The disconnect between phase II and phase III trials of drugs for heart failure

Although evidence supports the efficacy of biofeedback for treating a number of disorders and for enhancing performance, significant barriers block both needed research and payer support for this method. Biofeedback has demonstrated effects in changing psychophysiological substrates of various emotional, physical, and psychosomatic problems, but payers are reluctant to reimburse for biofeedback services. A considerable amount of biofeedback research is in the form of relatively small well-controlled trials (Phase II trials). This article argues for greater payer support and research support for larger trials in the “real life” clinical environment (Phase III trials) and meta-analytic reviews.

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Targeting Angiogenesis in Prostate Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms20112676 ◽

2019 ◽

Vol 20 (11) ◽

pp. 2676 ◽

Cited By ~ 17

Author(s):

Zsombor Melegh ◽

Sebastian Oltean

Keyword(s):

Prostate Cancer ◽

Phase Ii ◽

Phase Iii ◽

Refractory Disease ◽

Phase Ii Trials ◽

Angiogenic Activity ◽

Angiogenic Therapy ◽

Resistant Refractory ◽

Castration Resistant ◽

Phase Iii Trials

Prostate cancer is the most commonly diagnosed cancer among men in the Western world. Although localized disease can be effectively treated with established surgical and radiopharmaceutical treatments options, the prognosis of castration-resistant advanced prostate cancer is still disappointing. The objective of this study was to review the role of angiogenesis in prostate cancer and to investigate the effectiveness of anti-angiogenic therapies. A literature search of clinical trials testing the efficacy of anti-angiogenic therapy in prostate cancer was performed using Pubmed. Surrogate markers of angiogenic activity (microvessel density and vascular endothelial growth factor A (VEGF-A) expression) were found to be associated with tumor grade, metastasis, and prognosis. Six randomizedstudies were included in this review: two phase II trials on localized and hormone-sensitive disease (n = 60 and 99 patients) and four phase III trials on castration-resistant refractory disease (n = 873 to 1224 patients). Although the phase II trials showed improved relapse-free survival and stabilisation of the disease, the phase III trials found increased toxicity and no significant improvement in overall survival. Although angiogenesis appears to have an important role in prostate cancer, the results of anti-angiogenic therapy in castration-resistant refractory disease have hitherto been disappointing. There are various possible explanations for this lack of efficacy in castration-resistant refractory disease: redundancy of angiogenic pathways, molecular heterogeneity of the disease, loss of tumor suppressor protein phosphatase and tensin homolog (PTEN) expression as well as various VEGF-A splicing isoforms with pro- and anti-angiogenic activity. A better understanding of the molecular mechanisms of angiogenesis may help to develop effective anti-angiogenic therapy in prostate cancer.

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Comparison of treatment effect from randomised controlled phase II trials and subsequent phase III trials using identical regimens in the same treatment setting

European Journal of Cancer ◽

10.1016/j.ejca.2019.08.006 ◽

2019 ◽

Vol 121 ◽

pp. 19-28 ◽

Cited By ~ 4

Author(s):

Fei Liang ◽

Zhenyu Wu ◽

Miao Mo ◽

Changming Zhou ◽

Jie Shen ◽

...

Keyword(s):

Phase Ii ◽

Treatment Effect ◽

Treatment Setting ◽

Phase Iii ◽

Phase Ii Trials ◽

Phase Iii Trials ◽

Subsequent Phase ◽

Randomised Controlled

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Anti-Angiogenic Agents in Management of Sarcoma Patients: Overview of Published Trials

Frontiers in Oncology ◽

10.3389/fonc.2020.594445 ◽

2020 ◽

Vol 10 ◽

Author(s):

Pierre-Yves Cren ◽

Loïc Lebellec ◽

Thomas Ryckewaert ◽

Nicolas Penel

Keyword(s):

