A phase II trial of sunitinib in women with metastatic or recurrent endometrial carcinoma: a study of the Princess Margaret, Chicago and California Consortia.

OBJECTIVE: Treatment options remain limited for women with relapsed/metastatic endometrial cancer (EC). Angiogenesis is one of the major components of tumor progression and thus an attractive target. The aim of this phase II trial was to assess the efficacy and tolerability of sunitinib, an oral multitargeted receptor tyrosine-kinase inhibitor with antiangiogenic and antitumor activity in the treatment of recurrent EC. METHODS: We performed a multicenter, single arm, two-stage phase II study of sunitinib, 50mg daily administered on a 4 weeks on-2 weeks off schedule. Eligibility criteria included recurrent/metastatic EC or carcinosarcoma with no more than one prior line of chemotherapy. The primary endpoint was objective response rate. RESULTS: 34 women were enrolled; 33 received at least one dose of sunitinib and were included in the analyses. Six women (18.1%) had a partial response and six additional women (18.1%) stable disease. In total, ten patients (30.3%) had disease control for at least 6 months and of these, seven were controlled for more than one year. Median progression free and overall survival times were 3 months and 19.4 months, respectively. Adverse events related to treatment were frequent. At least one grade 3 toxicity occurred in 30 patients and dose reductions were required in 17 patients (52%). The most common grade 3 toxicities were fatigue, hypertension, palmar-plantar erythrodysesthesia, diarrhea and hematologic. CONCLUSION: Sunitinib therapy showed promising activity in women with recurrent EC. Toxicity was seen frequently but was manageable. Anti-angiogenic agents warrant further investigation in EC to define which patients will derive the greatest benefit.

Application of a single-objective, hybrid genetic algorithm approach to pharmacokinetic model building.

A limitation in traditional stepwise population pharmacokinetic model building is the difficulty in handling interactions between model components. To address this issue, a method was previously introduced which couples NONMEM parameter estimation and model fitness evaluation to a single-objective, hybrid genetic algorithm for global optimization of the model structure. In this study, the generalizability of this approach for pharmacokinetic model building is evaluated by comparing (1) correct and spurious covariate relationships in a simulated dataset resulting from automated stepwise covariate modeling, Lasso methods, and single-objective hybrid genetic algorithm approaches to covariate identification and (2) information criteria values, model structures, convergence, and model parameter values resulting from manual stepwise versus single-objective, hybrid genetic algorithm approaches to model building for seven compounds. Both manual stepwise and single-objective, hybrid genetic algorithm approaches to model building were applied, blinded to the results of the other approach, for selection of the compartment structure as well as inclusion and model form of inter-individual and inter-occasion variability, residual error, and covariates from a common set of model options. For the simulated dataset, stepwise covariate modeling identified three of four true covariates and two spurious covariates; Lasso identified two of four true and 0 spurious covariates; and the single-objective, hybrid genetic algorithm identified three of four true covariates and one spurious covariate. For the clinical datasets, the Akaike information criterion was a median of 22.3 points lower (range of 470.5 point decrease to 0.1 point decrease) for the best single-objective hybrid genetic-algorithm candidate model versus the final manual stepwise model: the Akaike information criterion was lower by greater than 10 points for four compounds and differed by less than 10 points for three compounds. The root mean squared error and absolute mean prediction error of the best single-objective hybrid genetic algorithm candidates were a median of 0.2 points higher (range of 38.9 point decrease to 27.3 point increase) and 0.02 points lower (range of 0.98 point decrease to 0.74 point increase), respectively, than that of the final stepwise models. In addition, the best single-objective, hybrid genetic algorithm candidate models had successful convergence and covariance steps for each compound, used the same compartment structure as the manual stepwise approach for 6 of 7 (86 %) compounds, and identified 54 % (7 of 13) of covariates included by the manual stepwise approach and 16 covariate relationships not included by manual stepwise models. The model parameter values between the final manual stepwise and best single-objective, hybrid genetic algorithm models differed by a median of 26.7 % (q1 = 4.9 % and q3 = 57.1 %). Finally, the single-objective, hybrid genetic algorithm approach was able to identify models capable of estimating absorption rate parameters for four compounds that the manual stepwise approach did not identify. The single-objective, hybrid genetic algorithm represents a general pharmacokinetic model building methodology whose ability to rapidly search the feasible solution space leads to nearly equivalent or superior model fits to pharmacokinetic data.

