scholarly journals Considering indirect benefits is critical when evaluating SARS-CoV-2 vaccine candidates

2020 ◽  
Author(s):  
Molly E. Gallagher ◽  
Andrew J. Sieben ◽  
Kristin N. Nelson ◽  
Alicia N. M. Kraay ◽  
Ben Lopman ◽  
...  
Keyword(s):  
Indirect Effects ◽  
Model Development ◽  
Phase Iii ◽  
Vaccine Candidates ◽  
Indirect Benefits ◽  
Risk Of Death ◽  
Phase Iii Clinical Trials ◽  
Direct Benefits ◽  
Phase Iii Trials ◽  
Made In

Significant progress has already been made in development and testing of SARS-CoV-2 vaccines, and Phase III clinical trials have begun for 6 novel vaccine candidates to date. These Phase III trials seek to demonstrate direct benefits of a vaccine on vaccine recipients. However, vaccination is also known to bring about indirect benefits to a population through the reduction of virus circulation. The indirect effects of SARS-CoV-2 vaccination can play a key role in reducing case counts and COVID-19 deaths. To illustrate this point, we show through simulation that a vaccine with strong indirect effects has the potential to reduce SARS-CoV-2 circulation and COVID-19 deaths to a greater extent than an alternative vaccine with stronger direct effects but weaker indirect effects. Protection via indirect effects may be of particular importance in the context of this virus, because elderly individuals are at an elevated risk of death but are also less likely to be directly protected by vaccination due to immune senescence. We therefore encourage ongoing data collection and model development aimed at evaluating the indirect effects of forthcoming SARS-CoV-2 vaccines.

Efficacy and Safety of AZD1222, BNT162b2 and mRNA-1273 vaccines against SARS-CoV-2

2021 ◽  
Vol 5 (1) ◽  
pp. 791-796
Author(s):  
Ilir Alimehmeti
Keyword(s):  
Clinical Trials ◽  
Diagnostic Tests ◽  
Web Of Science ◽  
Rapid Development ◽  
Phase Iii ◽  
Efficacy And Safety ◽  
Vaccine Candidates ◽  
Genetic Sequence ◽  
Phase Iii Clinical Trials ◽  
Clinical Trial Results

SARS-CoV-2, the beta coronavirus causing COVID-19, was isolated and categorizes as a novel one on January 7th, 2020 in China.[1] To date, official reports depict that SARS-CoV-2 has already infected 88.828.387 persons and caused 1.926.625 deaths worldwide.[2] On January 12th, 2020, China officials made public its genetic sequence, thus paving the way towards the research and development of diagnostic tests and vaccines. With regard to vaccination, e large number of clinical trials were designed and are currently undergoing, of which 189 are listed in ClinicalTrials.gov. [3] However, up to date, only three vaccines have published their respective phase III clinical trial results in peer-reviewed medical journals. [4-6] Vaccines are needed to reduce the morbidity and mortality associated with Covid-19, and multiple vaccine platforms as AZD1222 (AstraZeneca) [4], BNT162b2 (Pfizer/BioNTech) [5] and mRNA-1273 (Moderna) have been involved in the rapid development of vaccine candidates. Methodology: In this review, PubMed, Embase, Web of Science, Scopus, medRxiv, and bioRxiv were systematically scrutinized for peer-reviewed and preprint articles on phase III clinical trials of vaccines against SARS-CoV-2. In total, only three peer-reviewed papers fulfilling the search criteria were identified. Conclusions; All vaccine candidates should publish in peer-reviewed journals their efficacy and safety well before requesting approval to the national or international authorities…

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 Evaluating Intermittent Androgen-Deprivation Therapy Phase III Clinical Trials: The Devil Is in the Details

2016 ◽  
Vol 34 (3) ◽  
pp. 280-285 ◽  
Author(s):  
Maha Hussain ◽  
Catherine Tangen ◽  
Celestia Higano ◽  
Nicholas Vogelzang ◽  
Ian Thompson
Keyword(s):  
Prostate Cancer ◽  
Statistical Power ◽  
Progression Free Survival ◽  
Androgen Deprivation ◽  
Phase Iii ◽  
End Point ◽  
Phase Iii Clinical Trials ◽  
Noninferiority Trials ◽  
Phase Iii Trials

