scholarly journals The Damaging Outcome of the POLAR Phase III Trials Was Due to Avoidable Time-Dependent Redox Interaction between Oxaliplatin and PledOx

Antioxidants ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 1937
Author(s):  
Jan Olof G. Karlsson ◽  
Per Jynge ◽  
Louis J. Ignarro
Keyword(s):  
Clinical Trial ◽  
Phase Iii ◽  
Polar Phase ◽  
Negative Results ◽  
M Phase ◽  
Phase Iii Trials ◽  
Modified Folfox6 ◽  
Redox Interaction ◽  
Administration Procedure ◽  
Time Point

On 2 July 2021, highly negative results were reported from the POLAR A and M phase III trials in patients with colorectal cancer, treated with an oxaliplatin-based regimen and co-treated with calmangafodipir (CaM; PledOx®; PledPharma AB/Egetis Therapeutics AB) or placebo. The results revealed persistent chemotherapy-induced peripheral neuropathy (CIPN) in 54.8% of the patients treated with PledOx, compared with 40.0% of the patients treated with the placebo (p < 0.05), i.e., a 37% increase in incidence of the side effect that the trial was aimed to prevent. The damaging outcome of the trials differed diametrically from an in-parallel conducted mice study and from a clinical trial with mangafodipir, the active ingredient of CaM. According to the authors of the POLAR report, the etiology of the profound increase in CIPN in the PledOx arm is unclear. However, these devastating effects are presumably explained by intravenous administrations of PledOx and oxaliplatin being too close in time and, thereby, causing unfavorable redox interactions between Mn2+ and Pt2−. In the mice study as well as in the preceding phase II clinical trial (PLIANT), PledOx was administered 10 min before the start of the oxaliplatin infusion; this was clearly an administration procedure, where the devastating interactions between PledOx and oxaliplatin could be avoided. However, when it comes to the POLAR trials, PledOx was administered, for incomprehensible reasons, “on Top of Modified FOLFOX6” at day one, i.e., after the two-hour oxaliplatin infusion instead of before oxaliplatin. This is a time point when the plasma concentration of oxaliplatin and Pt2+-metabolites is at its highest, and where the risk of devastating redox interactions between PledOx and oxaliplatin, in turn, is at its highest.

scholarly journals A Review of Phase III Clinical Trials of Prostate Cancer Chemoprevention

2007 ◽  
Vol 89 (3) ◽  
pp. 207-211 ◽  
Author(s):  
JF Thorpe ◽  
S Jain ◽  
TH Marczylo ◽  
AJ Gescher ◽  
WP Steward ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Trial ◽  
Clinical Trials ◽  
Cancer Prevention ◽  
Age Of Onset ◽  
Cancer Chemoprevention ◽  
Phase Iii ◽  
Phase Iii Clinical Trials ◽  
Prostate Cancer Prevention ◽  
Phase Iii Trials

INTRODUCTION Prostate cancer is an excellent target for chemoprevention strategies; given its late age of onset, any delay in carcinogenesis would lead to a reduction in its incidence. This article reviews all the completed and on-going phase III trials in prostate cancer chemoprevention. PATIENTS AND METHODS All phase III trials of prostate cancer chemoprevention were identified within a Medline search using the keywords ‘clinical trial, prostate cancer, chemoprevention’. RESULTS In 2003, the Prostate Cancer Prevention Trial (PCPT) became the first phase III clinical trial of prostate cancer prevention. This landmark study was terminated early due to the 24.8% reduction of prostate cancer prevalence over a 7-year period in those men taking the 5α-reductase inhibitor, finasteride. This article reviews the PCPT and the interpretation of the excess high-grade prostate cancer (HGPC) cases in the finasteride group. The lack of relationship between cumulative dose and the HGPC cases, and the possible sampling error of biopsies due to gland volume reduction in the finasteride group refutes the suggestion that this is a genuine increase in HGPC cases. The other on-going phase III clinical trials of prostate cancer chemoprevention – the REDUCE study using dutasteride, and the SELECT study using vitamin E and selenium – are also reviewed. CONCLUSIONS At present, finasteride remains the only intervention shown in long-term prospective phase III clinical trials to reduce the incidence of prostate cancer. Until we have the results of trials using alternative agents including the on-going REDUCE and SELECT trials, the advice given to men interested in prostate cancer prevention must include discussion of the results of the PCPT. The increased rate of HGPC in the finasteride group continues to generate debate; however, finasteride may still be suitable for prostate cancer prevention, particularly in men with lower urinary tract symptoms.

scholarly journals ‘Optimism bias’ in contemporary national clinical trial network phase III trials: are we improving?

