Survival prediction in everolimus-treated patients with metastatic renal cell carcinoma incorporating tumor burden response in the RECORD-1 trial.

Background: The phase 3 RECORD-1 study demonstrated clinical benefit of everolimus over placebo (median progression-free survival: 4.9 mo compared with 1.9 mo, p<0.

Using pharmacokinetic and pharmacodynamic data in early decision making regarding drug development: a phase I clinical trial evaluating tyrosine kinase inhibitor, AEE788.

Purpose: In this first-in-human study of AEE788, a tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR), HER-2, and VEGFR-2, a comprehensive pharmacodynamic program was implemented in addition to the evaluation of safety, pharmacokinetics, and preliminary efficacy of AEE788 in cancer patients.

Experimental Design: Patients with advanced, solid tumors received escalating doses of oral AEE788 once daily. Primary endpoints were to determine dose-limiting toxicities (DLTs) and maximum-tolerated dose (MTD).

Phase I study of AEE788, a novel multitarget inhibitor of ErbB- and VEGF-receptor-family tyrosine kinases, in recurrent glioblastoma patients.

Purpose: Vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR) play a significant role in glioblastoma angiogenesis and proliferation, making tyrosine kinase (TK) receptors logical targets for treatment. We evaluated AEE788, a reversible TK inhibitor that inhibits EGFR and VEGFR, in recurrent glioblastoma patients.

Methods: In this dose-escalation, phase I study, patients with recurrent glioblastoma received AEE788 once daily in 28-day cycles in stratified subgroups: those receiving (1) non-enzyme-inducing anticonvulsants drugs or no anticonvulsants (Group A) and (2) enzyme-inducing anticonvulsant drugs (Group B).

Pharmacokinetic drug interaction between AEE788 and RAD001 causing thrombocytopenia in patients with glioblastoma.

Purpose: Treating glioblastoma through the simultaneous inhibition of multiple transduction pathways may prove more effective than single-pathway inhibition. We evaluated the safety, biologic activity, and pharmacokinetic profile of oral AEE788, a selective inhibitor of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF), plus oral RAD001, a mammalian target of rapamycin inhibitor, in glioblastoma patients.

Methods: This phase IB/II, open-label, multicenter, 2-arm, dose-escalation study enrolled adult glioblastoma patients at first or second recurrence/relapse.

An efficient algorithm to determine the optimal two-stage randomized multinomial designs in oncology clinical trials.

Sun et al. (2009) proposed an optimal two-stage randomized multinomial design that incorporates both response rate (RR) and early progression rate (EPR) in designing phase II oncology trials. However, determination of the design parameters in their approach requires evaluating huge numbers of combinations among possible values of design parameters, and thus requires highly intensive computation.

Statistical methods for a phase II oncology trial with a growth modulation index (GMI) endpoint.

For cytostatic cancer therapies, alternatives to traditional phase II endpoints are needed. Von Hoff (1998) proposed an intrapatient progression-free survival (PFS) ratio, the growth modulation index (GMI). Current practice in estimation of the GMI success rate is conservative and omits a measure of uncertainty.

Phase III study of valspodar (PSC 833) combined with paclitaxel and carboplatin compared with paclitaxel and carboplatin alone in patients with stage IV or suboptimally debulked stage III epithelial ovarian cancer or primary peritoneal cancer.

Purpose: To compare the safety and efficacy of carboplatin and paclitaxel administered with or without the multidrug resistance modulator valspodar (PSC 833) in untreated patients with advanced ovarian or primary peritoneal cancer.

Patients And Methods: Seven hundred sixty-two patients with stage IV or suboptimally debulked stage III ovarian or primary peritoneal cancer were randomly assigned to receive either valspodar 5 mg/kg every 6 hours for 12 doses, paclitaxel 80 mg/m(2), and carboplatin area under the curve (AUC) 6 (PC-PSC; n = 381) or paclitaxel 175 mg/m(2) and carboplatin AUC 6 (PC; n = 381). Time to disease progression (TTP) was the primary end point.

Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL.

Background: Resistance to imatinib mesylate can occur in chronic myelogenous leukemia (CML). Preclinical in vitro studies have shown that nilotinib (AMN107), a new BCR-ABL tyrosine kinase inhibitor, is more potent than imatinib against CML cells by a factor of 20 to 50.

Methods: In a phase 1 dose-escalation study, we assigned 119 patients with imatinib-resistant CML or acute lymphoblastic leukemia (ALL) to receive nilotinib orally at doses of 50 mg, 100 mg, 200 mg, 400 mg, 600 mg, 800 mg, and 1200 mg once daily and at 400 mg and 600 mg twice daily.

Dynamic contrast-enhanced magnetic resonance imaging as a biomarker for the pharmacological response of PTK787/ZK 222584, an inhibitor of the vascular endothelial growth factor receptor tyrosine kinases, in patients with advanced colorectal cancer and liver metastases: results from two phase I studies.

Purpose: PTK787/ZK 222584 (PTK/ZK), an orally active inhibitor of vascular endothelial growth factor (VEGF) receptor tyrosine kinases, inhibits VEGF-mediated angiogenesis. The pharmacodynamic effects of PTK/ZK were evaluated by assessing changes in contrast-enhancement parameters of metastatic liver lesions using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in patients with advanced colorectal cancer treated in two ongoing, dose-escalating phase I studies.

Patients And Methods: Twenty-six patients had DCE-MRI performed at baseline, day 2, and at the end of each 28-day cycle.