Paclitaxel plus oxaliplatin for recurrent or metastatic cervical cancer: a New York Cancer Consortium Study.

OBJECTIVE: Survival in women with recurrent or metastatic cervical cancer remains poor. More effective and less toxic regimens are needed. Cisplatin is an effective radiosensitizer, but its single agent activity in recurrent cervical cancer, especially after prior cisplatin exposure, is disappointing, with a response rate of only 13%. Oxaliplatin has preclinical activity in cisplatin-resistant tumors and may have synergic activity when combined with paclitaxel. Our objective is to determine the efficacy and toxicity of paclitaxel and oxaliplatin in patients with recurrent or metastatic cervical cancer. METHODS: Patients with histologic confirmation of primary metastatic or recurrent cervical cancer not amenable to surgical management were eligible. Treatment consisted of paclitaxel 175 mg/m(2) IV and oxaliplatin 130 mg/m(2) IV every 21 days. The primary endpoints were toxicity, recorded every cycle, and response, determined by RECIST criteria and were assessed every 9 weeks, with subsequent confirmation as required. Sample size determinations were made using a Simon's two-stage design with a projected overall response proportion of 13% with cisplatin alone. Survival rates were calculated with Kaplan-Meier methods. RESULTS: Of the 35 patients enrolled, 32 were evaluable. The median age was 56 (27-78); 30 had had prior radiation (23 concomitant with cisplatin). Patients completed a mean of 4.2 cycles (1-11). There were 2 complete and 5 partial responses for a total response rate of 7/32 (22%; 95% CI: 9.3%-40.0%). Eight patients had stable disease for an overall clinical benefit rate of 15/32 (47%; 95% CI: 29.1%-65.3%). The mean time to best response was 13.5 weeks (95% CI: 10.6, 16.4). The mean progression-free survival was 21 weeks (95% CI: 14.7, 27.2) and mean overall survival was 52 weeks (95% CI: 39.4, 64.8). A total of 135 cycles were administered. There were 28 (20.1%) grade 3/4 hematologic toxicities and 46 (34.1%) grade 3/4 non-hematologic toxicities, which were predominantly sensory neuropathy. There were 13 treatment delays, 4 dose reductions, and no treatment-related deaths. CONCLUSIONS: The combination of paclitaxel and oxaliplatin is an effective regimen in patients with recurrent or persistent cervical cancer including a majority previously exposed to cisplatin. Further study and comparison with other platinum-based regimens is warranted.

Improving the quality of abstract reporting for phase I cancer trials.

PURPOSE: Conference abstracts of phase I trials (P1T) communicate important anticancer drug development information. Our objectives were to determine elements essential for good P1T abstract reporting, to assess the quality of P1T abstracts submitted to American Society of Clinical Oncology (ASCO) meetings, and to propose reporting guidelines. EXPERIMENTAL DESIGN: A survey of developmental therapeutics experts established elements of P1T reporting quality, and a scoring system was generated. All P1T abstracts published in ASCO Annual Proceedings from 1997 to 2006 were reviewed, and the scoring system was applied. RESULTS: A survey was distributed twice to 69 experts, with a response rate of 39% (27 of 69). Experts rated 37 elements using a five-point scale, and elements with mean ratings over 3.75 were included in the final scoring system. One thousand six hundred and eighty three P1T abstracts were reviewed. A positive and linear association was observed between average expert rating of the elements and the proportion of P1T abstracts including those elements (Spearman correlation coefficient, rho = 0.60, P < 0.001). The median for all 1,683 abstracts was 62.5% (range, 25-95%; SD, 12.3%). Year of presentation was found to be significantly associated with higher quality scores (rho = 0.20, P < 0.001), with later years possessing better quality scores. The quality score was statistically significant as a predictor of type of presentation (odds ratio, 1.10; 95% confidence interval, 1.02-1.19 per 10% increase; P = 0.014), with oral presentations having the highest scores. CONCLUSIONS: The quality of P1T abstract reporting at ASCO has improved over time, although there is room for optimization. The quality of P1T abstract reporting may be enhanced using guidelines derived from our expert consensus.