2018 ◽  
Vol 29 (10) ◽  
pp. 2135-2139 ◽  
Author(s):  
Kaveh Zakeri ◽  
Sonal Noticewala ◽  
Lucas Vitzthum ◽  
E. Sojourner ◽  
Hanjie Shen ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase Iii ◽  
Optimism Bias ◽  
Trial Network ◽  
Clinical Trial Network ◽  
Phase Iii Trials

Compendium of Unpublished Phase III Trials in Oncology: Characteristics and Impact on Clinical Practice

2011 ◽  
Vol 29 (23) ◽  
pp. 3133-3139 ◽  
Author(s):  
Vincent C. Tam ◽  
Ian F. Tannock ◽  
Christine Massey ◽  
Jennifer Rauw ◽  
Monika K. Krzyzanowska
Keyword(s):  
Clinical Trials ◽  
Clinical Practice ◽  
Phase Iii ◽  
Institutional Review Boards ◽  
Negative Results ◽  
Institutional Review ◽  
Subsequent Publication ◽  
Phase Iii Trials ◽  
Asco Meeting ◽  
American Society

Purpose Many phase III trials presented at annual meetings of the American Society of Clinical Oncology (ASCO) remain unpublished. The results of these unpublished trials, if more generally known, might have an impact on clinical practice. Methods Abstracts of large phase III trials evaluating systemic cancer treatment were identified from conference proceedings of the 1989 to 2003 ASCO annual meetings. PubMed, Medline, and Embase were searched for corresponding publications. A compendium of unpublished phase III trials was assembled. Clinical significance of nonpublication was determined by disease site-specific oncology experts from two academic cancer centers in Canada. Results A total of 709 phase III trials were identified of which 66 (9.3%) remain without a subsequent publication at a minimum of 6.5 years of follow-up and 94 (13%) were published after a delay of ≥ 5 years from their initial presentation. Of the unpublished trials, 48% were presented as oral sessions at an ASCO meeting, and 71% of the abstracts reported negative results. The experts judged that 70% of the unpublished trials addressed an important question and 59% might have had clinical impact if their results had been published promptly. Conclusion A substantial number of cancer clinical trials with potential influence on clinical practice remain unpublished and many other trials are published after a substantial delay. Nonpublication of clinical trials breaks an implicit contract with participants, institutional review boards, and sponsors.

Self-reported conflicts of interest (sfCOI) of authors and the interpretation of randomized phase III trials (RCT) and related editorials (REd) in cancer research.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 6055-6055
Author(s):  
Giovanni Mendonca Bariani ◽  
Anezka Carvalho Rubin De Celis Ferrari ◽  
Paulo Marcelo Hoff ◽  
Rachel Riechelmann
Keyword(s):  
Cancer Research ◽  
Logistic Regression ◽  
Conflicts Of Interest ◽  
Multivariable Analysis ◽  
Phase Iii ◽  
Experimental Therapy ◽  
Negative Results ◽  
Study Results ◽  
Phase Iii Trials ◽  
Cancer Studies

