs published in the New England Journal of Medicine. For 18 RCTs with extended follow-ups, uOHR was higher than OHR in 8. Conclusions: The majority of published RCTs evaluating PD-1/PD-L1 targeting mAbs did not achieve their hypothesized magnitude of effect. Investigators’ optimism regarding these agents should be combined with more realistic expectations. The optimism bias requires attention from the cancer clinical research community given the number of these agents in development and the intense interest in evaluating these agents in various disease settings.

EXPRESS: Comparison of Mothership versus Drip-and-Ship Models in treating patients with Acute Ischemic Stroke: A systematic review and meta-analysis

2021 ◽  
pp. 174749302110132
Author(s):  
Ahmed Mohamed ◽  
Nida Fatima ◽  
Ashfaq Shuaib ◽  
Maher Saqqur
Keyword(s):  
Functional Outcome ◽  
Meta Analysis ◽  
Critical Time ◽  
Functional Independence ◽  
Models Of Care ◽  
Randomized Control Trials ◽  
Symptomatic Intracerebral Hemorrhage ◽  
Significant Difference ◽  
The Mean ◽  
Randomized Control

Introduction There is controversy if direct to comprehensive center “mothership” (MS) or stopping at primary center for thrombolysis before transfer to comprehensive center “drip-and- ship” (DS) are best models of treatment of acute stroke. In this study, we compare MS and DS models to evaluate the best option of functional outcome. Methods Studies between 1990 and 2020 were extracted from online electronic databases. We compared the clinical outcomes, critical time measurements, functional independence and mortality were then compared. Results A total of 7,824 patients’ data were retrieved from 13 publications (3 randomized control trials and 10 retrospective ones). 4,639 (59.3%) patients were treated under MS model and 3,185 (40.7%) followed the DS model with mean age of 70.01±3.58 vs. 69.03±3.36; p< 0 .001, respectively. The National Institute Health Stroke Scale was 15.57±3.83 for the MS and 15.72±2.99 for the DS model (p=<0.001). The mean symptoms onset-to-puncture time was significantly shorter in the MS group compared to the DS (159.69 min vs. 223.89 min; p=<0.001, respectively). Moreover, the collected data indicated no significant difference between symptom’s onset to intravenous (IV) thrombolysis time and stroke onset-to-successful recanalization time (p=0.205 and p=<0.001, respectively). Patients had significantly worse functional outcome [modified rankin score (mRS)] (3-6) at 90-days in the DS model [Odds Ratio (OR): 1.47, 95% Confidence Interval (CI): 1.13-1.92, p<0.004] and 1.49-folds higher likelihood of symptomatic intracerebral hemorrhage (OR: 1.49, 95%CI: 1.22-1.81, p<0.0001) compared to MS. However, there were no statistically significant difference in terms of mortality (OR: 1.16, 95%CI: 0.87-1.55, p=0.32) and successful recanalization (OR: 1.12, 95%CI: 0.76-1.65, p=0.56) between the two models of care. Conclusion Patients in the MS model have significantly improved functional independence and recovery. Further studies are needed as the data from prospectively randomized studies is not of sufficient quality to make definite recommendations.

Speed of accrual into published phase III oncology trials: A comparison across geographic locations.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 6074-6074
Author(s):  
Nancy R. Ruther ◽  
Alcee Jumonville ◽  
Michelle A. Mathiason ◽  
Ann E. Emmel ◽  
Sandra K Wee ◽  
...  
Keyword(s):  
Phase Iii ◽  
Funding Source ◽  
Cancer Type ◽  
Cooperative Groups ◽  
Geographic Locations ◽  
Funding Sources ◽  
Therapeutic Trials ◽  
Number Of Patients ◽  
The Us ◽  
The Mean

6074 Background: There is a perception that patient accrual may be slower in the US than it is in Europe (Wang-Gillam A et al, J Clin Oncol 2010;28:3803-3807). However, a systematic study has not been performed. We seek to determine the speed at which patients are accrued into published phase III oncology trials across geographic locations and to identify factors that may influence this process. Methods: We searched MEDLINE and identified all original phase III oncology therapeutic trials published in 2006-2010 (N = 567). Trials with no reported activation and completion dates were excluded (n = 20). Accrual speed per trial was expressed as patients per month and was calculated by dividing the number of patients enrolled by number of months a trial was open. Results: The 547 trials included in our study enrolled 281,340 patients. Most trials were for adults only (95.6%), late stage cancers (77.5%), and involved multinational participation (44.1%). Funding sources were cooperative groups (45.5%), industry (33.8%) and academic centers (20.5%). The top 5 cancers studied were hematologic (19.2%), gastrointestinal (16.5%), lung (16.3%), breast (15.4%), and gynecologic (8.4%). Trial results were negative (57.4%), positive (38.2%), or equivalent (4.4%). The mean (+SD) accrual speeds varied according to trial location (multinational [25.0+25.4], US [13.3+16.5], other countries [11.4+15.7], Europe [8.7+11.8]; [P= .001]), funding source (industry [28.3+24.7], cooperative groups [13.3+19.0], academic [6.8+6.5]; [P= .001]), and cancer type (breast [24.0+29.4], gastrointestinal [20.2+24.2], lung [19.3+22.7], gynecologic [15.3+19.2], hematologic [11.2+10.7]; [P= .001]). After adjusting for funding source, accrual speeds were significantly different across trial locations only in 2 cancers: gastrointestinal (multinational [25.2+3.7], US [24.1+8.2], Europe [11.5+3.7], other [7.5+8.5]; P= .046) and gynecologic (multinational [28.9+5.4], other [10.5+7.8], US [6.6+5.3], Europe [4.2+5.9]; P= .004) studies. Conclusions: Among published phase III oncology trials, multinational studies accrued patients faster in gastrointestinal and gynecologic cancers and at a similar speed in other cancers.

