Targeted agents: How to select the winners in preclinical and early clinical studies?

Goodwin, Rachel; Giaccone, Giuseppe; Calvert, Hilary; Lobbezoo, Marinus W.; Eisenhauer, Elizabeth

doi:10.1016/j.ejca.2011.09.024

Cited by 33 publications

(15 citation statements)

References 10 publications

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“…Because of the limited size and statistical uncertainty of phase II trials, that decision will always be imperfect but it will be strengthened by (i) the observation of a predefined threshold of activity, and (ii) pharmacodynamic (PD) studies confirming proof-of-concept that the agent is inhibiting its target (18). Results of our survey indicate that many phase III trials proceed despite a threshold of activity not being reached in phase II evaluation, and few include PD studies to confirm target inhibition.…”

Section: Early-phase Clinical Trialsmentioning

confidence: 99%

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: 99%

Failures in Phase III: Causes and Consequences

Šeruga

Ocaña

Amir

et al. 2015

Clinical Cancer Research

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“…Targeted agents, however, may have more favorable toxicity profiles because they are designed to inhibit molecular aberrations specific to cancer cells, and high doses that induce toxicity may not correlate with greater efficacy. Targeted drugs, such as kinase inhibitors, may require an alternative metric to MTD that defines the dose-response relationship using suitable pharmacodynamic or other endpoints (4,5).…”

Section: Introductionmentioning

confidence: 99%

Dose Selection, Pharmacokinetics, and Pharmacodynamics of BRAF Inhibitor Dabrafenib (GSK2118436)

Falchook

Long

Kurzrock

et al. 2014

Clinical Cancer Research

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Purpose: Dabrafenib is a selective, potent ATP-competitive inhibitor of the BRAFV600-mutant kinase that has demonstrated efficacy in clinical trials. We report the rationale for dose selection in the first-inhuman study of dabrafenib, including pharmacokinetics, tissue pharmacodynamics, 2[18F]fluoro-2-deoxy-D-glucose-positron emission tomography (FDG-PET) pharmacodynamics, and dose-response relationship.Experimental Design: Dabrafenib was administered orally once, twice (BID), or three times daily (TID). Selected dose cohorts were expanded to collect adequate data on safety, pharmacokinetics, or pharmacodynamics. A recommended phase II dose (RP2D) was chosen based on safety, pharmacokinetic, pharmacodynamic, and response data.Results: One hundred and eighty-four patients were enrolled and treated with doses ranging from 12 mg once daily to 300 mg BID in 10 cohorts. Pharmacokinetic assessment of dabrafenib demonstrated a lessthan-dose-proportional increase in exposure after repeat dosing above 150 mg BID. Similar to parent drug concentrations, exposure for all metabolites demonstrated less-than-dose-proportional increases. Predicted target inhibition of pERK (>80%) was achieved at 150 mg BID, with a similar magnitude of inhibition at higher doses in BRAFV600 mutation melanoma biopsy samples. Although there was large variability between patients, FDG uptake decreased with higher daily doses in patients with BRAFV600 mutationpositive melanoma. A favorable activity and tolerability profile was demonstrated at 150 mg BID. There was no improvement with TID dosing compared with BID dosing, based on FDG-PET and tumor response analyses in patients with melanoma.Conclusion: The RP2D of dabrafenib was determined to be 150 mg BID after considering multiple factors, including pharmacokinetics, tissue pharmacodynamics, FDG-PET pharmacodynamics, and the dose-response relationship. A maximum tolerated dose for dabrafenib was not determined. Clin Cancer Res; 20(17); 4449-58. Ó2014 AACR.

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“…Despite this limitation, cell lines are very useful for the initial characterization of potential anticancer compounds for their low cost compared to other more complex systems and the feasibility to perform high-throughput screening. The selection of successful candidates (“winners”) for early clinical trials is recognized as a crucial aspect of the drug screening program [25]. As seen in the algorithm depicted in Figure 1, all GO decisions are made after tests in animal models.…”

Section: Discussionmentioning

confidence: 99%

An Algorithm for the Preclinical Screening of Anticancer Drugs Effective against Brain Tumors

Yakisich

2012

ISRN Pharmacology

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The anticancer drugs screening program is a long and expensive process. It is estimated that only 5% of drugs entering clinical trials are approved by the FDA. Moreover, many of the drugs that enter clinical trials are often of limited use in clinical practice, and most cancers remain untreatable. Brain tumors are particularly difficult to treat due to the presence of the blood brain barrier that limits the penetration of anticancer drugs. Additionally the isolation from most brain tumors of putative cancer stem cells and novel models of cancer stem cell biology suggest that anticancer drugs should be delivered for prolonged time and at higher concentrations to deplete any potential tumorigenic cell. In this paper, current concepts of cancer stem cell biology and novel concepts of anticancer drugs screening are integrated to develop a seven-steps algorithm as a guideline for the preclinical evaluation of active compounds for the treatment of brain tumors. The flexibility of the algorithm allows the inclusion of alternative studies to exhaustively investigate anticancer drugs and creates multiple opportunities where decisions to engage or not in early clinical trials can be made providing a useful tool for translational research in neurooncology.

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Targeted agents: How to select the winners in preclinical and early clinical studies?

Cited by 33 publications

References 10 publications

Failures in Phase III: Causes and Consequences

Failures in Phase III: Causes and Consequences

Dose Selection, Pharmacokinetics, and Pharmacodynamics of BRAF Inhibitor Dabrafenib (GSK2118436)

An Algorithm for the Preclinical Screening of Anticancer Drugs Effective against Brain Tumors

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