A phase I and pharmacokinetic study of weekly oxaliplatin followed by paclitaxel in patients with solid tumors.

PURPOSE: Oxaliplatin and paclitaxel are widely used in treating solid tumors. We designed a phase I study with the purpose of determining the maximal tolerated dose and pharmacokinetic properties of weekly oxaliplatin followed by paclitaxel based on evidence suggesting that weekly administration of both drugs allows equivalent dose intensity with less neurotoxicity. EXPERIMENTAL DESIGN: Twenty-three patients with advanced solid tumors were treated. Starting doses were 35 mg/m2 oxaliplatin followed by 45 mg/m2 paclitaxel weekly for 4 weeks every 6 weeks. Dose was escalated as follows: 45 mg/m2 oxaliplatin and 45 mg/m2 paclitaxel, 60 mg/m2 oxaliplatin and 45 mg/m2 paclitaxel, and 60 mg/m2 oxaliplatin and 60 mg/m2 paclitaxel. Pharmacokinetic studies were evaluated during the first course of therapy for oxaliplatin using population kinetics approach. RESULTS: A total of 49 courses were administered. The dose-limiting toxicity was peripheral neuropathy with oxaliplatin and paclitaxel both at 60 mg/m2. There were three partial responses. There was evidence of pharmacokinetic interaction with a significant amount of total platinum (46.2-49.5%/24 h) eliminated in the urine in this group of patients, consistent with published data from others. The total body clearance values of plasma platinum and ultrafiltrable platinum were higher in this combination compared with corresponding values from our previous study with oxaliplatin only (P < 0.001). CONCLUSIONS: The recommended phase II dose of this combination is 60 mg/m2 oxaliplatin followed by 45 mg/m2 paclitaxel. Evidence of antitumor activity and acceptable toxicity with this combination and schedule warrants further investigation. We have obtained more definitive pharmacokinetic properties of oxaliplatin and confirmed its drug interaction with paclitaxel in the current sequence.

Quantitation of paclitaxel, and its 6-alpha-OH and 3-para-OH metabolites in human plasma by LC-MS/MS.

We have developed a high performance liquid chromatography mass spectrometry method for quantitating paclitaxel and its 6-alpha-OH and 3-para-OH metabolites in 0.1 mL human plasma. After MTBE liquid-liquid extraction, chromatographic separation was achieved with a Phenomenex synergy polar reverse phase (4 µm, 2 mm × 50 mm) column and a gradient of 0.1% formic acid in acetonitrile and water over an 8 min run time. Mass spectrometric detection was performed on an ABI SCIEX 4000Q with electrospray, positive-mode ionization. The assay was linear from 10-10,000 ng/mL for paclitaxel and 1-1000 ng/mL for both metabolites and proved to be accurate (94.3-110.4%) and precise (<11.3%CV). Recovery from plasma was 59.3-91.3% and matrix effect was negligible (-3.5 to 6.2%). Plasma freeze thaw stability (90.2-107.0%), stability for 37 months at -80 °C (89.4-112.6%), and stability for 4 h at room temperature (87.7-100.0%) were all acceptable. This assay will be an essential tool to further define the metabolism and pharmacology of paclitaxel and metabolites in the clinical setting. The assay may be utilized for therapeutic drug monitoring of paclitaxel and may also reveal the CYP2C8 and CYP3A4 activity phenotype of patients.