Soft Tissue ◽

Soft Tissue Sarcoma ◽

Phase Ii ◽

Progression Free Survival ◽

Phase Iii ◽

Phase Ii Trials ◽

Double Blind ◽

Multikinase Inhibitors ◽

Randomized Phase Ii ◽

Phase Iii Trials

We reviewed all fully published clinical trials assessing anti-angiogenic agents in sarcoma patients (last issue, January 13, 2020). Anti-angiogenic macromolecules (e.g., bevacizumab or ombrabulin) provide disappointing results. Many multikinase inhibitors have been assessed with non-randomized phase II trials with limited samples and without stratification according to histological subtypes, therefore interpretation of such trials is very challenging. On the contrary, pazopanib, regorafenib, and sorafenib have been assessed using double-blind placebo-controlled randomized phase II or phase III trials. Compared to placebo, sorafenib demonstrates activity in desmoid-type fibromatosis patients. Based on results of phase 3 trial, pazopanib had obtained approval for treatment of pretreated non-adipocytic soft tissue sarcoma. Regorafenib is currently assessed in several clinical settings and provides significant improvement of progression-free survival in pre-treated non-adipocytic soft tissue sarcoma and in advanced pretreated osteosarcoma. Multikinase inhibitors are a breakthrough in sarcoma management. Many trials are ongoing. Nevertheless, predictive factors are still missing.

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Phase II Trial of 4′-Epi-Doxorubicin in Locally Advanced or Metastatic Gastric Cancer

Tumori Journal ◽

10.1177/030089168807400312 ◽

1988 ◽

Vol 74 (3) ◽

pp. 313-315 ◽

Cited By ~ 2

Author(s):

Eduardo Cazap ◽

Roberto Estevez ◽

Mario Bruno ◽

Daniel Levy ◽

Carlos Algamiz ◽

...

Keyword(s):

Gastric Cancer ◽

Gastric Adenocarcinoma ◽

Phase Ii ◽

Response Rate ◽

Phase Ii Trial ◽

Locally Advanced ◽

Metastatic Gastric Cancer ◽

Phase Iii ◽

Future Studies ◽

Phase Iii Trials

Patients with locally advanced or metastatic gastric adenocarcinoma received an i.v. bolus of 4′-epi-doxorubicin, 75/mg/m2/cycle, every 21 days. Partial responses were observed in 5 of 23 evaluable patients (21.7%). Treatment was generally well tolerated and toxicity was mild. The response rate to epirubicin appears to be very similar to that reported for doxorubicin. Larger doses of epirubicin could be safely used in future studies, and further evaluation of epirubicin in phase III trials is indicated.

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Pooled Analysis of external-beam RADiotherapy parameters in phase II and phase III trials in radiochemotherapy in Anal Cancer (PARADAC)

European Journal of Cancer ◽

10.1016/j.ejca.2019.08.022 ◽

2019 ◽

Vol 121 ◽

pp. 130-143 ◽

Cited By ~ 1

Author(s):

Eleonor Rivin del Campo ◽

Oscar Matzinger ◽

Karin Haustermans ◽

Didier Peiffert ◽

Robert Glynne-Jones ◽

...

Keyword(s):

Phase Ii ◽

Anal Cancer ◽

External Beam Radiotherapy ◽

Pooled Analysis ◽

Phase Iii ◽

External Beam ◽

Phase Iii Trials

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Interleukin-1 and the Inflammasome as Therapeutic Targets in Cardiovascular Disease

Circulation Research ◽

10.1161/circresaha.120.315937 ◽

2020 ◽

Vol 126 (9) ◽

pp. 1260-1280 ◽

Cited By ~ 32

Author(s):

Antonio Abbate ◽

Stefano Toldo ◽

Carlo Marchetti ◽

Jordana Kron ◽

Benjamin W. Van Tassell ◽

...