scholarly journals Hospital-Acquired Hyponatremia in Children Following Hypotonic versus Isotonic Intravenous Fluids Infusion

Children ◽  
2018 ◽  
Vol 5 (10) ◽  
pp. 139 ◽  
Author(s):  
Spyridon Karageorgos ◽  
Panagiotis Kratimenos ◽  
Ashley Landicho ◽  
Joshua Haratz ◽  
Louis Argentine ◽  
...  
Keyword(s):  
Chart Review ◽  
Univariate Analysis ◽  
Retrospective Chart Review ◽  
Fold Increase ◽  
Intravenous Fluids ◽  
Randomized Control Trials ◽  
Unadjusted Odds Ratio ◽  
The Mean ◽  
Randomized Control ◽  
Hospital Acquired

Hypotonic solutions have been used in pediatrics for maintenance of intravenous (IV) hydration. However, recent randomized control trials and cohort studies have raised significant concerns for association with hospital-acquired hyponatremia (HAH). The study aimed to assess whether the use of hypotonic parenteral solutions (PS) compared with isotonic PS is associated with increased HAH risk in children with common pediatric conditions. Retrospective chart review of 472 patients aged 2 months to 18 years who received either isotonic or hypotonic PS as maintenance fluids. Administration of hypotonic PS was associated with a four-fold increase in risk of developing HAH in the univariate analysis, (unadjusted odds ratio (OR) = 3.99; 95% confidence interval (CI): 1.36–11.69, p = 0.01). Hypotonic PS were associated with HAH (p = 0.04) when adjusted for the level of admission serum CO2. There was a mean decrease of serum sodium of 0.53 mEq/L in the hypotonic group compared to the mean increase of 4.88 mEq/L in the isotonic group. These data suggest that hypotonic PS are associated with HAH in children admitted for common pediatric conditions. Isotonic PS should be considered as a safer choice for maintenance fluid hydration.

The outcome of patients with advanced hepatocellular carcinoma (HCC) in pre- and post-sorafenib eras using the SEER database.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 276-276
Author(s):  
Jiahuai Tan ◽  
Minsig Choi ◽  
Philip Agop Philip ◽  
Gregory Dyson ◽  
Anthony Frank Shields ◽  
...  
Keyword(s):  
Overall Survival ◽  
Median Survival ◽  
Cox Regression ◽  
Hazard Ratio ◽  
Phase Iii ◽  
Advanced Hepatocellular Carcinoma ◽  
Sorafenib Treatment ◽  
Advanced Hcc ◽  
Number Of Patients ◽  
The Impact

276 Background: HCC is the third most common cause of cancer-related death globally. Prognosis for advanced HCC is dismal due to lack of effective treatment options for the majority of patients who present with advanced disease. Sorafenib was the first agent reported to improve overall survival in patients with good liver function enrolled in phase III clinical trials. However, survival impact of sorafenib on the general population with advanced HCC has not been studied to date. Methods: Sorafenib was approved for patients with advanced HCC and Child-Pugh A liver disease in 2007. We analyzed 2005-2006 and 2008-2009 clinical outcome data from the SEER to compare the impact of this targeted therapy in the population based setting. The Kaplan-Meier method was used to estimate the median survival and 95% confidence intervals (CI). The log-rank test was used to test the difference in survival curves. Cox regression analyses were utilized for the estimation of hazard ratios. Results: We identified 2297 and 2808 stage III and IV HCC cases diagnosed in [2005, 2006] and [2008, 2009], respectively. Seventy-seven percent of the patients were male and the median age was 61 years old for males and 66 for females. The median survival estimates (95% CIs) are 3 (3, 4) months and 4 (4, 4) months for patients diagnosed in [2005, 2006] and [2008, 2009], respectively. The hazard ratio (95% CI) for overall survival comparing [2008, 2009] to [2005, 2006] was 0.92 (0.87, 0.98, p-value = 0.01). We performed multivariable Cox regression modeling and African American patients have a hazard ratio of death [1.14 (1.06, 1.23)] as compared to European American patients. Younger females have a decreased hazard of dying relative to younger men, while older females have an increase hazard of dying relative to older men. Conclusions: The approval of sorafenib treatment produced very modest median survival gain in advanced HCC patients based on SEER population study. However, the small benefit in hazard ratio may have been impacted by small number of patients with advanced HCC who are being treated or are able to be treated with sorafenib in this era.