6055 Background: Growing participation from industry in cancer research has resulted in increased reporting of COI. We aimed to test any association between author’s conclusion and sfCOI in cancer studies. Methods: All RCT and REd published in 6 major cancer journals in a 3.5 year period were selected. Two investigators blinded to COI disclosure independently analyzed each RCT and REd, classifying authors’ conclusions as highly positive, positive, neutral, negative, and highly negative with respect to author’s opinion on the experimental therapy. The agreement rate between investigators for conclusion classification was 90% (consensus was achieved for the remaining 10%). We also collected data on study results, COI and sponsorship. COI was defined as any self-reported financial tie between author and industry except for research funds. Predictors of positive/highly positive conclusions of RCT and of REd were tested separately in logistic regression multivariable models. Results: From Jan 2008 to Oct 2011, 1,485 articles were retrieved: 150 RCT and 140 REd were eligible. Among the RCT, 82 (55%) were positive, and 78 (52%) were entirely or partially funded by industry. Any sfCOI was present in 103 (69%) RCT and in 71 (47%) REd. Conclusions of REd and RCT were: 7.3% and 11.3% highly positive, 42.7% and 57.3% positive, 8.0% and 2.0% neutral, 29.3% and 18.7% negative, and 12.7% and 10.7% highly negative, respectively. Multivariable analysis showed that RCT positive result was the only significant predictor for positive conclusion by RCT authors (OR=109, 95% CI: 21-567; p<0.001). The only factor associated with positive conclusions of REd authors was a positive conclusion by RCT author (OR=42, 95% CI: 7-244; p<0.001). While 64 (43%) RCT reported negative results, 103 (68.7%) RCT authors interpreted studies positively. Logistic regression for discordance between RCT result and RCT conclusion did not find any association with COI. Conclusions: The interpretation of RCT results by authors was not influenced by sfCOI or trial sponsorship. Authors of REd were not influenced by study results or by their sfCOI when discussing cancer RCT.

scholarly journals Changes in Efficacy Indicators for Adalimumab Biosimilar Candidate (HS016) for the Treatment of Active Ankylosing Spondylitis at Various Time Points

2020 ◽  
Vol 11 ◽  
Author(s):  
Jinmei Su ◽  
Mengtao Li ◽  
Lan He ◽  
Dongbao Zhao ◽  
Weiguo Wan ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Back Pain ◽  
Ankylosing Spondylitis ◽  
Disease Activity ◽  
Activity Index ◽  
Phase Iii ◽  
Chest Expansion ◽  
Significant Difference ◽  
Individual Efficacy ◽  
Time Point

Objectives: A phase III, 24-weeks Chinese clinical trial demonstrated that efficacy and safety outcomes of treatments with 40 mg/0.8 ml HS016 (n = 416) or adalimumab (n = 232) for active ankylosing spondylitis (AS) patients was comparable. In the present study, a subanalysis of the clinical trial was conducted to determine whether also individual efficacy indicators were comparable between HS016 and adalimumab.Methods: The individual efficacy indicators total and nocturnal back pain, global assessment of disease activity, swollen joint count, Maastricht AS Enthesitis Score, Bath AS Disease Activity Index, Bath AS Functional Index, Bath AS Metrology Index and chest expansion, were assessed at baseline and every 2 weeks during the treatment period.Results: This subanalysis revealed no significant difference between the patient groups treated with HS016 or adalimumab for any individual efficacy indicator investigated at any time point (all p &gt; 0.05) beside faster total back pain score improvements in the adalimumab group on week 10, 12 and 22, which became equal at week 24. Among these indicators, chest expansion showed a significant increase at each time point compared with baseline, whereas all other efficacy indicators showed significant decreases compared with baseline at each time point (all p &lt; 0.05). All efficacy indicators had increased or decreased rapidly by week 2, and the values continued to increase/decrease up to week 12, with subsequent smaller changes thereafter up to week 24 of treatment.Conclusion: The response trajectory of most individual efficacy indicators was comparable between HS016 and adalimumab at each time point during the 24 weeks of the trial.Clinical Trial Registration:http://www.chictr.org.cn/showproj.aspx?proj=37910, identifier [ChiCTR1900022520]

Role of Sensitivity Analyses in Assessing Progression-Free Survival in Late-Stage Oncology Trials

2009 ◽  
Vol 27 (35) ◽  
pp. 5958-5964 ◽  
Author(s):  
Suman Bhattacharya ◽  
Gwen Fyfe ◽  
Robert J. Gray ◽  
Daniel J. Sargent
Keyword(s):  
Clinical Trial ◽  
Late Stage ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Sensitivity Analyses ◽  
Potential Bias ◽  
Primary Analysis ◽  
Free Survival ◽  
End Point ◽  
Phase Iii Trials

