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

2019 ◽  
Vol 121 ◽  
pp. 19-28 ◽  
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

Biofeedback

2016 ◽  
Vol 4 (1) ◽  
pp. 57-63 ◽  
Author(s):  
Paul Lehrer
Keyword(s):  
Phase Ii ◽  
Real Life ◽  
Phase Iii ◽  
Controlled Trials ◽  
Clinical Environment ◽  
Phase Ii Trials ◽  
Research Support ◽  
Phase Iii Trials ◽  
Psychosomatic Problems ◽  
Biofeedback Research

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.

scholarly journals Targeting Angiogenesis in Prostate Cancer

2019 ◽  
Vol 20 (11) ◽  
pp. 2676 ◽  
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.

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

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.

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

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.

The prevalence of objectively measurable disease in phase III trials of metastatic castration-resistant prostate cancer (mCRPC).

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 215-215 ◽  
Author(s):  
Ankit Madan ◽  
Mary K Baker ◽  
Jori E May ◽  
Gurudatta Naik ◽  
Sejong Bae ◽  
...  
Keyword(s):  
Phase Ii ◽  
Bone Scan ◽  
Strong Association ◽  
Specific Antigen ◽  
Phase Iii ◽  
Disease Rate ◽  
Phase Ii Trials ◽  
Significant Difference ◽  
Measurable Disease ◽  
Phase Iii Trials

215 Background: Given the historical low prevalence of measurable disease in mCRPC, phase II trials have employed suboptimal endpoints accounting for prostate specific antigen (PSA) and bone scan changes. Changes in bone scan and PSA have not always translated to survival improvement. Improved computerized tomography technology may be increasing the proportion of men with measurable disease, suggesting that measurable changes need to be reconsidered. We analyzed phase III trials of mCRPC to systematically quantitate the proportion of mCRPC with measurable disease. Methods: Data from the both arms of published phase III trials of mCRPC were eligible for analysis. Baseline characteristics were required including the number enrolled, setting (pre-docetaxel [D], D-based, post-D), proportion of patients with measurable disease and the year of completion of trial accrual. General Linear Model was used to evaluate the difference in measurable disease rate based on setting and year of completion of accrual. Results: Seventeen phase III trials totaling 17,609 men with mCRPC were evaluable; 5160 were pre-D, 7573 were D-based and 4876 were post-D. The trials completed accrual between 2002 and 2012. Ten trials used RECIST 1.0, 5 trials used RECIST 1.1 and 2 trials used other criteria. The overall proportion of men with measurable disease was 47.8%. The measurable disease rate (range) in trials in the pre-D setting was 40.5% (30.5-57), in the D-based setting was 51.9% (29.1-87.5), and in the post-D setting was 48.9% (38.8-56.6). There was no statistical difference in the proportion of men with measurable disease based on setting or year of completion of accrual. Conclusions: The proportion of men with measurable disease in phase III trials of mCRPC completing accrual between 2002 and 2012 was 47.8%% with no significant difference based on setting or year of completing accrual. Given these higher measurable disease rates compared to historical rates and recent demonstration of strong association of RECIST changes with OS in mCRPC, RECIST changes need to be considered as a co-primary endpoint in phase II trials to obtain a firm signal of efficacy before launching phase III trials.

Where have we gone wrong? Phase II trials (Ph2t) do not inform the results of phase III trials (Ph3t) in platinum resistant ovarian cancer (PROC).

