Targeted Therapy Trials: Approval Strategies, Target Validation, or Helping Patients?

Hoff, Paulo M.; Ellis, Lee M.

doi:10.1200/jco.2006.09.8384

Cited by 14 publications

(8 citation statements)

References 8 publications

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“…The paradigm of oncology drug development is expanding from traditional cytotoxic agents to biological agents (Hoff and Ellis, 2007;Mandrekar and Sargent, 2009). Examples of biological agents include biospecimens targeting a specific tumour pathway, gene products aiming for DNA repair and immunotherapies stimulating the immune system to attack a tumour.…”

Section: Introductionmentioning

confidence: 99%

A Bayesian Dose Finding Design for Oncology Clinical Trials of Combinational Biological Agents

Cai

Yuan

2013

Journal of the Royal Statistical Society Series C: Applied Statistics

121

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Treating patients with novel biological agents is becoming a leading trend in oncology. Unlike cytotoxic agents, for which efficacy and toxicity monotonically increase with dose, biological agents may exhibit non-monotonic patterns in their dose-response relationships. Using a trial with two biological agents as an example, we propose a dose-finding design to identify the biologically optimal dose combination (BODC), which is defined as the dose combination of the two agents with the highest efficacy and tolerable toxicity. A change-point model is used to reflect the fact that the dose-toxicity surface of the combinational agents may plateau at higher dose levels, and a flexible logistic model is proposed to accommodate the possible non-monotonic pattern for the dose-efficacy relationship. During the trial, we continuously update the posterior estimates of toxicity and efficacy and assign patients to the most appropriate dose combination. We propose a novel dose-finding algorithm to encourage sufficient exploration of untried dose combinations in the two-dimensional space. Extensive simulation studies show that the proposed design has desirable operating characteristics in identifying the BODC under various patterns of dose-toxicity and dose-efficacy relationships.

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Section: Introductionmentioning

confidence: 99%

A Bayesian Dose Finding Design for Oncology Clinical Trials of Combinational Biological Agents

Cai

Yuan

2013

Journal of the Royal Statistical Society Series C: Applied Statistics

121

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“…Moreover, the same may be applied to other RTK inhibitors in a variety of cancers. For example, for unknown reasons, tumor EGFR status does not predict the response of colorectal cancers to EGFR inhibitors (59). Extrapolation of our results suggests that antiapoptotic proteins may be an important biomarker predictive of response to treatment with RTK inhibitors and that targeting the apoptotic pathway in conjunction with RTK inhibition may have the potential to further improve tumor responses.…”

Section: Discussionmentioning

confidence: 75%

Resistance of human glioblastoma multiforme cells to growth factor inhibitors is overcome by blockade of inhibitor of apoptosis proteins

Ziegler¹,

Wright²,

Kesari³

et al. 2008

J. Clin. Invest.

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Multiple receptor tyrosine kinases (RTKs), including PDGFR, have been validated as therapeutic targets in glioblastoma multiforme (GBM), yet inhibitors of RTKs have had limited clinical success. As various antiapoptotic mechanisms render GBM cells resistant to chemo-and radiotherapy, we hypothesized that these antiapoptotic mechanisms also confer resistance to RTK inhibition. We found that in vitro inhibition of PDGFR in human GBM cells initiated the intrinsic pathway of apoptosis, as evidenced by mitochondrial outer membrane permeabilization, but downstream caspase activation was blocked by inhibitor of apoptosis proteins (IAPs). Consistent with this, inhibition of PDGFR combined with small molecule inactivation of IAPs induced apoptosis in human GBM cells in vitro and had synergistic antitumor effects in orthotopic mouse models of GBM and in primary human GBM neurospheres. These results demonstrate that concomitant inhibition of IAPs can overcome resistance to RTK inhibitors in human malignant GBM cells, and suggest that blockade of IAPs has the potential to improve treatment outcomes in patients with GBM.

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“…1 Although it seems that the authors mostly agree with our initial comments, we think it is important to clarify a few issues. To those less familiar with the Latin literature, "cui prodest" is a well-known expression, popular since its use in Cicero's work.…”

mentioning

confidence: 74%

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Hoff

Ellis

2007

JCO

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Targeted Therapy Trials: Approval Strategies, Target Validation, or Helping Patients?

Cited by 14 publications

References 8 publications

A Bayesian Dose Finding Design for Oncology Clinical Trials of Combinational Biological Agents

A Bayesian Dose Finding Design for Oncology Clinical Trials of Combinational Biological Agents

Resistance of human glioblastoma multiforme cells to growth factor inhibitors is overcome by blockade of inhibitor of apoptosis proteins

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