Purpose Intermittent androgen deprivation (IAD) has been widely tested in prostate cancer. However, phase III trials testing continuous androgen deprivation (CAD) versus IAD have reached inconclusive and seemingly contradictory results. Different design and conduct issues must be critically evaluated to better interpret the results. Patients and Methods Seven published phase III trials were examined for prespecified design and outcomes. Treatment specifications; primary end point; superiority versus noninferiority design assumptions, including magnitude of assumed versus observed noninferiority margin (NIM); duration of follow-up; and quality-of-life (QOL) outcomes were considered in terms of the results and conclusions reported. Results Five trials had a superiority and three had a noninferiority primary hypothesis. Only three trials had a uniform population and overall survival (OS) end point. All trials observed better outcomes in terms of OS and progression-free survival (PFS) than assumed at time of study design, translating into prespecified NIMs or hazard ratios that reflected larger absolute differences in OS or PFS between arms. Lower-than-expected event rates also reduced statistical power for the trials. Other factors, including length of follow-up, cause of death, QOL, and primary end point, and their impact on trial interpretation are discussed. Conclusion No trial to date has demonstrated survival superiority of IAD compared with CAD. Trials concluding IAD is noninferior to CAD were based on wide NIMs that included clinically important survival differences, not likely to be considered comparable by physicians or patients. Interim analyses relying on short follow-up and including a majority of non–prostate cancer deaths will favor a noninferiority conclusion and should be interpreted cautiously. Adequate follow-up is required to ensure capture of prostate cancer deaths in both superiority and noninferiority trials.

Elucidating the mechanisms responsible for the previous failure of phase III clinical trials with eniluracil (EU) and development of a novel scheduling approach to optimize the efficacy of EU/5-fluorouracil (5-FU) combination therapy

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 2557-2557
Author(s):  
V. Guarcello ◽  
J. Fourie ◽  
M. J. Lawton ◽  
W. W. Peters ◽  
M. J. Heslin ◽  
...  
Keyword(s):  
Tumor Tissue ◽  
Competitive Inhibition ◽  
Dihydropyrimidine Dehydrogenase ◽  
Phase Iii ◽  
Clinical Failure ◽  
Peripheral Blood Mononuclear ◽  
Phase Iii Clinical Trials ◽  
Phase Iii Trials ◽  
Dosing Regimens

2557 Background: Irreversible inhibition of dihydropyrimidine dehydrogenase (DPD) by EU blocks 5-FU catabolism allowing for oral 5-FU administration with complete bioavailability. Unfortunately, phase III trials with co-administered EU/5-FU showed inferiority vs. 5-FU/leucovorin, and were discontinued. We recently reported that competitive inhibition of human uridine phosphorylase (UP) and thymidine phosphorylase (TP) 5-FU-anabolic enzymes by EU is an important mechanism potentially responsible for clinical failure of the combined EU/5- FU regimen. We hypothesize that EU inhibition of UP and TP is transient, while that of DPD is prolonged, allowing for novel schedule dependent optimization of EU/5-FU dosing regimens with improved efficacy. Methods: In this phase I study, five patients received a single oral dose (2 mg, 5 mg or 10 mg) of EU 12–14 hours prior to scheduled resection of primary/metastatic colorectal cancer. Dosage was as follows: Two patients received the 2 mg dose, one patient received the 5 mg dose and two patients received the 10 mg dose. Matched normal and tumor tissue biopsies were immediately snap frozen and subsequently UP, TP and DPD activity was measured in vitro via HPLC detection of [6- 14C]-5-FU catabolites/anabolites. Peripheral blood mononuclear cell (PBMC) DPD activity was determined at baseline prior to EU administration, 30 min prior to surgery (Day 1), and on Days 2, 5 and 14 following EU administration. Results: At 12–14 hours following EU administration, there was an absence of inhibition of UP and TP, while DPD was significantly inhibited in matched tumor and normal tissue. Importantly, PBMC DPD activity was significantly inhibited by EU on Day 1 (12–14 hours after EU administration) and Day 2 (36 hours after EU administration) at 0 ± 0% and 17 ± 11% (mean ± SD) of baseline, respectively. Conclusions: These data demonstrate a differential recovery time of EU mediated inhibition of UP and TP compared to DPD, which permits future schedule dependent optimization of EU/5-FU therapy. No significant financial relationships to disclose.

