Yi-Lin Chiu

Navitoclax, a targeted high-affinity inhibitor of BCL-2, in lymphoid malignancies: a phase 1 dose-escalation study of safety, pharmacokinetics, pharmacodynamics, and antitumour activity.

BACKGROUND Proteins of the BCL-2 family regulate clonal selection and survival of lymphocytes, and are frequently overexpressed in lymphomas. Navitoclax is a targeted high-affinity small molecule that inhibits the anti-apoptotic activity of BCL-2 and BCL-XL. We aimed to assess the safety and antitumour activity of navitoclax in patients with lymphoid tumours, and establish the drugs pharmacokinetic and pharmacodynamic profiles. METHODS In this phase 1 dose-escalation study, patients (aged ≥18 years) with relapsed or refractory lymphoid malignancies were enrolled and treated at seven sites in the USA between November, 2006, and November, 2009. A modified Fibonacci 3+3 design was used to assign patients to receive oral navitoclax once daily by one of two dosing schedules: intermittently for the first 14 days of a 21-day cycle (14/21) at doses of 10, 20, 40, 80, 110, 160, 225, 315, or 440 mg/day; or continuously for 21 days of a 21-day cycle (21/21) at doses of 200, 275, 325, or 425 mg/day. Study endpoints were safety, maximum tolerated dose, pharmacokinetic profile, pharmacodynamic effects on platelets and T cells, and antitumour activity. This trial is registered with ClinicalTrials.gov, number NCT00406809. FINDINGS 55 patients were enrolled (median age 59 years, IQR 51-67), 38 to receive the 14/21 dosing schedule, and 17 to receive the 21/21 dosing schedule. Common toxic effects included grade 1 or 2 anaemia (41 patients), infection (39), diarrhoea (31), nausea (29), and fatigue (21); and grade 3 or 4 thrombocytopenia (29), lymphocytopenia (18), and neutropenia (18). On the intermittent 14/21 schedule, dose-limiting toxic effects were hospital admissions for bronchitis (one) and pleural effusion (one), grade 3 increase in aminotransferases (one), grade 4 thrombocytopenia (one), and grade 3 cardiac arrhythmia (one). To reduce platelet nadir associated with intermittent 14/21 dosing, we assessed a 150 mg/day lead-in dose followed by a continuous 21/21 dosing schedule. On the 21/21 dosing schedule, two patients did not complete the first cycle and were excluded from assessment of dose-limiting toxic effects; dose-limiting toxic effects were grade 4 thrombocytopenia (one), grade 3 increase in aminotransferases (one), and grade 3 gastrointestinal bleeding (one). Navitoclax showed a pharmacodynamic effect on circulating platelets and T cells. Clinical responses occurred across the range of doses and in several tumour types. Ten of 46 patients with assessable disease had a partial response, and these responders had median progression-free survival of 455 days (IQR 40-218). INTERPRETATION Navitoclax has a novel mechanism of peripheral thrombocytopenia and T-cell lymphopenia, attributable to high-affinity inhibition of BCL-XL and BCL-2, respectively. On the basis of these findings, a 150 mg 7-day lead-in dose followed by a 325 mg dose administered on a continuous 21/21 dosing schedule was selected for phase 2 study. FUNDING Abbott Laboratories, Genentech, and National Cancer Institute, National Institutes of Health.

Drug Interactions with the Direct-Acting Antiviral Combination of Ombitasvir and Paritaprevir-Ritonavir

ABSTRACT The two direct-acting antiviral (2D) regimen of ombitasvir and paritaprevir (administered with low-dose ritonavir) is being developed for treatment of genotype subtype 1b and genotypes 2 and 4 chronic hepatitis C virus (HCV) infection. Drug-drug interactions were evaluated in healthy volunteers to develop dosing recommendations for HCV-infected subjects. Mechanism-based interactions were evaluated for ketoconazole, pravastatin, rosuvastatin, digoxin, warfarin, and omeprazole. Interactions were also evaluated for duloxetine, escitalopram, methadone, and buprenorphine-naloxone. Ratios of geometric means with 90% confidence intervals for the maximum plasma concentration and the area under the plasma concentration-time curve were estimated to assess the magnitude of the interactions. For most medications, coadministration with the 2D regimen resulted in a <50% change in exposures. Ketoconazole, digoxin, pravastatin, and rosuvastatin exposures increased by up to 105%, 58%, 76%, and 161%, respectively, and omeprazole exposures decreased by approximately 50%. Clinically meaningful changes in ombitasvir, paritaprevir, or ritonavir exposures were not observed. In summary, all 11 medications evaluated can be coadministered with the 2D regimen, with most medications requiring no dose adjustment. Ketoconazole, digoxin, pravastatin, and rosuvastatin require lower doses, and omeprazole may require a higher dose. No dose adjustment is required for the 2D regimen.