Sensitivity analysis is an important statistical technique that assesses whether the results of phase III trials are robust and likely to be generalizable. Until recently, sensitivity analyses were rarely included in phase III trials, and they remain poorly understood by many oncologists. Sensitivity analyses are critical to understanding the strength of conclusions made in the primary analysis of a late-stage clinical trial. They examine the influence of protocol design errors, unintended biases, deviations from assumptions underlying statistical models, and any unanticipated treatment delivery or practice patterns on trial results. In trials with complex or subjective end points, they also allow an understanding of the extent to which a positive outcome is driven by a single, possibly subjective, and therefore biased, element of an end point. The purposes of this article are to explain how sensitivity analyses are performed, to discuss areas of a clinical trial where sensitivity analyses should focus, and to illuminate the importance of this technique in the rigorous evaluation of late-stage clinical trial data, using specific examples. This article focuses on late-stage trials that use progression-free survival or time to progression as their primary end point, because sensitivity analyses are particularly important in these cases for which the end point is potentially subject to bias. Three sources of potential bias are explored: assessment time, symptomatic (ie, nonradiologic) disease progression, and missing data. For each source of potential bias, case studies are presented to highlight the role that sensitivity analyses play in determining whether the trial's conclusions are robust.

scholarly journals Changing Perspectives in Diabetic Macular Oedema – Recognising and Understanding Chronic Diabetic Macular Oedema

2014 ◽  
Vol 08 (02) ◽  
pp. 145
Author(s):  
Usha Chakravarthy ◽  
Albert Augustin ◽  
Yit Yang ◽  
Michael Diestelhorst ◽  
Pascale Massin ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Macular Oedema ◽  
Diabetic Macular Oedema ◽  
Clinical Trial Data ◽  
Fluocinolone Acetonide ◽  
Phase Iii ◽  
Real World Data ◽  
First Line Therapy ◽  
Line Therapy ◽  
Phase Iii Trials

The satellite symposium moderated by Usha Chakravarthy entitled ‘Changing Perspectives in Diabetic Macular Oedema: Recognising and Understanding Chronic Diabetic Macular Oedema’ was convened at the 2014 EURETINA Congress. The symposium discussed the multiple processes involved in chronic diabetic macular oedema (DMO) and the use of medications, in particular, corticosteroids in its management. As DMO progresses, inflammatory cytokines are up-regulated relative to vascular endothelial growth factor (VEGF) and these promote various pathways that ultimately result in retinal damage in chronic disease. It is important therefore that treatments for chronic DMO address this altered inflammatory cytokine profile to effectively manage the condition. ILUVIEN®, a 190 μg intravitreal implant in applicator (with a daily release rate of 0.2 μg/day fluocinolone acetonide [FAc] implant) is a second-line therapy indicated for the treatment of chronic DMO. This implant has been shown in phase III trials to lead to marked improvements in visual acuity and in retinal thickness in patients with chronic DMO that were insufficiently response to first-line therapy (i.e. laser). Clinical trial data strongly support the use of the FAc implant in chronic DMO and now ‘real world’ data from its use in regular clinical practice are becoming available and interim results complement those reported in a clinical trial setting.

A sense of urgency: Evaluating the link between clinical trial development time and the accrual performance of CTEP-sponsored studies

2009 ◽  
Vol 27 (18_suppl) ◽  
pp. CRA6509-CRA6509 ◽  
Author(s):  
S. Cheng ◽  
M. Dietrich ◽  
S. Finnigan ◽  
A. Sandler ◽  
J. Crites ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Odds Ratio ◽  
Development Time ◽  
Phase Iii ◽  
Multivariable Logistic Regression Analysis ◽  
Study Phase ◽  
Calendar Time ◽  
Activation Barriers ◽  
Oncology Clinical Trials ◽  
Phase Iii Trials