2016 ◽  
Vol 34 (15_suppl) ◽  
pp. 5559-5559 ◽  
Author(s):  
Tami Grunewald ◽  
Monica Tang ◽  
Julia Chen ◽  
Sally Lord ◽  
Michael Friedlander ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Phase Ii ◽  
Phase Iii ◽  
Phase Ii Trials ◽  
Platinum Resistant ◽  
Phase Iii Trials

scholarly journals Interval and point estimation in adaptive Phase II trials with binary endpoint

2018 ◽  
Vol 28 (9) ◽  
pp. 2635-2648 ◽  
Author(s):  
Arsénio Nhacolo ◽  
Werner Brannath
Keyword(s):  
Phase Ii ◽  
Large Scale ◽  
Interval Estimation ◽  
Point Estimation ◽  
Phase Iii ◽  
Phase Ii Trials ◽  
Sequential Designs ◽  
Group Sequential ◽  
Fixed Sample ◽  
Phase Iii Trials

Phase II clinical trials are concerned with making decision of whether a treatment is sufficiently efficacious to be worth further investigations in late large scale Phase III trials. In oncology Phase II trials, frequentist single-arm two-stage group-sequential designs with a binary endpoint are commonly used. To allow for more flexibility, adaptive versions of these designs have been proposed. In this paper, we propose point and interval estimation for adaptive designs in which the second stage sample size is a pre-specified function of first stage’s number of responses. Our approach is based on sample space orderings, from which we derive p-values, and point and interval estimates. Simulation studies show that our proposed methods perform better, in terms of bias and root mean square error, than the fixed-sample maximum likelihood estimator.

scholarly journals Accelerated Approval of Cancer Drugs: Improved Access to Therapeutic Breakthroughs or Early Release of Unsafe and Ineffective Drugs?

2009 ◽  
Vol 27 (26) ◽  
pp. 4398-4405 ◽  
Author(s):  
Elizabeth A. Richey ◽  
E. Alison Lyons ◽  
Jonathan R. Nebeker ◽  
Veena Shankaran ◽  
June M. McKoy ◽  
...  
Keyword(s):  
Orphan Drug ◽  
Phase Ii ◽  
Phase Iii ◽  
Drug Status ◽  
Cancer Drugs ◽  
Phase Ii Trials ◽  
Development Times ◽  
Phase Iii Trials ◽  
Accelerated Approval ◽  
Confirmatory Trials

Purpose Accelerated approval (AA) was initiated by the US Food and Drug Administration (FDA) to shorten development times of drugs for serious medical illnesses. Sponsors must confirm efficacy in postapproval trials. Confronted with several drugs that received AA on the basis of phase II trials and for which confirmatory trials were incomplete, FDA officials have encouraged sponsors to design AA applications on the basis of interim analyses of phase III trials. Methods We reviewed data on orphan drug status, development time, safety, and status of confirmatory trials of AAs and regular FDA approvals of new molecular entities (NMEs) for oncology indications since 1995. Results Median development times for AA NMEs (n = 19 drugs) and regular-approval oncology NMEs (n = 32 drugs) were 7.3 and 7.2 years, respectively. Phase III trials supported efficacy for 75% of regular-approval versus 26% of AA NMEs and for 73% of non–orphan versus 45% of orphan drug approvals. AA accounted for 78% of approvals for oncology NMEs between 2001 and 2003 but accounted for 32% in more recent years. Among AA NMEs, confirmatory trials were nine-fold less likely to be completed for orphan drug versus non–orphan drug indications. Postapproval, black box warnings were added to labels for four oncology NMEs (17%) that had received AA and for two oncology NMEs (9%) that had received regular approval. Conclusion AA oncology NMEs are safe and effective, although development times are not accelerated. A return to endorsing phase II trial designs for AA for oncology NMEs, particularly for orphan drug indications, may facilitate timely FDA approval of novel cancer drugs.

scholarly journals Spleen and Symptom Responses of JAK Inhibitors in Myelofibrosis; A Systematic Review of Phase 2 and 3 Trials

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 26-27
Author(s):  
Muhammad Ans Sharif ◽  
Muhammad Salman Faisal ◽  
Yazan Samhouri ◽  
Laila Hashim ◽  
Muhammad Yasir ◽  
...  
Keyword(s):  
Systematic Review ◽  
Side Effects ◽  
Phase Ii ◽  
Janus Kinase ◽  
Phase Iii ◽  
Symptom Improvement ◽  
Jak Inhibitors ◽  
Phase Ii Trials ◽  
Phase Iii Trials ◽  
Symptom Response

