Sukyung Woo

Phase II Trial of Bevacizumab, Thalidomide, Docetaxel, and Prednisone in Patients With Metastatic Castration-Resistant Prostate Cancer

PURPOSE We previously demonstrated that thalidomide appears to add to the activity of docetaxel in metastatic castration-resistant prostate cancer (CRPC). Phase II studies combining docetaxel with bevacizumab have had substantial antitumor activity. We hypothesized that the combination of docetaxel plus these antiangiogenic drugs with different targets would have substantial clinical activity. To explore safety and efficacy, this was tested in mice and in human patients. PATIENTS AND METHODS Preclinical efficacy of the combination therapy was evaluated in PC3 xenograft mice. Sixty patients with progressive metastatic CRPC received intravenous docetaxel and bevacizumab plus oral thalidomide and prednisone. The primary end point was a prostate-specific antigen (PSA) decline of > or = 50%. Secondary end points included time to progression, overall survival, and safety. Results In the mouse model, combination therapy of docetaxel, bevacizumab, and thalidomide inhibited tumor growth most effectively. In the clinical trial, 90% of patients receiving the combination therapy had PSA declines of > or = 50%, and 88% achieved a PSA decline of > or = 30% within the first 3 months of treatment. The median time to progression was 18.3 months, and the median overall survival was 28.2 months in this group with a Halabi-predicted survival of 14 months. While toxicities were manageable, all patients developed grade 3/4 neutropenia. CONCLUSION The addition of bevacizumab and thalidomide to docetaxel is a highly active combination with manageable toxicities. The estimated median survival is encouraging, given the generally poor prognosis of this patient population. These results suggest that definitive clinical trials combining antiangiogenic agent combinations with docetaxel are warranted to improve treatment outcomes for patients with metastatic CRPC.

A Phase I Combination Study of Olaparib with Cisplatin and Gemcitabine in Adults with Solid Tumors

Purpose: To determine the safety and tolerability of olaparib with cisplatin and gemcitabine, establish the maximum tolerated dose (MTD), and evaluate the pharmacodynamic and pharmacokinetic profile of the combination. Experimental Design: We conducted a phase I study of olaparib with cisplatin and gemcitabine in patients with advanced solid tumors. Treatment at dose level 1 (DL1) consisted of olaparib 100 mg orally every 12 hours on days 1 to 4, gemcitabine 500 mg/m2 on days 3 and 10, and cisplatin 60 mg/m2 on day 3. PAR levels were measured in peripheral blood mononuclear cells (PBMC). Results: Dose-limiting toxicities (DLT) in two of three patients at DL1 included thrombocytopenia and febrile neutropenia. The protocol was amended to enroll patients treated with ≤2 prior severely myelosuppressive chemotherapy regimens and treated with olaparib 100 mg once daily on days 1 to 4 (DL−1). No DLTs were seen in six patients at DL−1. Because of persistent thrombocytopenia and neutropenia following a return to DL1, patients received 100 mg olaparib every 12 hours on day 1 only. No hematologic DLTs were observed; nonhematologic DLTs included gastrointestinal bleed, syncope, and hypoxia. Of 21 patients evaluable for response, two had partial response. Olaparib inhibited PARP in PBMCs and tumor tissue, although PAR levels were less effectively inhibited when olaparib was used for a short duration. Conclusions: Olaparib in combination with cisplatin and gemcitabine is associated with myelosuppression even at relatively low doses. Modified schedules of olaparib in chemotherapy naive patients will have to be explored with standard doses of chemotherapy. Clin Cancer Res; 18(8); 2344–51. ©2012 AACR.

Safety and feasibility of long-term intravenous sodium nitrite infusion in healthy volunteers