Keyword(s):

Myocardial Infarction ◽

Heart Failure ◽

Acute Myocardial Infarction ◽

Cardiovascular Diseases ◽

Phase Ii ◽

Nlrp3 Inflammasome ◽

Wide Spectrum ◽

Phase Iii ◽

Intracellular Sensing ◽

Inflammasome Inhibitors

The intracellular sensing protein termed NLRP3 (for NACHT, LRR, and PYD domains-containing protein 3) forms a macromolecular structure called the NLRP3 inflammasome. The NLRP3 inflammasome plays a major role in inflammation, particularly in the production of IL (interleukin)-1β. IL-1β is the most studied of the IL-1 family of cytokines, including 11 members, among which are IL-1α and IL-18. Here, we summarize preclinical and clinical findings supporting the key pathogenetic role of the NLRP3 inflammasome and IL-1 cytokines in the formation, progression, and complications of atherosclerosis, in ischemic (acute myocardial infarction), and nonischemic injury to the myocardium (myocarditis) and the progression to heart failure. We also review the clinically available IL-1 inhibitors, although not currently approved for cardiovascular indications, and discuss other IL-1 inhibitors, not currently approved, as well as oral NLRP3 inflammasome inhibitors currently in clinical development. Canakinumab, IL-1β antibody, prevented the recurrence of ischemic events in patients with prior acute myocardial infarction in a large phase III clinical trial, including 10 061 patients world-wide. Phase II clinical trials show promising data with anakinra, recombinant IL-1 receptor antagonist, in patients with ST-segment–elevation acute myocardial infarction or heart failure with reduced ejection fraction. Anakinra also improved outcomes in patients with pericarditis, and it is now considered standard of care as second-line treatment for patients with recurrent/refractory pericarditis. Rilonacept, a soluble IL-1 receptor chimeric fusion protein neutralizing IL-1α and IL-1β, has also shown promising results in a phase II study in recurrent/refractory pericarditis. In conclusion, there is overwhelming evidence linking the NLRP3 inflammasome and the IL-1 cytokines with the pathogenesis of cardiovascular diseases. The future will likely include targeted inhibitors to block the IL-1 isoforms, and possibly oral NLRP3 inflammasome inhibitors, across a wide spectrum of cardiovascular diseases.

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Promise of autologous CD34+ stem/progenitor cell therapy for treatment of cardiovascular disease

Cardiovascular Research ◽

10.1093/cvr/cvaa027 ◽

2020 ◽

Vol 116 (8) ◽

pp. 1424-1433 ◽

Cited By ~ 4

Author(s):

Megha Prasad ◽

Michel T Corban ◽

Timothy D Henry ◽

Allan B Dietz ◽

Lilach O Lerman ◽

...

Keyword(s):

Heart Failure ◽

Cell Therapy ◽

Therapeutic Potential ◽

Microvascular Disease ◽

Microvascular Dysfunction ◽

Therapeutic Angiogenesis ◽

Phase Iii ◽

Potential Safety ◽

Cd34 Cells ◽

Phase Iii Trials

Abstract CD34+ cells are haematopoietic stem cells used therapeutically in patients undergoing radiation or chemotherapy due to their regenerative potential and ability to restore the haematopoietic system. In animal models, CD34+ cells have been associated with therapeutic angiogenesis in response to ischaemia. Several trials have shown the potential safety and efficacy of CD34+ cell delivery in various cardiovascular diseases. Moreover, Phase III trials have now begun to explore the potential role of CD34+ cells in treatment of both myocardial and peripheral ischaemia. CD34+ cells have been shown to be safe and well-tolerated in the acute myocardial infarction (AMI), heart failure, and angina models. Several studies have suggested potential benefit of CD34+ cell therapy in patients with coronary microvascular disease as well. In this review, we will discuss the therapeutic potential of CD34+ cells, and describe the pertinent trials that have used autologous CD34+ cells in no-options refractory angina, AMI, and heart failure. Lastly, we will review the potential utility of autologous CD34+ cells in coronary endothelial and microvascular dysfunction.