Vascular endothelial growth factor tyrosine kinase inhibitor AZD2171 and fractionated radiotherapy in mouse models of lung cancer.

The vascular endothelial growth factor receptor (VEGFR) tyrosine kinases are being explored as targets for antiangiogenic cancer therapy. Radiotherapy also inhibits tumor growth and affects vasculature. We investigated the combination of the potent VEGFR tyrosine kinase inhibitor AZD2171 and ionizing radiation in cell culture and mouse models of lung cancer. We show that ionizing radiation induces expression of phosphorylated VEGFR-2 (Flk-1) in endothelial cells and that this phosphorylation is inhibited by AZD2171. Human umbilical vascular endothelial cells become more sensitive to radiation after treatment with AZD2171 as determined by clonogenic assay. Matrigel assay showed a decrease in in vitro endothelial tubule formation with AZD2171/radiation combination treatment. When similar combination was applied to the H460 lung cancer xenograft model in nude mice, loss of radiation-induced phosphorylated Flk-1 was observed in the combination treatment group, which also showed a large decrease in tumor vascular density by staining of the von Willebrand factor. H460 tumor growth delay was enhanced in the combination treatment group compared with the groups treated with AZD2171 or radiation alone. Additionally, after therapy, Ki67 index showed >4-fold reduction of tumor proliferation in the combination therapy group, which also showed increased intratumoral apoptotic index by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining. In conclusion, AZD2171 sensitizes lung tumor xenografts to radiation and inhibits angiogenesis both in vitro and in vivo. When used as a radiation enhancer, AZD2171 has the potential to improve tumor growth delay by inhibiting tumor proliferation and promoting apoptosis. Clinical trials are needed to determine the potential of this combination therapy in patients with locally advanced lung cancer.

Population pharmacokinetic analysis of 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) in adult patients with solid tumors.

PURPOSE: To identify sources of exposure variability for the tumor growth inhibitor 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) using a population pharmacokinetic analysis. METHODS: A total 67 solid tumor patients at 2 centers were given 1 h infusions of 17-DMAG either as a single dose, daily for 3 days, or daily for 5 days. Blood samples were extensively collected and 17-DMAG plasma concentrations were measured by liquid chromatography/mass spectrometry. Population pharmacokinetic analysis of the 17-DMAG plasma concentration with time was performed using nonlinear mixed effect modeling to evaluate the effects of covariates, inter-individual variability, and between-occasion variability on model parameters using a stepwise forward addition then backward elimination modeling approach. The inter-individual exposure variability and the effects of between-occasion variability on exposure were assessed by simulating the 95 % prediction interval of the AUC per dose, AUC(0-24 h), using the final model and a model with no between-occasion variability, respectively, subject to the five day 17-DMAG infusion protocol with administrations of the median observed dose. RESULTS: A 3-compartment model with first order elimination (ADVAN11, TRANS4) and a proportional residual error, exponentiated inter-individual variability and between occasion variability on Q2 and V1 best described the 17-DMAG concentration data. No covariates were statistically significant. The simulated 95% prediction interval of the AUC(0-24 h) for the median dose of 36 mg/m(2) was 1,059-9,007 mg/L h and the simulated 95 % prediction interval of the AUC(0-24 h) considering the impact of between-occasion variability alone was 2,910-4,077 mg/L h. CONCLUSIONS: Population pharmacokinetic analysis of 17-DMAG found no significant covariate effects and considerable inter-individual variability; this implies a wide range of exposures in the population and which may affect treatment outcome. Patients treated with 17-DMAG may require therapeutic drug monitoring which could help achieve more uniform exposure leading to safer and more effective therapy.