Improvements in first-line systemic mRCC therapy: Challenging insights from a cross trial comparison of overall survival and subsequent therapies in recent phase III trials.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 705-705
Author(s):  
Jochen Casper ◽  
Samantha Henderson ◽  
Hannah Casper ◽  
Claus-Henning Kohne
Keyword(s):  
Overall Survival ◽  
Phase Iii ◽  
Lower Percentage ◽  
Primary Study ◽  
Special Focus ◽  
The Sun ◽  
Phase Iii Clinical Trials ◽  
Phase Iii Trials ◽  
Risk Patients ◽  
Recent Phase

705 Background: Using sunitinib (SUN) as the comparator, two out of three recent phase III clinical trials have shown an overall survival (OS) benefit in the alternative treatment arm (Checkmate 214 (C), Keynote 426 (K)). The Javelin 101(J) trial has yet to show a significant improvement. Methods: A cross-study comparison of OS for the sunitinib arms of C, K and J was carried out. Special focus was given to risk group stratification and subsequent therapies. Data from the SUN pivotal trial (SP) was also taken into account. Results: Across the C, K and SP trials, OS was similar at approximately 78%. Despite a lower percentage of favourable risk patients compared to K and SP, an OS of 82% was observed in J. At 18 months, OS survival curves split ranging from 65% ©, 72.1% (K) to 76% (J). OS in the SUN arm in J at 18 months was comparable to OS of Nivolumab/Ipilimumab in C (78%). The rate of subsequent therapies ranged from 34.3% (K), 39.2% (J) to 54% (C) in the SUN arms. At the time of the SP trial almost no subsequent therapy options existed. In the experimental arms, the rate of subsequent therapies was 51.8% ©, 20.5% (K) and 20.8% (J). The existing data give no clear evidence of a correlation between subsequent therapies and OS. However, an analysis of the subsequent therapies/patients discontinuing therapy ratio (ST/DIS) and type of subsequent therapy (PD1/L1 directed or therapy with proven OS benefit (pOS) in randomized trials) in the SUN arms may be more conclusive (see table). The rate of subsequent therapies (ST/DIS) as well as PD(L)1 or pOS therapies were highest in J, followed by K and C. Conclusions: Despite the difficulties of a cross trial comparison, this data should raise awareness of the influence of a more intense subsequent therapy. It points to the necessity to standardize subsequent therapies in 1st line trials if OS is a primary study aim. Given this analysis, it may be pertinent to ask if an optimal or near optimal subsequent therapy following SUN might be equal to a 1st line IO/IO therapy with regards to OS.[Table: see text]

New and Emerging Therapies for Sepsis

2002 ◽  
Vol 36 (4) ◽  
pp. 648-654 ◽  
Author(s):  
Daniel P Healy
Keyword(s):  
Severe Sepsis ◽  
Inflammatory Response ◽  
Protein C ◽  
Drotrecogin Alfa ◽  
Activated Protein C ◽  
Antibody Fragment ◽  
Phase Iii ◽  
Human Form ◽  
Risk Of Death ◽  
Phase Iii Trials

OBJECTIVE: To review the recent advances related to the pathophysiology of sepsis and the rationale for recombinant human-activated protein C (drotrecogin alfa) and other antisepsis agents currently in Phase III trials. DATA SOURCES: A MEDLINE (1990–December 2001) search was performed to identify pertinent literature on the pathophysiology of sepsis and treatment strategies. The search was supplemented with AdisInsight (Adis International) using the search terms sepsis, severe sepsis, or septic shock combined with agents in Phase II or higher clinical development. Abstracts presented at infectious diseases and critical care meetings were also reviewed. STUDY SELECTION AND DATA EXTRACTION: Clinical efficacy studies were selected for drotrecogin alfa and other Phase III investigational agents. DATA SYNTHESIS: Our current understanding of the pathophysiology of sepsis underscores the contribution of increased coagulation and diminished fibrinolytic activity working in conjunction with an excessive and dysregulated inflammatory response. The loss of homeostatic balance among these systems results in a systemic inflammatory response with generalized coagulopathy, microvascular thrombosis, and, ultimately, acute organ failure and death. As a result of these advances, several compounds are now in various phases of development. A recombinant human form of endogenous activated protein C (drotrecogin alfa) was recently approved by the Food and Drug Administration for severe sepsis in adults who have a high risk of death. It possesses anticoagulant, profibrinolytic, and antiinflammatory properties. Other compounds currently in Phase III trials include tissue-factor pathway inhibitor, tumor-necrosis factor antibody fragment, platelet-activating factor acetylhydrolase, antithrombin III, and pyridoxylated hemoglobin polyoxyethylene. CONCLUSIONS: With the recent approval of drotrecogin alfa, there is renewed optimism that we can effectively reduce sepsis-associated mortality.