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Ethical guidelines for deliberately infecting volunteers with COVID-19

Journal of Medical Ethics ◽

10.1136/medethics-2020-106322 ◽

2020 ◽

Vol 46 (8) ◽

pp. 502-504 ◽

Cited By ~ 4

Author(s):

Adair D Richards

Keyword(s):

Phase Ii ◽

Development Time ◽

Ethics Committees ◽

Phase Iii ◽

Ethical Standards ◽

Ethical Guidelines ◽

Phase Iii Trials

Global fatalities related to COVID-19 are expected to be high in 2020–2021. Developing and delivering a vaccine may be the most likely way to end the pandemic. If it were possible to shorten this development time by weeks or months, this may have a significant effect on reducing deaths. Phase II and phase III trials could take less long to conduct if they used human challenge methods—that is, deliberately infecting participants with COVID-19 following inoculation. This article analyses arguments for and against such methods and provides suggested broad guidelines for regulators, researchers and ethics committees when considering these matters. It concludes that it may be possible to maintain current ethical standards yet still permit human challenge trials in a context where delay is critical. The implications are that regulators and researchers need to work together now to design robust but short trials and streamline ethics approval processes so that they are in place when applications for trials are made.

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Capecitabine and irinotecan (XELIRI) in first-line treatment of metastatic colorectal cancer (mCRC): A systematic review of controlled clinical trials

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.e15100 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. e15100-e15100

Author(s):

S. Sukumaran ◽

N. Pavlakis ◽

K. B. Pittman ◽

K. Patterson ◽

T. J. Price

Keyword(s):

Phase Ii ◽

Phase Iii ◽

Line Treatment ◽

Phase Ii Trials ◽

First Line ◽

Hand Foot Syndrome ◽

Phase Iii Trials ◽

Grade 3 ◽

Phase Ii And Iii ◽

First Line Treatment

e15100 Background: Irinotecan and 5-Fluorouracil based combination is an effective regimen for mCRC. Capecitabine, an oral fluoropyrimidine, is a convenient alternative to intravenous 5- Fluorouracil. This study aims to systematically review all published and unpublished controlled phase II and III trials of XELIRI combination, used in first line treatment of mCRC, reported from 2000–2008, to describe its efficacy and safety. Methods: A literature search of MEDLINE, EMBASE, CINAHL and proceedings from ASCO, ESMO and WGIC was conducted. The primary end point was response rate (RR), secondary endpoints include: time to progression (TTP), overall survival (OS) and toxicity. Results: Thirty non-randomised phase II trials (n = 1380) along with 6 randomised phase II and 3 phase III trials, were included (pooled n = 1478). The daily dose of capecitabine ranged from 1,800 mg/m2 to 2,500 mg/m2 for 7 to 14 days per cycle and the dose of irinotecan varied from 180mg/m2 to 350 mg/m2, over a 3 week period per cycle. Amongst the non-randomised studies, the median patient age was 61 years (53–72).The median RR was 46.75% (25–78%). The median reported TTP was 7.9 months (mo) (5- 9.9 mo) and the median OS was 15.6 months (7–24.8 mo). Grade 3–4 toxicity incidence was: diarrhoea (21.5%), neutropenia (12%), vomiting (12.5%), fatigue (6%) and Hand-foot syndrome (6%). The pooled incidence of febrile neutropenia was 2.5%. Amongst the randomised trials, the comparator regimens were XELOX or FOLFIRI. Median age was 65 years (61–74). RR for XELIRI was 39% (34–56%) compared to 47% (27–61.8%) for the non XELIRI comparator arms. Median reported TTP was 8.2 mo (5.7–12.5 mo) for the XELIRI arms and 9.2 mo for the comparator arms. Conclusions: XELIRI is an effective and feasible regime in the first line management of mCRC. However the optimal role of this combination remains to be established. No significant financial relationships to disclose.

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