Glade Bender JL, Lee A, Reid JM, Baruchel S, Roberts T, Voss SD, Wu B, Ahern CH, Ingle AM, Harris P, Weigel BJ, Blaney SM. Phase I pharmacokinetic and pharmacodynamic study of pazopanib in children with soft tissue sarcoma and other refractory solid tumors: a children's oncology group phase I consortium report. J Clin Oncol. 2013 Aug 20;31(24):3034-43.
This study describes a phase I clinical trial of “Pazopanib” in pediatric patients suffering from soft tissue sarcoma (STS). Pazonapib is an anti-angiogenic drug. It is a competitive inhibitor of ATP molecule1,2. It competes with the ‘substrate’ ATP, for the binding site of vascular endothelial growth factor receptor tyrosine kinase (VEGFR)-1,-2 and -33,4 PDGFR and c-kit. Pazonapib is approved in adults for treatment of soft tissue sarcoma and advanced renal cells carcinoma5-7.
The study was performed to calculate the MTD of pazopanib administered either as an oral tablet or as a suspension. The study also looked at the degree of toxicities and pharmacokinetic and pharmacodynamic parameters of the two drug formulations .The study were conducted for a period of up to two years. The initial dose for the tablet was 275 mg/m2. The dosage was escalated to 350, 450 and 600 mg/m2. Dose escalation was carried out according to rolling six design8. The initial concentration of the suspension was 150 mg/mL, which was escalated at 50% of the MTD of tablet9. Patients in the second part of the study received tablets at the MTD which was calculated from the part 1 of the study. This patient sub set was used for Ki and the blood tumor volume analysis.
The patients were routinely examined for safety and efficacy. Blood pressure and cardiac toxicity was measured at the beginning of the study and before cycles 2, 5 and after every sixth cycle. Dose limiting toxicity was graded as grade 2, 3 and 4. The maximum tolerated dose (MTD) was defined as the highest dose of the drug at which less than a third of patients experienced dose limiting toxicity. The MTD was determined to be 450 mg/m2 for tablet and 160 mg/m2 for the suspension.
Blood was drawn from the patients and toxicities associated with the dosage, steady state plasma trough concentration (Css), maximal drug serum concentration (Cmax), area under curve (AUC), time required to achieve maximum serum concentration (Tmax) were evaluated. AUC was measured for 0-8 and 0-24 hours post drug treatment at days 1, 15 and 22 in the dosage cycle. The effect of the drug treatment on the vascular permeability (Ki) and the blood tumor volume was also evaluated. Patients who were administered the MTD had to undergo extended PK studies. The concentration of Pazopanib was measured by using a tandem liquid chromatography/mass spectrometry device10. The standard method of WINNolin was used to measure the concentration time data. The Pearson correlation coefficients were used to draw association between the PK parameters and dose and toxicity and were compared by using two tailed t test.
The patients’ ages ranged from 2-22 years with mean age being 13 years. There was a great degree of variance in the maximum serum concentration Cmax and area under curve (AUC 0-24 hours). In fact, there was a big overlap between the dose levels. The Cmax average value was 21.5 g/ml on day 1 and was very similar to the Cmax in adults. The average AUC0-24 hours values for tablet were 639+403 g/mL.h and 418+297 g/mL.h for the suspension and were generally similar to observed in adults11. It was identified that the drug Pazopanib accumulated over time with accumulation factor of 2.3. The half life of the drug was 29.6 hours. The oral clearance for the drugs was fairly identical between patients <or equal to 12 and patients>12 years. Patients who experienced greater drug limiting toxicity (DLT) had higher values of AUC0-24 hours as opposed to patients with no toxicity. It was observed that the toxicity correlated to exposure as opposed to dose. The children did not demonstrate a statistically significant difference in bioavailability between the tablets and the suspension (which was the case in adults)9.It was observed that at a steady state concentration of 20g/mL clinical benefits were observed in the patients, while a Css of 30 g/mL produced disease stabilization for over 1 year. It was also observed that increase in BP was an indicator of anti-tumor efficacy. It correlated with improved VEGF inhibition and greater average Css.
The soluble form of the VEGFR-2 receptor and endoglin ENG levels went down13,14. The down-regulation of VEGFR-2 correlated to Css level. The level of PlGF went up, while VEGF and sVEGFR-1 level did not change over the course of first cycle. The result from the gene expression study correlated to the ELISA assay study. Patients who benefitted from pazopanib expressed low levels of VEGF and PlGF. It was observed that both the blood volume and tumor permeability decreased consistent to the anti-angiogenic effect of the drug. The result of this phase 1 trial was that Pazopanib was generally well tolerated in pediatric patients and had potential for clinical benefits in pediatric cancer patients with STS. Partial response was observed in two patients while another 16% demonstrated stabilization of disease for more than 6 months.
I feel that the study was performed by using appropriate methodology. The major PK parameters were analyzed. The MTD of the drug was calculated and robust statistical analyses were performed. The one problem I have with the data was that the Cmax and AUC values had very high standard deviations. The values of AUC overlapped between different drug dosages. The authors suggest that decrease in VEGFR-2 is associated with clinical benefits; however the receptor levels go down in both groups of patients with and without clinical benefit making the role of VEGFR-2 as a biomarker in this study questionable. The average trough plasma concentration was lower with higher drug dose, while a lower drug dose had elevated level (table A4). It was reported that 20g/mL of Css results in clinical benefits; however the MTD fails to attain this Css level at various time points. The study utilizes DCE-MRI, a novel pharmacodynamic marker for the first time in pediatric oncology patients.
There are a few key challenges associated with conducting pharmacokinetic studies in infants15,16. Patients, <6 months of age usually have 3-6 times higher half life than in adults. Drug metabolizing pathway such as the CYP450 pathway, drug transporters and certain phase II conjugation and renal elimination pathways required for metabolism of some drugs are far less developed. This may result in very high internal dose in infants or affect the bioavailabilty17. Oral drug administration poses significant challenges that may affect the actual drug concentration in infants. Children differ from adults in having lower blood pressure, having a higher rate of metabolism, faster heart rate and less developed immune system. Infants also have a greater body to surface are to body mass ratio. Another problem associated with clinical trials in infants is the small numbers of children that suffer from a given medical problem making it difficult to generate clinically meaningful data. Infants have variation in sizes of their internal organs; mechanism of plasma binding of proteins and the physiological method of removing harmful chemicals from CNS are usually underdeveloped in infants. Drug clearance pathways exhibit high degree of variability in infants. As observed in this study the children exhibited very high variance in Cmax and AUC. Many drugs also exhibit adverse effect due to the fact that children are growing. Drugs like corticosteroids can inhibit or alter physical growth in children. The phase I study recruited patients with STS as opposed to healthy subjects and also evaluated clinical benefit which is contrary to adult phase I trials.
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