scholarly journals Gray Areas in the Gray Matter: IDH1/2 Mutations in Glioma

2020 ◽  
pp. 96-103
Author(s):  
Martin J. van den Bent ◽  
Ingo K. Mellinghoff ◽  
Ranjit S. Bindra
Keyword(s):  
Human Cancer ◽  
Acquired Resistance ◽  
Relative Sensitivity ◽  
Phase Iii ◽  
Substrate Affinity ◽  
Idh Mutations ◽  
Phase Iii Trials ◽  
Intracellular Changes ◽  
Gray Areas ◽  
Made In

Since the first discovery of isocitrate dehydrogenase ( IDH) mutations in cancer, considerable progress has been made in our understanding of their contribution to cancer development. For glioma, this has helped to identify two diagnostic groups of tumors (oligodendroglioma and astrocytoma IDHmt) with distinct clinical characteristics and that are now diagnosed by the presence of the IDH mutations. The metabolic changes occurring as the consequence of the altered substrate affinity of the mutant IDH protein results in a cascade of intracellular changes, also inducing a relative sensitivity to chemotherapy and radiotherapy compared with IDHwt tumors. Pharmacologic blockade of the mutant enzyme with first-in-class inhibitors has been efficacious for the treatment of IDH-mutant acute myeloid leukemia (AML) and is currently being evaluated in phase III trials for IDH-mutant glioma (INDIGO) and cholangiocarcinoma (ClarIDHy). It seems likely that acquired resistance to mutant IDH inhibitors will eventually emerge, and combination therapies to augment the antitumor activity of mutant IDH inhibitors have already been initiated. Approaches to exploit, rather than inhibit, the unique metabolism of IDH-mutant cancer cells have emerged from laboratory studies and are now also being tested in the clinic. Results of these clinical trials are eagerly awaited and will likely provide new key insights and direction of the treatment of IDH-mutant human cancer.

Clinical importance of including new and nontarget lesion assessment of disease progression (PD) to predict overall survival (OS): Implications for randomized phase II study design.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 2543-2543 ◽  
Author(s):  
William Leonard Mietlowski ◽  
Weichao Bao ◽  
Patricia Ann Wood ◽  
Denise E Williams ◽  
Mona El-Hashimy ◽  
...  
Keyword(s):  
Decision Making ◽  
Phase Ii ◽  
Primary Endpoint ◽  
Target Lesion ◽  
Tumor Burden ◽  
Percentage Change ◽  
Phase Iii ◽  
Risk Of Death ◽  
Randomized Phase Ii ◽  
Phase Iii Trials

2543 Background: Fridlyand (2011) retrospectively compared PFS vs. change in tumor burden as a primary endpoint in phase II non-small cell lung cancer (NSCLC) trials to inform phase III decision making and found the use of PFS was superior. Since the classic tumor burden model only uses measurements of target lesions, we investigated whether the model could be strengthened by incorporating new and non-target lesion progression. The ability to use a strong tumor burden model has the benefit of potentially earlier decision making and considerable timeline savings. Methods: We analyzed five phase III trials of combination chemotherapy ± targeted therapies with an OS primary endpoint: 1st, 2nd line NSCLC (ATTRACT-1, -2), 1st, 2nd line colorectal carcinoma (CONFIRM-1, -2), and 2nd line ovarian cancer (EPO906A2303). We applied Cox’s proportional hazards model to OS using the covariates of baseline tumor burden, 1st tumor assessment percentage change from baseline, new lesions, and non-target PD. Results: See table. Conclusions: We show that predictive models for OS should consider new and non-target lesions for PD, as well as target lesion tumor burden, findings independently corroborated by Suzuki (2011). We propose a longitudinal rank-based randomized phase II design, ranking a patient’s risk of death, differentially weighting PDs by type and time of PD, and percentage change in tumor burden. This may be more informative for phase II decision making for phase III trials based on OS, than PFS which only uses time of PD. Further studies with other tumor types and treatment modalities are warranted. [Table: see text]

Treatment-associated mortality in head and neck cancer: Analysis of phase III trials.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 6064-6064
Author(s):  
Marina Shcherba ◽  
Shankar Viswanathan ◽  
Dukagjin Blakaj ◽  
Madhur Garg ◽  
Missak Haigentz
Keyword(s):  
Relative Risk ◽  
Head And Neck ◽  
Early Death ◽  
Early Mortality ◽  
Phase Iii ◽  
Eligibility Criteria ◽  
Curative Intent ◽  
Mortality Statistics ◽  
Risk Of Death ◽  
Phase Iii Trials

