Vaccine-induced immune responses against SARS-CoV-2 infections

Vaccination against coronavirus disease 2019 (COVID-19) is one of the most effective tools to curb the pandemic. Multiple vaccine candidates based on different platforms are available for emergency use presently. However, in common all the vaccines target spike protein, which is a dominant immunogen of severe acute respiratory syndrome corona virus 2 (SARS-CoV-2). Adequate immunogenicity and efficacy are demonstrated by many of the vaccines in clinical phase III trials. The emergence of the new variant of concern is believed to be associated with less susceptibility to the post-infection or post-vaccination mounted immunity. It is a global concern currently threatening the progression of the vaccination drive. Nevertheless, the results of the presently available phase III clinical trials promote COVID-19 vaccination to prevent disease severity and COVID-19 related deaths. Cross-immunity towards the new variants of concern especially against the South African variant is yet to be explored and managed adequately.

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A Review of Phase III Clinical Trials of Prostate Cancer Chemoprevention

Annals of The Royal College of Surgeons of England ◽

10.1308/003588407x179125 ◽

2007 ◽

Vol 89 (3) ◽

pp. 207-211 ◽

Cited By ~ 18

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.

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Current Vaccine Trials in Glioblastoma: A Review

Journal of Immunology Research ◽

10.1155/2014/796856 ◽

2014 ◽

Vol 2014 ◽

pp. 1-10 ◽

Cited By ~ 32

Author(s):

Linda W. Xu ◽

Kevin K. H. Chow ◽

Michael Lim ◽

Gordon Li

Keyword(s):

Immune Responses ◽

Primary Brain Tumor ◽

Phase Iii ◽

Tumor Vaccines ◽

Vaccine Trials ◽

Average Survival ◽

Current Vaccine ◽

Phase Iii Trials ◽

Future Care ◽

Potential Impact

Glioblastoma (GBM) is the most common primary brain tumor, and despite aggressive therapy with surgery, radiation, and chemotherapy, average survival remains at about 1.5 years. The highly infiltrative and invasive nature of GBM requires that alternative treatments for this disease be widespread and targeted to tumor cells. Immunotherapy in the form of tumor vaccines has the potential to meet this need. Vaccines against GBM hold the promise of triggering specific and systemic antitumor immune responses that may be the key to eradicating this unrelenting cancer. In this review, we will discuss past and present clinical trials of various GBM vaccines and their potential impact on the future care of GBM patients. There have been many promising phase I and phase II GBM vaccine studies that have led to ongoing and upcoming phase III trials. If the results of these randomized trials show a survival benefit, immunotherapy will become a standard part of the treatment of this devastating disease.

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

Journal of Clinical Oncology ◽

10.1200/jco.2015.62.8065 ◽

2016 ◽

Vol 34 (3) ◽

pp. 280-285 ◽

Cited By ~ 23

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.

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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

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.2557 ◽

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.

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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.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.6_suppl.705 ◽

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]

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

10.1101/2020.08.07.20170456 ◽

2020 ◽

Cited By ~ 5

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.

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

Blood ◽

10.1182/blood-2020-136330 ◽

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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The treatment of glioblastomas: A systematic update on clinical Phase III trials

Critical Reviews in Oncology/Hematology ◽

10.1016/j.critrevonc.2013.01.007 ◽

2013 ◽

Vol 87 (3) ◽

pp. 265-282 ◽

Cited By ~ 23

Author(s):

An-an Yin ◽

Jin-xiang Cheng ◽

Xiang Zhang ◽

Bo-lin Liu

Keyword(s):

Phase Iii ◽

Clinical Phase ◽

Phase Iii Trials

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Do post-approval phase III trials for accelerated approved cancer drugs violate equipoise?

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.6026 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 6026-6026 ◽

Cited By ~ 1

Author(s):

A. J. Lurie ◽

B. Djulbegovic ◽

J. R. Nebeker ◽

C. Angelotta ◽

L. I. Gordon ◽

...

Keyword(s):

Clinical Trials ◽

Phase Iii ◽

Necessary Condition ◽

Marketing Approval ◽

The Novel ◽

Cancer Drugs ◽

Novel Therapy ◽

Phase Iii Clinical Trials ◽

Phase Iii Trials ◽

Accelerated Approval

6026 Background: Since 1992, the Food and Drug Administration (FDA) has allowed accelerated approval of novel cancer drugs based on improvements in surrogate outcomes, provided that subsequent phase III trials, in compliance with subpart H, show evidence of clinical benefits. However, drugs that receive accelerated approval must already show promise, making it difficult to recruit for randomized studies in which patients might get other drugs which are likely to be inferior. We evaluated whether drugs granted accelerated approval were just as likely to be superior as inferior to standard therapy during phase III clinical trials, a necessary condition known as equipoise, which is used as the ethical basis for recruitment. Methods: Descriptions of marketing approval decisions and subpart H commitments for all drugs that received accelerated approval for oncology indications between 1992 and 2005 were obtained from the FDA website, transcripts of the Oncologic Drug Advisory Committee of the FDA, and PubMed searches. Results: Accelerated approval has been granted for 25 drugs and 29 indications. These approvals have been based on phase II clinical trials (23 indications) or phase III trials (6 indications). 14 approvals were for novel cancer therapeutic drugs. Post-approval phase III clinical trials, outlined in subpart H commitments, have been reported for 9 indications associated with common cancers of the colon, lung, or breast, and 1 indication associated with multiple myeloma, a less common cancer, for which 9 studies identified improved clinical outcomes with the accelerated approved drug. Of 15 drugs that received accelerated approval prior to 2003 for cancers that affect small numbers of patients, 13 are years behind planned recruitment milestones for post-approval phase III trials. Conclusion: While the equipoise theory would predict that 50% of the completed phase III trials would support the novel therapy, empirical data have identified that 90% of the studies required by subpart H commitments support the novel therapy. Therefore, it is likely to hinder recruitment to ongoing phase III trials evaluating other accelerated approved cancer drugs. No significant financial relationships to disclose.

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