Background: The JAK-STAT pathway is a vital signaling pathway for various cytokines and growth factors. An abnormal upregulation of this pathway is seen in myeloproliferative disorders, especially the classic BCR-ABL negative myelofibrosis (MF). Janus kinase inhibitors (JAKi) have been evaluated in various clinical trials regarding their efficacy in improving the outcomes for MF patients. In this review, we looked at the reduction of splenomegaly and symptom improvement as markers for efficacy of JAKi. Methods: We did a comprehensive literature search, following PRISMA guidelines, on PubMed, Cochrane, clinicaltrials.gov and Embase databases. We used MeSH terms and related keywords for MF and JAKi, including generic and trade names. We screened 3261 articles and selected 23 trials for our study. Case reports, case series, meta-analysis, review articles, observational studies, phase I trials and studies not reporting spleen response were excluded. Spleen and symptom responses were used to determine the efficacy of JAK inhibitors. Spleen volume reduction (SVR) by >35%, spleen length reduction (SLR) by >50% and total symptom score (TSS) improvement by >50% were set as benchmarks for a positive response. Results: We included 23 trials (n= 4739) in our review. There were 15 phase II trials (n=964) and 8 phase III trials (n=3775). Of these 23 trials, 7 trials (n=598) included patients with median age below 65 years, while 16 trials (n=4141) included patients of median age more than 65 years. Of the 9 of trials of ruxolitinib, 4 were phase III trials (n= 2809) and 5 were phase II trials (n= 416). The dose of ruxolitinib used in these trials ranged from 5 mg twice daily to 20 mg twice daily. The percentage of patients who achieved spleen response ranged from 15.6% to 71.7%. There were 5 trials (n= 861) that evaluated efficacy of momelotinib. Three were phase II trials (n= 221), while 2 were phase III trials (n=326). The doses ranged from 150mg to 300mg. The splenic response in patients ranged from 7% to 48%. In one phase 3 randomized control trial, efficacy of momelotinib (N=215)and roxulotinib (N=217) were compared, and were found to be equally efficacious in terms of spleen response (26.5% in the momelotinib group while 29% in the ruxolitinib group) and symptom response (28.4% in the momelotinib group and 42.2% in the ruxolitinib group). In 4 trials (n= 453) of fedratinib, there were 2 phase II trials (n= 127) and 2 phase III trials (n=326). The splenic response ranged from 31% to 73% of the patient population. In phase II JAKARTA2 study, patients who were resistant or intolerant to ruxolitinib showed SVR of 31%. Lestaurtunib, Ilgitanib, pacritinib and itacitinib were studied in 2,1,1, and 1 phase II trials, respectively. The splenic response was 75%, 31%, 31%, and 68.8% respectively. Symptom response was reported in 12 studies (N=1477). The percentage of patients who achieved symptom response receiving roxulotinib were 20.8-49%, momelotinib (28.4-30.7%), ictatinib (51.1-59.4%), practinib (48%), and fedratinib (27-36%). In terms of safety, the most common hematological side effects seen were anemia (15% - 65%), thrombocytopenia (1.3% - 64%) and neutropenia (1% - 28%). These side effects were seen equally with different medications. The most common non hematological adverse effects included diarrhea (4% - 32%), abdominal pain (2.6% - 27.1%) and fatigue (1.3% - 10%). Conclusion Splenomegaly and associated symptoms are major source of morbidity in MF patients. The rapid advancement in novel agents in the last decade changed the treatment paradigm in this disorder. Our systematic review summarizes the effect of JAKi on spleen and symptom responses. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau. Fazal:Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Speakers Bureau; Karyopharm: Speakers Bureau; Incyte: Honoraria, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Agios: Consultancy, Speakers Bureau; GlaxoSmithKline: Consultancy, Speakers Bureau; Gilead/Kite: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Stemline: Consultancy, Speakers Bureau; Jazz: Consultancy, Speakers Bureau; Janssen: Speakers Bureau.

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