scholarly journals Treatment of double-refractory multiple myeloma

2021 ◽  
Vol 16 (3) ◽  
pp. 58-73
Author(s):  
S. V. Semochkin
Keyword(s):  
Multiple Myeloma ◽  
Monoclonal Antibodies ◽  
High Risk ◽  
Confidence Interval ◽  
Progression Free Survival ◽  
Hazard Ratio ◽  
Phase Iii ◽  
Free Survival ◽  
Refractory Multiple Myeloma ◽  
Median Progression Free Survival

In most publications on relapsed and refractory multiple myeloma, the term double-refractory refers to the loss of response to lenalidomide and proteasome inhibitors. The prognosis in the case of double-refractory multiple myeloma is poor. Usually, these are severely pretreated patients who have accumulated drug toxicity after 2 or more lines of therapy, with limited reserves of bone marrow hematopoiesis and often decompensated comorbidities. A partial solution to the problem was to use certain new drugs that have demonstrated activity as monotherapy or in combination with dexamethasone in this group of patients. This review is aimed to provide a critical review of recent clinical studies addressing this issue. According to the recent European Hematology Association and European Society for Medical Oncology (EHA-ESMO) 2021 guidelines for the diagnosis and treatment of double-refractory multiple myeloma, triple combinations should be considered, including monoclonal antibodies (elotuzumab (Elo), isatuximab (Isa), daratumumab (Dara)), dexamethasone and pomalidomide (Elo-­Pd, Isa-­Pd, Dara-­Pd) or carfilzomib (Isa-Kd, Dara-Kd). In Russia, as of March 2021, the first two regimens were approved (Elo-­Pd, Isa-­Pd). Elotuzumab was tested in combination with pomalidomide in the randomized phase II ELOQUENT-3 trial (Elo-­Pd vs. Pd; n = 177). Median progression-free survival was 10.3 months on Elo-­Pd vs. 4.7 months on Pd (hazard ratio 0.54; 95 % confidence interval 0.34–0.86; р = 0.008). Elo-­Pd superiority was observed in all subgroups, including patients with double-refractory MM, high-risk cytogenetic aberrations del17p, t(4;14), t(14;16), and increased serum LDH. The Isa-­Pd triplet was approved in the randomized phase III ICARIA-MM study (Isa-­Pd vs. Pd; n = 307). The median progression-free survival in this protocol was 11.5 months in the Isa-­Pd group vs. 6.5 months in the Pd group (hazard ratio 0.596; 95 % confidence interval 0.44–0.81; р = 0.001). Isa-­Pd triplet superiority was demonstrated in all unfavorable prognostic subgroups, including lenalidomide-refractory patients, patients with high-risk cytogenetics, and doublerefractory patients. New triplets with monoclonal antibodies represent an important option for the treatment of doublerefractory multiple myeloma.

Abstract 15579: Multivessel Coronary Artery Revascularization During Index Hospitalization Has Favorable Outcomes Compared to Infarct Related Artery Only Revascularization in STEMI Patients- Meta-Analysis of Randomized Control Trials

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Sainath Gaddam ◽  
Viswajit Reddy Anugu ◽  
Deepak Asti ◽  
Muhammad Raza ◽  
Bhavi Pandya ◽  
...  
Keyword(s):  
Coronary Artery ◽  
Meta Analysis ◽  
Complete Revascularization ◽  
Randomized Control Trials ◽  
Primary Pci ◽  
Index Hospitalization ◽  
Repeat Revascularization ◽  
Number Of Patients ◽  
Randomized Control

Introduction: Multivessel coronary artery disease is present in about half of the patients presenting with STEMI. Timing of revascularization for the non-culprit vessels has been a long debate, with few trials suggesting benefit at index hospitalization rather than staging them at a later time. Current ACCF/AHA 2013 STEMI guidelines do not recommend PCI of non-infarct artery at the time of primary PCI but recommend it at a later time if patients are symptomatic. We hypothesized, complete revascularization during primary PCI or index hospitalization would have favorable outcomes compared to culprit vessel only revascularization. Aim: We performed meta-analysis of randomized control trials comparing multivessel vs. infarct artery only revascularization during primary PCI or index hospitalization. Methods and Results: Pubmed, Embace and Google scholar databases were searched for randomized control trials comparing multivessel vs. culprit vessel only revascularization during primary PCI or index hospitalization. We compared deaths, non-fatal MI and repeat revascularization events for the groups. Total number of patients in our study was 1819, with 919 patients in multivessel revascularization and 900 patients in infarct artery only revascularization groups. Mean follow up period was 28 months. Pooled analysis showed significant favorability for multivessel coronary revascularization comparing events of repeat revascularization (OR= 0.39, p<0.0001). There was also non-significant decrease in mortality (OR=0.92, p=0.7) and non-fatal MI (OR=0.68, p=0.09) with complete revascularization. Conclusions: In our study of STEMI patients, complete revascularization during primary PCI or index hospitalization has significantly decreased need for repeat revascularization and there was also non-significant decrease in mortality and non-fatal MI. Studies with larger sample size and longer follow up are needed for stronger evidence.

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