Motesanib diphosphate in progressive differentiated thyroid cancer

BACKGROUND: The expression of vascular endothelial growth factor (VEGF) is characteristic of differentiated thyroid cancer and is associated with aggressive tumor behavior and a poor clinical outcome. Motesanib diphosphate (AMG 706) is a novel oral inhibitor of VEGF receptors, platelet-derived growth-factor receptor, and KIT. METHODS: In an open-label, single-group, phase 2 study, we treated 93 patients who had progressive, locally advanced or metastatic, radioiodine-resistant differentiated thyroid cancer with 125 mg of motesanib diphosphate, administered orally once daily. The primary end point was an objective response as assessed by an independent radiographic review. Additional end points included the duration of the response, progression-free survival, safety, and changes in serum thyroglobulin concentration. RESULTS: Of the 93 patients, 57 (61%) had papillary thyroid carcinoma. The objective response rate was 14%. Stable disease was achieved in 67% of the patients, and stable disease was maintained for 24 weeks or longer in 35%; 8% had progressive disease as the best response. The Kaplan-Meier estimate of the median duration of the response was 32 weeks (the lower limit of the 95% confidence interval [CI] was 24; the upper limit could not be estimated because of an insufficient number of events); the estimate of median progression-free survival was 40 weeks (95% CI, 32 to 50). Among the 75 patients in whom thyroglobulin analysis was performed, 81% had decreased serum thyroglobulin concentrations during treatment, as compared with baseline levels. The most common treatment-related adverse events were diarrhea (in 59% of the patients), hypertension (56%), fatigue (46%), and weight loss (40%). CONCLUSIONS: Motesanib diphosphate can induce partial responses in patients with advanced or metastatic differentiated thyroid cancer that is progressive. (ClinicalTrials.gov number, NCT00121628.

Assessment of Incurred Sample Reanalysis for Macromolecules to Evaluate Bioanalytical Method Robustness: Effects from Imprecision

Incurred sample reanalysis (ISR) is recommended by regulatory agencies to demonstrate reproducibility of validated methods and provide confidence that methods used in pharmacokinetic and toxicokinetic assessments give reproducible results. For macromolecules to pass ISR, regulatory recommendations require that two thirds of ISR samples be within 30% of the average of original and reanalyzed values. A modified Bland–Altman (mBA) analysis was used to evaluate whether total error (TE), the sum of precision and accuracy, was predictive of a method’s passing ISR and to identify potential contributing parameters for ISR success. Simulated studies determined minimum precision requirements for methods to have successful ISR and evaluated the relationship between precision and the probability of a method’s passing ISR acceptance criteria. The present analysis evaluated ISRs conducted for 37 studies involving ligand-binding assays (LBAs), with TEs ranging from 15% to 30%. An mBA approach was used to assess accuracy and precision of ISR, each with a threshold of 30%. All ISR studies met current regulatory criteria; using mBA, all studies met the accuracy threshold of 30% or less, but two studies (5%) failed to meet the 30% precision threshold. Simulation results showed that when an LBA has ≤15% imprecision, the ISR criteria for both the regulatory recommendation and mBA would be met in 99.9% of studies. Approximately 71% of samples are expected to be within 1.5 times the method imprecision. Therefore, precision appears to be a critical parameter in LBA reproducibility and may also be useful in identifying methods that have difficulty passing ISR

Phase II study of safety and efficacy of motesanib in patients with progressive or symptomatic, advanced or metastatic medullary thyroid cancer

PURPOSE: This phase II study investigated the efficacy and tolerability of motesanib, an investigational, highly selective inhibitor of vascular endothelial growth factor receptors 1, 2, and 3; platelet-derived growth factor receptor; and Kit in advanced medullary thyroid cancer (MTC). PATIENTS AND METHODS: Patients with locally advanced or metastatic, progressive or symptomatic MTC received motesanib 125 mg/d orally for up to 48 weeks or until unacceptable toxicity or disease progression. The primary end point was objective response by independent review. Other end points included duration of response, progression-free survival, safety, pharmacokinetics, and changes in tumor markers. RESULTS: Of 91 enrolled patients who received motesanib, two (2%) achieved objective response (95% CI, 0.3% to 7.7%); their duration of response was 32 weeks (censored) and 21 weeks (disease progressed). Eighty-one percent of patients had stable disease (48% had durable stable disease > or = 24 weeks), 8% had disease progression as best response, and 9% were not evaluated; 76% experienced a decrease from baseline in target lesion measurement. Median progression-free survival was 48 weeks (95% CI, 43 to 56 weeks). Among patients with tumor marker analysis, 69 (83%) of 83 and 63 (75%) of 84 had decreased serum calcitonin and carcinoembryonic antigen during treatment, respectively, compared with baseline. The most common treatment-related adverse events were diarrhea (41%), fatigue (41%), hypothyroidism (29%), hypertension (27%), and anorexia (27%). In pharmacokinetic analyses, motesanib trough concentrations were lower compared with differentiated thyroid cancer patients from the same study. CONCLUSION: Although the objective response rate was low, a significant proportion of MTC patients (81%) achieved stable disease while receiving motesanib