CRA6509 Background: Post-activation barriers to oncology clinical trial accruals are well documented; however, potential barriers prior to trial opening are not. We investigate one such barrier: trial development time. Methods: National Cancer Institute Cancer Therapy Evaluation Program (NCI-CTEP) sponsored trials for all therapeutic, non-pediatric phase I,I/II, II, and III studies activated in an eight year period (2000–2007) were investigated (n=553). Successful trials were those achieving 100% of minimum accrual goal. Time to open a study was the calendar time from initial CTEP submission to trialactivation. Multivariable logistic regression analysis was used tocalculate unadjusted and adjusted odds ratios, controlling for study phase and size of expected accruals. Results: 40.0 percent (n=221) of CTEP-approved oncology trials failed to achieve minimum accrual goals, with 49.2 percent (n=30) of phase III trials failing to achieve at least 25 percent of accrual goals. A total of 8,723 patients (17.0% of accruals) accrued to those studies that were unable to achieve the projected minimum accrual goal. Trials requiring 9–12 months development were significantly more likely to achieve accrual goals (odds ratio, 1.94; 95% CI, 1.06 to 3.52, P=0.031) than trials requiring the median time (15–18 months); trials that exceeded 27 months of development time were significantly less likely of achieving accrual goals (odds ratio, 0.14; 95% CI, 0.04 to 0.54, P=0.004). Conclusions: A large percentage of oncology clinical trials do not achieve minimum projected accruals. Trial development time appears to be one important predictor of the likelihood of successfully achieving the minimum accrual goals. [Table: see text] No significant financial relationships to disclose.

Chemotherapy for patients with advanced gastric cancer with performance status 2

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e15627-e15627
Author(s):  
K. Muro ◽  
K. Shitara ◽  
T. Ura ◽  
D. Takahari ◽  
T. Yokota ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Clinical Trial ◽  
Mortality Rate ◽  
Treatment Failure ◽  
Performance Status ◽  
Phase Iii ◽  
Treatment Results ◽  
Time To Treatment Failure ◽  
Phase Iii Trials ◽  
Line Chemotherapy

e15627 Background: S-1 plus cisplatin is considered to be the standard chemotherapy for Japanese patients with advanced gastric cancer (AGC) according to the results of three phase III trials (JCOG9912/SPIRITS/TOP-002). However, since few patients with poor performance status (PS2) were included in these phase III trials (27 of 1317; 2%), the standard treatment of patients with PS2 has not been established yet. In also, the characteristics and prognosis of AGC patients with PS2 has not been reported in detail. Methods: We retrospectively analyzed 545 patients with AGC treated by chemotherapy during the period from January 2003 to June 2008. Patients characteristic and treatment results were compared between PS0–1 and PS2. Results: At the beginning of 1st-line chemotherapy, PS0–1/2/3–4 was 454/69/22 cases respectively. Patients with peritoneal/pleural dissemination was more common in PS2 than PS0–1 (75% vs. 43%, p<0.001). Patients with multiple metastatic places was more common in PS2 (62% vs. 43%; p=0.007). Fewer patients in PS2 were registered in clinical trial (1.4% vs. 25%, p<0.001). First-line chemotherapy using oral drug (S- 1/capecitabine) was significantly fewer in PS2 (43% vs. 75%, P<0.001). Median time to treatment failure was significantly shorter in PS2 (2.3 months vs. 4.2 months, p<0.001). Patients who could receive second-line chemotherapy were significantly fewer in PS2 (50% vs. 75%, p<0.001). With the median follow up time of 42 months, median survival time of patients with PS0–1 was 14.8 months (95% CI;13.1–16.5) and that of patients with PS2 was 6.1 months (4.3 to 7.4 months; hazard ratio for death 3.0: 95% CI2.3–4.0; p<0.001). Mortality rate within 30 days was higher in PS2 (3% vs. 0.2%; p<0.001). Conclusions: AGC patients with PS2 had not only had poor prognosis compared with PS0–1 but also had fewer chance of registration in the clinical trial, shorter time to treatment failure, and higher mortality rate within 30 days. Considering these different characteristics and treatment results of PS0–1 and PS2, clinical trial especially targeting AGC patients with PS2 is necessary to evaluate optimal chemotherapeutic regimens for PS2 patients. No significant financial relationships to disclose.

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