Review of Phase II Trial Designs Used in Studies of Molecular Targeted Agents: Outcomes and Predictors of Success in Phase III

El-Maraghi, Robert H.; Eisenhauer, Elizabeth

doi:10.1200/jco.2007.13.5913

Cited by 134 publications

(83 citation statements)

References 77 publications

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“…A recent review showed that a majority of phase II trials evaluating targeted agents are single-arm studies and that objective response rate (ORR), as used in most phase II trials evaluating chemotherapy, predicts (albeit imperfectly) eventual success in phase III trials (22). However, ORRs in most phase III RCTs were lower than those in preceding phase II studies, with a mean absolute difference of 12.9% (23).…”

Section: Early-phase Clinical Trialsmentioning

confidence: 90%

Failures in Phase III: Causes and Consequences

Šeruga

Ocaña

Amir

et al. 2015

Clinical Cancer Research

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Phase III randomized controlled trials (RCT) in oncology fail to lead to registration of new therapies more often than RCTs in other medical disciplines. Most RCTs are sponsored by the pharmaceutical industry, which reflects industry's increasing responsibility in cancer drug development. Many preclinical models are unreliable for evaluation of new anticancer agents, and stronger evidence of biologic effect should be required before a new agent enters the clinical development pathway. Whenever possible, early-phase clinical trials should include pharmacodynamic studies to demonstrate that new agents inhibit their molecular targets and demonstrate substantial antitumor activity at tolerated doses in an enriched population of patients. Here, we review recent RCTs and found that these conditions were not met for most of the targeted anticancer agents, which failed in recent RCTs. Many recent phase III RCTs were initiated without sufficient evidence of activity from earlyphase clinical trials. Because patients treated within such trials can be harmed, they should not be undertaken. The bar should also be raised when making decisions to proceed from phase II to III and from phase III to marketing approval. Many approved agents showed only better progression-free survival than standard treatment in phase III trials and were not shown to improve survival or its quality. Introduction of value-based pricing of new anticancer agents would dissuade the continued development of agents with borderline activity in early-phase clinical trials. When collaborating with industry, oncologists should be more critical and better advocates for cancer patients.

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Section: Early-phase Clinical Trialsmentioning

confidence: 90%

Failures in Phase III: Causes and Consequences

Šeruga

Ocaña

Amir

et al. 2015

Clinical Cancer Research

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“…The quality of phase II data may be one of the most important factors for predicting the success of a phase III trial (7,8). However, many phase II trials prove to be of limited value in the drug development trajectory.…”

Section: Discussionmentioning

confidence: 99%

Outcomes of Phase II Clinical Trials with Single-Agent Therapies in Advanced/Metastatic Non–Small Cell Lung Cancer Published between 2000 and 2009

Janků

Berry

Gong

et al. 2012

Clinical Cancer Research

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Purpose: We analyzed the outcomes of single-agent phase II clinical trials in non-small cell lung cancer (NSCLC) to determine trial parameters that predicted clinical activity.Exoerimental Design: Data on response rate (RR), progression-free survival (PFS), and overall survival (OS) from all English language, single-agent phase II trials in advanced/metastatic NSCLC indexed by PubMed (January 2000 through December 2009) were abstracted.Results: A total of 143 single-agent phase II trials (7,701 patients) were identified. The median RR was 10%, PFS 2.8 months, and OS 7.6 months. RR and PFS correlated with OS (r ¼ 0.46, P < 0.001, r ¼ 0.52, P < 0.001, respectively) and RR correlated with PFS (r ¼ 0.61, P < 0.001). Treatment arms enriched for patients with molecular targets had a higher median RR (48.8% vs. 9.7%, P ¼ 0.005), longer median PFS (6 vs. 2.8 months, P ¼ 0.005), and OS (11.3 vs. 7.5 months, P ¼ 0.05) as compared with those of unselected patients. In multivariate analysis, only studies enriched for patients with molecular targets or including drugs that eventually gained FDA/EMA approval were associated with a higher RR, and longer PFS/OS.Conclusions: In phase II trials in NSCLC, RR and PFS correlated with OS. Studies enriched for patients with putative molecular drug targets were associated with higher therapeutic benefit as compared with those of unselected populations.

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“…Objective response by sizebased decrease in tumor, may translate to an early clinical endpoint, in substitution for overall survival [18] . AntiVEGF therapy has primarily cytostatic effects, may prune and normalize the tumor vasculature, and can have substantial systemic effects such as modulation of circulating proangiogenic and proinflammatory cytokines and cells [1924] .…”

Section: Response Biomarkermentioning

confidence: 99%

Optimal combination of antiangiogenic therapy for hepatocellular carcinoma

Chang

2015

WJH

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Review of Phase II Trial Designs Used in Studies of Molecular Targeted Agents: Outcomes and Predictors of Success in Phase III

Cited by 134 publications

References 77 publications

Failures in Phase III: Causes and Consequences

Failures in Phase III: Causes and Consequences

Outcomes of Phase II Clinical Trials with Single-Agent Therapies in Advanced/Metastatic Non–Small Cell Lung Cancer Published between 2000 and 2009

Optimal combination of antiangiogenic therapy for hepatocellular carcinoma

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