6064 Background: Chemoradiotherapy is an accepted standard for patients with locoregionally advanced squamous cell carcinoma of the head and neck (SCCHN). Although acute and long-term toxicities of this approach are known, little is known about early mortality associated with curative-intent treatment. Methods: We reviewed 45 phase III trials of curative-intent radiotherapy in SCCHN published from 2000-2012 for adequate reporting of early mortality defined as deaths during and within 3 months of therapy, regardless of attribution. We estimated pooled proportions of deaths during prescribed therapy using a random effects model of radiotherapy alone (RT), concurrent chemoradiotherapy (CCRT) and induction chemotherapy (IC) regimens. The relative risk of death during CCRT vs. RT and CCRT/IC vs. RT were estimated. Results: Although all trials reported early mortality statistics, definitions had wide variability, and only 34 trials (75%) met adequate reporting characteristics. Ten trials excluded enrolled patients who died prior to initiating therapy. Of studies reporting early mortality statistics, crude frequency of death during prescribed therapy was 2.7% (308/11362). The pooled estimated rates of death observed during RT alone was 1.7% (SE: 0.3, I2=89.2%) from 29 studies, while 2.8% (SE: 0.4, I2=64.9%, 19 studies) and 3.1% (SE: 0.5, I2=53.5%, 9 studies) for CCRT and IC regimens, respectively. The pooled relative risk for death in CCRT compared to RT treatment was 1.08 (95%CI: 0.78, 1.48, p=0.63, I2=0, 15 studies). The relative risk for death in CCRT or IC therapy compared to RT was 1.06 (95%CI: 0.77, 1.45, p=0.72, I2=0, 15 studies). When reported, most early deaths were attributed to infectious complications or cardiovascular events. Conclusions: Early death remains an uncommon but important complication of curative-intent radiotherapy in SCCHN that necessitates consistent reporting. Despite strict eligibility criteria and protocol-defined care, treatment-associated death occurs with all regimens, though no clear increase was observed with CCRT/IC regimens over RT alone. Early mortality should be considered during treatment planning, particularly for patients with considerable comorbidities.

scholarly journals Level of Evidence for FDA Drug Approvals in Pivotal Clinical Trials of Hematological Malignancies

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 6-6
Author(s):  
Samer Al Hadidi ◽  
Carlos A. Ramos
Keyword(s):  
Clinical Trials ◽  
Early Phase ◽  
Hematological Malignancies ◽  
Phase Iii ◽  
Clinical Activity ◽  
Level Of Evidence ◽  
Phase Iii Clinical Trials ◽  
Early Phase Trials ◽  
Phase Iii Trials ◽  
Drug Approvals

BACKGROUND Clinical trials are integral to improve treatment outcomes for patients with hematological malignancies. Although early phase (I/II) clinical trials may provide evidence of clinical efficacy, the main goal for early phase trials is to assess safety signal. Results of phase III clinical trials provide the strongest evidence to support the use of new cancer medications. The Food and Drug Administration (FDA) is responsible to ensure appropriate control and supervision of pharmaceutical drugs. METHODS On the basis of publicly available study protocols and FDA reviews, the authors reviewed the level of evidence in 52 clinical trials supporting 49 drug approvals from 2016 to 2020. Data cut point was May 2020. These trials resulted in approval of medications to treat leukemia, non-Hodgkin lymphoma, Hodgkin lymphoma, myelodysplastic syndrome, myeloproliferative neoplasms and multiple myeloma. RESULTS A total of 52 clinical trials were assessed in the 5 years period. Phase III trials supported 61.5% while earlier phase trials supported 36.5% of subsequent FDA hematological malignancies approvals. The level of evidence to support FDA approvals improved with time with 50% of approvals in 2016 and 2017 supported by phase III clinical trials compared to 69% in 2019. Approvals were based on early phase trials in mantle cell lymphoma (100%), chronic myeloid leukemia (100%), diffuse large B cell lymphoma (100%), classic Hodgkin's lymphoma (67%) and acute myeloid leukemia (56%). Phase III trials enrolled 87% of the patients (14238 from16429 patients). Eighteen drug approvals (37% of all approvals) were based on 13% of the total number of patients in the studied period. CONCLUSIONS Level of evidence to support drug approvals in hematological malignancies was based on early phase trials in more than a third of the times. Although early phase studies are appropriate for safety signals, further clinical activity assessment should be done to support the use of new drugs to treat hematological malignancies. Previous successful early phase studies failed to show clinical activity in phase III studies. Despite the fact that use of new approved drugs based on early phase studies evidence may be needed, patients and healthcare providers should be aware of such possibility when using newly approved medications. Figure Disclosures Ramos: Novartis: Membership on an entity's Board of Directors or advisory committees; Tessa Therapeutics: Research Funding; Kuur Therapeutics: Research Funding.

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