Objective: To evaluate the absorption, metabolism, and excretion of tivozanib, a new investigational drug for renal cell carcinoma and solid malignancies. Methods: Eight healthy male participants ...received a single 1.5‐mg (˜160 μCi) dose of oral 14C‐tivozanib. Whole blood, serum, urine, and feces were evaluated up to 28 days postdose for pharmacokinetics, radioanalysis, and metabolites. Adverse events were recorded throughout the study. Results: 14C‐tivozanib concentration peaked at 10.9 ± 5.84 hours. The mean serum half‐life for 14C‐tivozanib was 89.3 ± 23.5 hours. The maximum concentration and area under the curve for 14C‐tivozanib were 12.1 ± 5.67 ng/mL and 1084 ± 417.0 ng·h/mL, respectively. Mean recovery of total radioactivity was 91.0% ± 11.0%; 79.3% ± 8.82% of the radioactivity was recovered in feces both as unchanged tivozanib and metabolites. In the urine, 11.8% ± 4.59% was recovered only as metabolites. No unchanged tivozanib was found in the urine. Conclusion: Tivozanib had a long half‐life with no major circulating metabolite, was well tolerated as a single dose, and was primarily eliminated via feces with no unchanged tivozanib found in urine. These pharmacokinetic data of 14C‐tivozanib are consistent with previous studies of unlabeled tivozanib.
We report the first prospective, international, natural history study of the ultra-rare genetic disorder fibrodysplasia ossificans progressiva (FOP). FOP is characterized by painful, recurrent ...flare-ups, and disabling, cumulative heterotopic ossification (HO) in soft tissues.
Individuals aged ≤65 years with classical FOP (ACVR1R206H variant) were assessed at baseline and over 36 months.
In total, 114 individuals participated; 33 completed the study (mean follow up: 26.8 months). Median age was 15.0 (range: 4-56) years; 54.4% were male. During the study, 82 (71.9%) individuals reported 229 flare-ups (upper back: 17.9%, hip: 14.8%, shoulder: 10.9%). After 84 days, 14 of 52 (26.9%) imaged flare-ups had new HO at the flare-up site (mean new HO volume: 28.8 × 103 mm3). Mean baseline low-dose whole-body computed tomography (excluding head) HO volume was 314.4 × 103 mm3; lowest at 2 to <8 years (68.8 × 103 mm3) and increasing by age (25-65 years: 575.2 × 103 mm3). The mean annualized volume of new HO was 23.6 × 103 mm3/year; highest at 8 to <15 and 15 to <25 years (21.9 × 103 and 41.5 × 103 mm3/year, respectively) and lowest at 25 to 65 years (4.6 × 103 mm3/year).
Results from individuals receiving standard care for up to 3 years in this natural history study show the debilitating effect and progressive nature of FOP cross-sectionally and longitudinally, with greatest progression during childhood and early adulthood.
Display omitted
Purpose
Exploratory subgroup analyses from the phase 3 global advanced renal cell carcinoma (ARCC) trial were conducted to assess the influence of tumor histology on outcome of patients treated with ...temsirolimus (Torisel™) or interferon-α (IFN).
Patients and methods
Patients with ARCC including clear cell and other types such as papillary and chromophobe histologies received either IFN (3 million units MU subcutaneously three times weekly, escalating to 18 MU) or temsirolimus (25 mg intravenously weekly).
Results
Approximately 80% of patients had clear cell and 20% of patients had other histologies, the majority of which were papillary. Patients with clear cell and other RCC histologies, treated with temsirolimus, demonstrated comparable median overall and progression-free survival. In contrast, patients with other RCC histologies, treated with IFN, demonstrated shorter median overall and progression-free survival than patients with clear cell RCC. Hazard ratios for death for treatment with temsirolimus versus IFN were less than 1 for patients regardless of tumor histology. For patients treated with temsirolimus, 59% with clear cell and 68% with other RCC histologies experienced tumor reductions. For patients treated with IFN, 35% with clear cell and 14% with other RCC histologies had tumor reductions. However, temsirolimus did not appear to improve the objective response rate compared to IFN. Temsirolimus resulted in a superior clinical benefit rate compared with IFN, regardless of tumor histology.
