Biomedical subjects

Catherine Wheeler

Publications and source records attributed to Catherine Wheeler.

7 recordsLinked to original sources

PubMed2006

Improving the design of phase II trials of cytostatic anticancer agents.

This paper examines the design of phase II trials in oncology and recommends departing from the traditional uncontrolled trial design. Entrance into phase II clinical evaluation represents a key milestone in the development of any new cancer therapy. As novel molecular-targeted therapies are introduced, whose primary action is to slow the growth of tumors, it will be important to ensure that the clinical trial design will effectively capture any clinical benefit of these agents. The objective of a phase II trial should, in addition to identifying active therapies, be extended to identifying those that are likely to be successful in pivotal trials. It is therefore necessary to quantify the likelihood of either incorrectly halting the development of an active agent or continuing development of an ineffective agent. We believe only randomized studies with comparative intent and including a concurrent active control, can reliably assess these risks corresponding to significance and power. Given that the objective of phase II studies is to identify promising treatments, it is important not be constrained by conventional levels of significance. This paper will review the various approaches to phase II trial design in oncology and provide a framework for fully powered randomized trials of a moderate size. For example, a randomized trial of just 100 patients could lead to the termination of development of 90% of inactive agents whereas at least 80% of agents with a meaningful and realistic increase in progression-free survival would be identified for confirmatory study. We believe randomized studies with progression-free survival endpoints are the most powerful and economical method of determining the clinical activity of new cytostatic agents.

Algorithms↗

PubMed2006

Optimizing randomized phase II trials assessing tumor progression.

The traditional development paradigm for phase II trials in oncology has been challenged in recent years by the introduction of cytostatic therapies. These agents slow the growth of tumors rather than cause high rates of shrinkage, this argues for the use of endpoints that measure growth inhibition such as progression free survival. We have previously argued the need for randomized trials in this setting. Here we discuss methodological solutions to enhance the development decision at the end of phase II in the context of progression endpoints employed in randomized trials. There are well recognized issues associated with progression endpoints relating to bias in the timing and interpretation of assessments. In this paper we present design and analysis solutions that will minimize bias by using methods that are either partially or completely time independent. We also discuss other design features to maximize the information yielded in a phase II setting. We advocate the creation of progression endpoints that utilize all available progression data rather than early fixed time-point analyses and show that little is to be gained by assessing progression status any more frequently than would be required in routine clinical practice. Such design and analysis measures will optimize the development decision made at the end of phase II clinical evaluation.

Algorithms↗

PubMed2006

Phase I clinical evaluation of weekly administration of the novel vascular-targeting agent, ZD6126, in patients with solid tumors.

PURPOSE: ZD6126 is a novel vascular-targeting agent that induces selective effects on the morphology of endothelial cells by disrupting the tubulin cytoskeleton. This leads to cell detachment and tumor vessel congestion, resulting in extensive central necrosis in a range of tumor xenograft models. Results from a phase I dose-escalation study of ZD6126 are reported. PATIENTS AND METHODS: Thirty-two patients with advanced cancer received weekly ZD6126 infusion (5 to 28 mg/m2). Assessments for safety and pharmacokinetics were performed. Circulating endothelial cells (CECs) were quantified as a pharmacodynamic marker of vascular damage. RESULTS: Maximum concentrations of the active species were observed 5 to 25 minutes from the start of infusion, and decayed in a biexponential manner with a half-life of 1 to 3 hours. Maximum serum concentration and area under the time-concentration curve increased with dose in a linear fashion across the dose range of 5 to 28 mg/m2. One patient treated at 10 mg/m2 with a history of ischemic heart disease experienced acute myocardial infarction 2 weeks after drug discontinuation. Four others had asymptomatic creatine phosphokinase-muscle-brain elevation. Maximum-tolerated dose (MTD) was reached at 20 mg/m2/wk. Dose-limiting toxicities at 28 mg/m2 were hypoxia caused by pulmonary embolism and an asymptomatic decrease in left ventricular ejection fraction. No objective antitumor responses were observed. CEC levels increased in the hours after infusion, indicating potential effect of the compound on the vasculature. CONCLUSION ZD6126 administered as a weekly infusion was clinically well tolerated. The MTD was reached at 20 mg/m2.

Adult↗

PubMed2005

ZD6474, a novel tyrosine kinase inhibitor of vascular endothelial growth factor receptor and epidermal growth factor receptor, inhibits tumor growth of multiple nervous system tumors.

PURPOSE: Primary central nervous system (CNS) tumors represent a diverse group of tumor types with heterogeneous molecular mechanisms that underlie their formation and maintenance. CNS tumors depend on angiogenesis and often display increased activity of ErbB-associated pathways. Current nonspecific therapies frequently have poor efficacy in many of these tumor types, so there is a pressing need for the development of novel targeted therapies. EXPERIMENTAL DESIGN: ZD6474 is a novel, orally available low molecular weight inhibitor of the kinase activities associated with vascular endothelial growth factor receptor-2 and epidermal growth factor receptor. We hypothesized that ZD6474 may provide benefit in the treatment of several CNS tumor types. RESULTS: In mice bearing established s.c. tumor xenografts of CNS tumors (malignant glioma and ependymoma) or rhabdomyosarcoma, a limited course of ZD6474 treatment produced significant tumor growth delays and a high rate of partial tumor regression in most models examined. Mice with i.c. malignant glioma xenografts treated with ZD6474 experienced a significant prolongation of survival. Tumors from mice treated with ZD6474 displayed a lower proliferative index and disrupted tumor vascularity. Notably, some of these models are insensitive to low molecular weight kinase inhibitors targeting only vascular endothelial growth factor receptor-2 or epidermal growth factor receptor functions, suggesting that the combined disruption of both epidermal growth factor receptor and vascular endothelial growth factor receptor-2 activities may significantly increase tumor control. CONCLUSIONS: In conclusion, ZD6474 shows significant activity against xenograft models of several primary human CNS tumor types. Consideration for clinical development in this disease setting seems warranted.