Background Infusion of sodium nitrite could provide sustained therapeutic concentrations of nitric oxide (NO) for the treatment of a variety of vascular disorders. The study was developed to determine the safety and feasibility of prolonged sodium nitrite infusion. Methodology Healthy volunteers, aged 21 to 60 years old, were candidates for the study performed at the National Institutes of Health (NIH; protocol 05-N-0075) between July 2007 and August 2008. All subjects provided written consent to participate. Twelve subjects (5 males, 7 females; mean age, 38.8±9.2 years (range, 21–56 years)) were intravenously infused with increasing doses of sodium nitrite for 48 hours (starting dose at 4.2 µg/kg/hr; maximal dose of 533.8 µg/kg/hr). Clinical, physiologic and laboratory data before, during and after infusion were analyzed. Findings The maximal tolerated dose for intravenous infusion of sodium nitrite was 267 µg/kg/hr. Dose limiting toxicity occurred at 446 µg/kg/hr. Toxicity included a transient asymptomatic decrease of mean arterial blood pressure (more than 15 mmHg) and/or an asymptomatic increase of methemoglobin level above 5%. Nitrite, nitrate, S-nitrosothiols concentrations in plasma and whole blood increased in all subjects and returned to preinfusion baseline values within 12 hours after cessation of the infusion. The mean half-life of nitrite estimated at maximal tolerated dose was 45.3 minutes for plasma and 51.4 minutes for whole blood. Conclusion Sodium nitrite can be safely infused intravenously at defined concentrations for prolonged intervals. These results should be valuable for developing studies to investigate new NO treatment paradigms for a variety of clinical disorders, including cerebral vasospasm after subarachnoid hemorrhage, and ischemia of the heart, liver, kidney and brain, as well as organ transplants, blood-brain barrier modulation and pulmonary hypertension. Clinical Trial Registration Information http://www.clinicaltrials.gov; NCT00103025

Sorafenib is an Inhibitor of UGT1A1 but is Metabolized by UGT1A9: Implications of Genetic Variants on Pharmacokinetics and Hyperbilirubinemia

Purpose: Several case reports suggest sorafenib exposure and sorafenib-induced hyperbilirubinemia may be related to a (TA)5/6/7 repeat polymorphism in UGT1A1*28 (UGT, uridine glucuronosyl transferase). We hypothesized that sorafenib inhibits UGT1A1 and individuals carrying UGT1A1*28 and/or UGT1A9 variants experience greater sorafenib exposure and greater increase in sorafenib-induced plasma bilirubin concentration. Experimental Design: Inhibition of UGT1A1-mediated bilirubin glucuronidation by sorafenib was assessed in vitro. UGT1A1*28 and UGT1A9*3 genotypes were ascertained with fragment analysis or direct sequencing in 120 cancer patients receiving sorafenib on five different clinical trials. Total bilirubin measurements were collected in prostate cancer patients before receiving sorafenib (n = 41) and 19 to 30 days following treatment and were compared with UGT1A1*28 genotype. Results: Sorafenib exhibited mixed-mode inhibition of UGT1A1-mediated bilirubin glucuronidation (IC50 = 18 μmol/L; Ki = 11.7 μmol/L) in vitro. Five patients carrying UGT1A1*28/*28 (n = 4) or UGT1A9*3/*3 (n = 1) genotypes had first dose, dose-normalized areas under the sorafenib plasma concentration versus time curve (AUC) that were in the 93rd percentile, whereas three patients carrying UGT1A1*28/*28 had AUCs in the bottom quartile of all genotyped patients. The Drug Metabolizing Enzymes and Transporters genotyping platform was applied to DNA obtained from six patients, which revealed the ABCC2-24C>T genotype cosegregated with sorafenib AUC phenotype. Sorafenib exposure was related to plasma bilirubin increases in patients carrying 1 or 2 copies of UGT1A1*28 alleles (n = 12 and n = 5; R2 = 0.38 and R2 = 0.77; P = 0.032 and P = 0.051, respectively). UGT1A1*28 carriers showed two distinct phenotypes that could be explained by ABCC2-24C>T genotype and are more likely to experience plasma bilirubin increases following sorafenib if they had high sorafenib exposure. Conclusions: This pilot study indicates that genotype status of UGT1A1, UGT1A9, and ABCC2 and serum bilirubin concentration increases reflect abnormally high AUC in patients treated with sorafenib. Clin Cancer Res; 18(7); 2099–107. ©2012 AACR.