Conclusion
Temsirolimus appears to be efficacious in patients with clear cell and non-clear cell histologies and can, therefore, be used for the treatment of all types of RCC.
Linkage disequilibrium (LD) is of great interest for gene mapping and the study of population history. We propose a multilocus model for LD, based on the decay of haplotype sharing (DHS). The DHS ...model is most appropriate when the LD in which one is interested is due to the introduction of a variant on an ancestral haplotype, with recombinations in succeeding generations resulting in preservation of only a small region of the ancestral haplotype around the variant. This is generally the scenario of interest for gene mapping by LD. The DHS parameter is a measure of LD that can be interpreted as the expected genetic distance to which the ancestral haplotype is preserved, or, equivalently, 1/(time in generations to the ancestral haplotype). The method allows for multiple origins of alleles and for mutations, and it takes into account missing observations and ambiguities in haplotype determination, via a hidden Markov model. Whereas most commonly used measures of LD apply to pairs of loci, the DHS measure is designed for application to the densely mapped haplotype data that are increasingly available. The DHS method explicitly models the dependence among multiple tightly linked loci on a chromosome. When the assumptions about population structure are sufficiently tractable, the estimate of LD is obtained by maximum likelihood. For more-complicated models of population history, we find means and covariances based on the model and solve a quasi-score estimating equation. Simulations show that this approach works extremely well both for estimation of LD and for fine mapping. We apply the DHS method to published data sets for cystic fibrosis and progressive myoclonus epilepsy.
Abstract only
4513
Background: Tivozanib (T) is a potent, selective inhibitor of all three VEGF receptors with a long half-life of 4.5–5.1 days. Superior progression-free survival (PFS) and overall ...response rate (ORR) with T versus sorafenib (S) were demonstrated in a Phase III trial (TIVO-1) in patients (pts) with metastatic renal cell carcinoma (mRCC) (in ITT population, PFS: 11.9 vs 9.1 months HR=0.797, 95% CI 0.639–0.993; P=0.042; ORR: 33% vs 23%, P=0.014). Hypertension was more common with T, while lower rates of certain off-target AEs and fewer dose adjustments relative to S were reported (J Clin Oncol 2012;30suppl:Abstract 4501). Here we present efficacy and safety analyses for the pre-specified subset of pts who received no prior systemic therapy for mRCC. Methods: In the ITT population (N=517), pts were treatment-naïve or had received no more than 1 prior systemic therapy for metastatic disease; pts receiving prior VEGF- or mTOR-targeted therapy were excluded. Pts were randomized 1:1 to T 1.5 mg/d (once daily, 3 weeks on, 1 week off) or S 400 mg/d (twice daily, continuously). Of these, 181 pts (70%) in each treatment arm had not received prior systemic therapy for mRCC. Results: In pts who received no prior systemic therapy for mRCC, demographics were well balanced between the 2 arms. Median PFS was 12.7 for T vs 9.1 months for S (HR=0.756, 95% CI 0.580–0.985, P=0.037). ORR was 34% for T vs 24% for S (P=0.038). The most common adverse event (AE; All grades/Grade ≥3) for T was hypertension (T: 40%/25% vs S: 35%/18%), suggesting “on-target” biological activity and was manageable medically, while the most common AE for S was hand-foot syndrome (T: 11%/2% vs S: 52%/16%). Other common AEs were diarrhea (T: 22%/2% vs S: 32%/7%), fatigue (T: 19%/6% vs S: 15%/3%), and weight decrease (T: 18%/1% vs S: 17%/2%). Dose reduction (T: 12% vs S: 42%) and interruption (T: 18% vs S: 35%) rates were lower in the T arm and similar to the ITT population. Conclusions: T demonstrated significant improvement in PFS and ORR compared with S in pts who had received no prior systemic therapy for metastatic RCC. T was generally well tolerated, with low rates of treatment-related reduction/interruption in this pre-specified subgroup of pts. Clinical trial information: NCT01030783.