Animals↗

PubMed2005

A multicenter phase II trial of ZD6474, a vascular endothelial growth factor receptor-2 and epidermal growth factor receptor tyrosine kinase inhibitor, in patients with previously treated metastatic breast cancer.

PURPOSE: To determine the efficacy and safety of ZD6474, an orally available inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase with additional activity against the epidermal growth factor receptor (EGFR) tyrosine kinase, in patients with previously treated metastatic breast cancer. PATIENTS AND METHODS: Eligible patients had histologically confirmed metastatic breast cancer and had received prior treatment with an anthracycline and taxane; measurable disease was required. Patients were enrolled sequentially into one of two dose cohorts, 100 or 300 mg orally once daily; 28 days defined one cycle. The primary end point was objective response rate; pharmacokinetics and serial pharmacodynamic studies were obtained. RESULTS: Forty-six patients were enrolled between May 2002 and April 2003, and 44 were evaluable for response. Diarrhea was the most commonly reported toxicity and seemed dose related (grade >/=2: 4.5% and 37.5% in the 100 and 300 mg cohorts, respectively). Rash was reported by 26% of patients but was never worse than grade 2. Seven patients in the 300 mg cohort had asymptomatic grade 1 prolongation of the QTc interval. Hypertension requiring treatment was not reported. There were no objective responses; one patient in the 300 mg cohort had stable disease >/=24 weeks. All patients in the 300 mg cohort and 90% of patients in the 100 mg cohort achieved steady-state concentrations exceeding the IC(50) for VEGF inhibition in preclinical models. CONCLUSION: ZD6474 monotherapy was generally well tolerated but had limited monotherapy activity in patients with refractory metastatic breast cancer.

Adult↗

PubMed2004

Magnetic resonance imaging measurements of the response of murine and human tumors to the vascular-targeting agent ZD6126.

PURPOSE: ZD6126 is a novel vascular targeting agent currently undergoing clinical evaluation. It acts by destabilizing the microtubulin of fragile and proliferating neoendothelial cells in tumors. The drug leads to blood vessel congestion, the selective destruction of the vasculature, and extensive necrosis in experimental tumors. The aim of the study reported here was to assess the ability of dynamic contrast enhanced magnetic resonance imaging (MRI) to measure the antivascular effects of ZD6126 in tumors. EXPERIMENTAL DESIGN: The work was carried out in mice bearing C38 colon adenocarcinoma and in patients with advanced cancers. MRI was performed before and 6 h (human tumors) or 24 h (C38 tumors) after i.v. drug administration. Contrast agent (gadolinium diethylenetriaminepentaacetate) enhancement was characterized by the initial area under the gadolinium diethylenetriaminepentaacetate uptake versus time curve (IAUC). IAUC reflects blood flow, vascular permeability, and the fraction of interstitial space. RESULTS: The median IAUC was reduced in all C38 tumors after ZD6126 administration [by 6-48% at 50 mg/kg (n = 3)], 58-91% at 100 mg/kg (n = 4), and 11-93% at 200 mg/kg (n = 6). In contrast, the administration of vehicle only led to no consistent change in median IAUC (n = 4). The ZD6126-induced changes in median IAUC appeared to be dose dependent (P = 0.045). No ZD6126-induced changes were apparent in murine muscle. Similar effects were seen in preliminary data from human tumors (11 tumors studied, 9 patients). At doses of 80 mg/m(2) and higher, the median IAUC post-ZD6126 treatment was reduced in all of the tumors studied (8 tumors, 6 patients) to 36-72% from the baseline value. There was a significant trend of increasing reductions with increasing exposure (P < 0.01). No drug-induced changes in human muscle or spleen IAUC were apparent. The reproducibility of the median IAUC parameter was investigated in patients. In 19 human tumors (measured in 19 patients) inter- and intratumor coefficients of variation were 64 and 18%. CONCLUSIONS: The contrast enhanced-MRI measured median IAUC is a useful end point for quantifying ZD6126 antivascular effects in human tumors.

Angiogenesis Inhibitors↗

PubMed2003

Behavioral phenotype of the reeler mutant mouse: effects of RELN gene dosage and social isolation.

Reeler (rl/rl) and reeler/wild-type (+/rl) mice synthesize Reln at subnormal rates, as do patients with schizophrenia, bipolar disorder, and autism, thereby forming the basis for a Reln hypothesis for vulnerability to these psychopathologies and justifying attention to the behavioral phenotypes of Reln-deficient mice. Tests of gait, emotionality, social aggression, spatial working memory, novel-object detection, fear conditioning, and sensorimotor reflex modulation revealed the behavioral phenotype of rl/rl, but not +/rl, mice to be different from that of wild-type (+/+) mice. These results reveal no effect of Reln gene dosage and provide significant challenges to both the Reln and the neurodevelopmental hypotheses of the etiology of major psychopathologies.

Analysis of Variance↗