Population pharmacokinetic analysis of sorafenib in patients with solid tumours

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT Sorafenib is a multikinase inhibitor with activity against B-raf, C-raf, VEGFR2, PDGFRβ and FGFR1. Sorafenib is clinically approved for the treatment of renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC). The pharmacokinetics (PK) of sorafenib are highly variable between subjects. Sorafenib exposure increases less than dose proportionally (likely due to limited solubility). Sorafenib undergoes enterohepatic recycling (EHC). WHAT THIS STUDY ADDS This is the first study to characterize the PK of sorafenib using a model based on sorafenibs known disposition characteristics such as delayed/solubility-limited GI absorption and EHC. The parameterization of the EHC model used a square wave function to describe the gall bladder emptying. This study evaluated the effect of baseline bodyweight, BSA, age, gender, liver function parameters, kidney function parameters and genotype with respect to CYP3A4*1B, CYP3A5*3C, UGT1A9*3 and UGT1A9*5 on sorafenib PK. No clinically important covariates were identified. This model can be used to simulate and explore alternative dosing regimens and to develop exposure-response relationships for sorafenib. AIMS To characterize the pharmacokinetics (PK) of sorafenib in patients with solid tumours and to evaluate the possible effects of demographic, clinical and pharmacogenetic (CYP3A4*1B, CYP3A5*3C, UGT1A9*3 and UGT1A9*5) covariates on the disposition of sorafenib. METHODS PK were assessed in 111 patients enrolled in five phase I and II clinical trials, where sorafenib 200 or 400 mg was administered twice daily as a single agent or in combination therapy. All patients were genotyped for polymorphisms in metabolic enzymes for sorafenib. Population PK analysis was performed by using nonlinear mixed effects modelling (NONMEM). The final model was validated using visual predictive checks and nonparametric bootstrap analysis. RESULTS A one compartment model with four transit absorption compartments and enterohepatic circulation (EHC) adequately described sorafenib disposition. Baseline bodyweight was a statistically significant covariate for distributional volume, accounting for 4% of inter-individual variability (IIV). PK model parameter estimates (range) for an 80 kg patient were clearance 8.13 l h(-1) (3.6-22.3 l h(-1) ), volume 213 l (50-1000 l), mean absorption transit time 1.98 h (0.5-13 h), fraction undergoing EHC 50% and average time to gall bladder emptying 6.13 h. CONCLUSIONS Overall, population PK analysis was consistent with known biopharmaceutical/PK characteristics of oral sorafenib. No clinically important PK covariates were identified.

Interspecies Comparisons of Pharmacokinetics and Pharmacodynamics of Recombinant Human Erythropoietin

Erythropoietin (EPO) has a highly conserved structure among mammals, and thus recombinant human EPO (rHuEPO) has biological activity in various species. This study explores the interspecies relationships of the pharmacokinetics (PK) and pharmacodynamics (PD) of rHuEPO. The PK parameters such as clearance (CL) and volume of distribution (Vss) after i.v. doses of rHuEPO were obtained in several species via noncompartmental analysis and were assessed using the traditional allometric approach. Also, PK/PD modeling of rHuEPO concentrations and responses [reticulocytes, red blood cells (RBCs), and hemoglobin] was performed following a range of i.v. and s.c. doses in rats, monkeys, and humans. Nonlinear disposition (Vmax, Km) and s.c. absorption rate and bioavailability parameters of rHuEPO were examined. A cascade, indirect, lifespan PD model was applied to recover efficacy (Smax) and potency (SC50) of rHuEPO on erythropoiesis and erythroid cell lifespan parameters. Despite nonlinear rHuEPO disposition, CL and Vss were highly correlated with body weight (R2 > 0.92) with allometric scaling exponents of 0.708 for CL and 0.853 for Vss. The s.c. bioavailability increased with dose in monkeys and humans but appeared to be dose-independent in rats. A correlation between Smax or SC50 and body weight was not obvious. However, RBC lifespans obeyed allometric principles. Size dependence was found for PK and lifespan parameters, whereas pharmacologic parameters were independent of body weight.

Pharmacokinetic and Pharmacodynamic Modeling of Recombinant Human Erythropoietin after Intravenous and Subcutaneous Administration in Rats

The pharmacokinetics (PK) and pharmacodynamics (PD) of recombinant human erythropoietin (rHuEPO) were studied in rats after single i.v. and s.c. administration at three dose levels (450, 1350, and 4050 IU/kg). The plasma concentrations of rHuEPO and its erythropoietic effects including reticulocyte (RET), red blood cell (RBC), and hemoglobin (Hb) levels were determined. A two-compartment model with dual input rate and nonlinear disposition was used to characterize the PK of rHuEPO. The catenary indirect response model with several compartments reflecting the bone marrow and circulating erythropoietic cells was applied. The s.c. doses exhibited slow absorption (Tmax = 12 h) and incomplete bioavailability (F = 0.59). In placebo groups, RBC and Hb values gradually increased over time with growth of the rats, and the changes in the baselines monitored from 8 to 32 weeks of age were described by a nonlinear growth function. All doses resulted in dose-dependent increases in RET counts followed by an immediate decline below the baseline at around 6 days and returned to the predose level in 21–24 days after dosing. A subsequent steady increase of RBC and Hb levels followed and reached peaks at 6 days. A tolerance phenomenon observed at all dose levels was modeled by a negative feedback inhibition with the relative change in Hb level. The PK/PD model well described the erythropoietic effects of rHuEPO as well as tolerance, thereby yielding important PD parameters (Smax = 1.87 and SC50 = 65.37 mIU/ml) and mean lifespans of major erythropoietic cell populations in rats.