Abstract only
4564
Background: Tivozanib hydrochloride (tivozanib) is a potent, selective, tyrosine kinase inhibitor of all three vascular endothelial growth factor receptors, with a long half-life. ...Superior progression-free survival (PFS) and overall response rate (ORR) with tivozanib versus sorafenib were demonstrated in a phase III trial (TIVO-1) in patients with advanced renal cell carcinoma (PFS: 11.9 vs 9.1 months in ITT population, 12.7 vs 9.1 months in patients who received no prior systemic treatment for mRCC; ORR: 33% vs 23% in ITT population). Hypertension was more common with tivozanib, while lower rates of certain off-target adverse events (AEs) relative to sorafenib were reported (J Clin Oncol 2012;30suppl:Abstract 4501). Here we present detailed dose adjustment data. Methods: In total, 517 patients were enrolled and randomized 1:1 to tivozanib 1.5 mg/d (once daily 3 weeks on, 1 week off) or sorafenib 400 mg/d (twice daily, continuously). Treatment duration and AEs leading to discontinuation and dose adjustment were assessed in these patients. Results: Median duration of treatment with tivozanib was 12.7 months vs 9.5 months with sorafenib; fewer patients in the tivozanib arm experienced drug reduction or dose interruption due to AEs (see Table). Treatment-related AEs, as defined by the investigator, led to drug discontinuation in 3.9% of tivozanib patients and 5.4% sorafenib patients. Conclusions: Lower rates of dose adjustment due to related AEs were observed in patients with metastatic RCC who received tivozanib compared to sorafenib. Clinical trial information: NCT01030783. Table: see text
Abstract
Background: Tivozanib, a potent, selective, long-half-life tyrosine kinase inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, has demonstrated antitumor activity in a ...Phase II study in patients with renal cell carcinoma (RCC), and is currently being studied in clinical trials in patients with RCC and other solid tumors. The goal of this study was to investigate the effect of food on the pharmacokinetics (PK) of a single 1.5 mg dose of tivozanib in healthy subjects. Methods: This was a single-center, open-label, randomized, two-period, crossover Phase I trial. Subjects were admitted to the clinical research unit (CRU) 1 day before dosing, fasted ∼10 hours, and were randomized to fed (standard high-fat breakfast)/fasted or fasted/fed sequence. In each phase of the sequence, subjects received a single oral dose of tivozanib 1.5 mg with a 6-week washout period between doses. Subjects remained at the CRU for at least 48 hours post dose for blood sample collection and safety monitoring, and were assessed on an outpatient basis for up to 504 hours post dose. PK data were analyzed by non-compartmental methods. The effect of food on PK was assessed using standard criteria for bioequivalence based on the exposure parameters AUC0-α and Cmax. If the 90% confidence intervals for the fed/fasted AUC0-α and Cmax fell within the range of 80% to 125%, it was concluded that food had no effect on exposure. Results: Thirty healthy volunteers were enrolled (19M/11F; mean age 39 years range 22-53 years). There was no significant difference in AUC0-α of serum tivozanib between the fed and fasted states (107.4%; Table 1). Food caused a significant decrease in serum tivozanib levels vs fasted state (Cmax: 77.5%). Conclusions: These results indicate that dosing tivozanib with food decreases maximal concentrations by ∼ 23%, but does not affect overall exposure. As tivozanib is dosed chronically in oncology patients and accumulates ∼6 to 7 times single-dose levels when at steady-state, these results are not likely to affect dosing.
Citation Format: {Authors}. {Abstract title} abstract. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 752. doi:1538-7445.AM2012-752
PDF