Phase I Study of Oral Lenalidomide in Patients With Refractory Metastatic Cancer

Objectives of this study were to determine the maximum tolerated dose and to characterize the side effect profile and pharmacokinetics of lenalidomide in patients with advanced refractory solid tumors. Patients were treated on a modified Fibronacci dose escalation scheme with an oral daily dose of lenalidomide. A total of 45 patients with 8 different tumor types were accrued. Doses administered included 5, 10, and 20 mg continuous daily doses, every 28 days (n = 15), later modified to intermittent doses of 15, 20, 25, 30, 35, and 40 mg, with a 21 days‐on and 7 days‐off schedule, due to observed side effects. Lenalidomide exhibited a linear pharmacokinetics over a wide range of doses with the mean half‐life of 3.9 hours. The renal function affected lenalidomide clearance, resulting in 50% reduction in patients with mild renal impairment compared with patients with normal function (CL/F = 243 mL/min). Stable disease was documented in 12 of 44 evaluable patients, of whom 9 patients had prostate cancer. Most frequent grade 1 and 2 toxicities included fatigue, nausea, pruritus/rash, neutropenia, and neuropathy. Grade 3/4 events were predominantly hematologic. Lenalidomide was well tolerated up to a 35‐mg/d intermittent dosing schedule at doses higher than previously indicated for hematologic malignancies.

Population Pharmacokinetics of Romidepsin in Patients with Cutaneous T-Cell Lymphoma and Relapsed Peripheral T-Cell Lymphoma

Purpose: Romidepsin is a potent histone deacetylase inhibitor under clinical development. The objective of this study was to evaluate the effect of demographic, clinical, and pharmacogenetic covariates on the pharmacokinetics of romidepsin in patients with T-cell lymphoma. Experimental Design: Pharmacokinetic assessment was done in 98 patients enrolled in a phase II study who received 14 or 18 mg/m2 of romidepsin as a 4-hour infusion on day 1 during their first treatment cycle. Population modeling was done using a nonlinear mixed effects modeling approach to explore the effects of polymorphic variations in CYP3A4, CYP3A5, SLCO1B3, and ABCB1, all of which encode genes thought to be involved in romidepsin disposition. Results: A two-compartment model with linear kinetics adequately described the romidepsin disposition. Population clearance was 15.9 L/h with between-patient variability of 37%. ABCB1 2677G>T/A variant alleles tended toward a reduced clearance and lower volume of tissue distribution, but this was not supported by a statistical significance. Genetic variations in CYP3A4/5 and SCLO1B3 had no effect on the systemic exposure. Conclusion: The population pharmacokinetic analysis indicates moderate interindividual variability in romidepsin pharmacokinetics and no clinically relevant covariates associated with the unexplained pharmacokinetic variability of romidepsin in this population.

Pharmacodynamic models for agents that alter production of natural cells with various distributions of lifespans

Indirect pharmacodynamic response (IDR) models were developed for agents which alter the generation of cell populations with arbitrary lifespan distributions. These models extend lifespan based IDR models introduced previously [J. Pharmacokinet. Biopharm. 27: 467, 1999] for cell populations with the same lifespan (“delta” distribution). Considered are cell populations exhibiting time-invariant lifespan distributions described by the probability density function ℓ(τ). It is assumed that cell response (R) is produced at a zero-order rate (kin(t)) and is eliminated from the population when the cell lifespan expires. The cell loss rate is calculated as kin*ℓ(t), where ‘*’ denotes the convolution operator. Therapeutic agents can stimulate or inhibit production rates according to the Hill function: 1 ± H(C(t)) where H(C(t)) contains the capacity (Smax) and potency (SC50) parameters and C(t) is a pharmacokinetic function. The production rate is kin(t)=kin· [ 1±H(C(t))]. The operational model is dR/dt = kin(t)−kin*ℓ(t) with the baseline condition R0 = kin· TR, where TR is the mean lifespan. Single populations as well as populations with precursors were examined by simulation to establish the role of lifespan distribution parameters (mean and standard deviation) in controlling the response vs. time profile. Estimability of parameters was assessed. Numerical techniques of solving differential equations with the convolution integral were proposed. In addition, the models were applied to literature data to describe the stimulatory effects of single doses of recombinant human erythropoietin on reticulocytes in blood. The estimates of Smax and SC50 for these agents were obtained along with means and standard deviations for reticulocyte lifespan distributions. The proposed models can be used to analyze the pharmacodynamics of agents which alter natural cell production yielding parameters describing their efficacy and potency as well as means and standard deviations for cell lifespan distributions.