Exposure-Response (Safety) Analysis to Identify Linifanib Dose for a Phase III Study in Patients With Hepatocellular Carcinoma

BACKGROUND Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths and the fifth most common cancer globally. Hepatocellular carcinoma produces highly vascular tumors that overexpress vascular endothelial growth factor (VEGF), thus making VEGF a promising therapeutic target. The competitive inhibitor linifanib (ABT-869) has selectivity for VEGF and platelet-derived growth factor (PDGF) receptors and minimal activity against unrelated tyrosine and serine and threonine kinases. However, the optimal dosing regimen for linifanib in HCC patients is not yet known. OBJECTIVE This study attempts to identify a linifanib dose or dosing regimen with an acceptable safety profile for a Phase III study in HCC patients. METHODS The pharmacokinetic (PK) properties of linifanib were characterized from 2 Phase I and 3 Phase II clinical trials. Of the 266 patients evaluated, the median weight was 68 kg (range, 35-177 kg), 64% were male, and 87.6% of patients received an oral solution of linifanib, whereas 12.4% received a tablet formulation. Approximately 95% of patients received drug based on weight, with the remaining on a fixed-dosing regimen. A population PK analysis was conducted to characterize the linifanib exposure for each patient. Linifanib Cmax and AUC derived from the population PK properties were correlated with the rates of adverse events (AEs). RESULTS Linifanib PK properties are dose proportional for the 0.10-mg/kg to 0.25-mg/kg once daily dose range and are time independent after repeated oral dosing. The Tmax of linifanib is approximately 3 hours, and the t½ is approximately 1 day. The most common AEs related to linifanib PK were hypertension (P = 0.02 for Cmax and P = 0.01 for AUC), diarrhea (P = 0.001 for Cmax and P = 0.0012 for AUC), proteinuria (P = 0.001 for Cmax and P = 0.002 for AUC), and asthenia (P = 0.03 for AUC). Weight and sex were identified as covariates for Cmax, and sex was identified as a covariate for AUC. The predicted AE range for females was slightly higher compared with males; however, the AE range is tighter for the weight range for fixed dosing compared with weight-based dosing, regardless of sex. CONCLUSIONS The PK properties of linifanib support a one-compartment model with first-order absorption and elimination. Comparison of weight-based and fixed dosing revealed predicted AE rates to be similar, with a tighter AE range for fixed dosing. The safety profile of linifanib, therefore, supports a 17.5 mg fixed starting dose for Phase III clinical studies.

A novel ritonavir paediatric powder formulation is bioequivalent to ritonavir oral solution with a similar food effect.

BACKGROUND A novel ritonavir oral powder formulation has been developed to eliminate the alcohol and propylene glycol contents in the current ritonavir oral solution for paediatric use. Two clinical studies were conducted to assess the bioequivalence of the powder formulation to the marketed oral solution and to evaluate the effect of food and vehicles on bioavailability. METHODS Study 1 was a randomized, partial-crossover, 4-period study in 48 subjects. Regimens included: oral solution under moderate-fat conditions, powder formulation in water under fasting, moderate-fat or high-fat conditions, and powder formulation in chocolate milk or pudding under moderate-fat conditions. Study 2 was a randomized, crossover, 4-period study in 24 subjects. Subjects were randomized to a sequence of the oral solution and powder formulation in water, infant formula and apple sauce, all under moderate-fat conditions. Bioavailability comparisons were assessed by the 90% CIs for the geometric least-squares mean ratios. RESULTS Ritonavir powder formulation in water was found to be bioequivalent to the marketed oral solution. Ritonavir powder formulation administered in chocolate milk, pudding, infant formula or apple sauce was bioequivalent to the powder formulation administered in water. Compared with fasting conditions, moderate-fat and high-fat meals were associated with approximately 25-40% and 35-50% reduction in ritonavir concentrations, respectively. CONCLUSIONS The novel ritonavir powder formulation is bioequivalent to marketed ritonavir oral solution under moderate-fat conditions with a similar effect of meals. None of the vehicles tested negatively affected the bioavailability, which suggests the potential for use of a broad range of vehicles for dose preparation.

Pharmacokinetics and Safety of the Lopinavir/Ritonavir Tablet 500/125 mg Twice Daily Coadministered With Efavirenz in Healthy Adult Participants

A study was conducted in healthy adults (n = 19) to evaluate the pharmacokinetics of lopinavir/ritonavir when coadministered with efavirenz. Participants were administered lopinavir/ritonavir 400/100 mg alone twice daily (bid) from the morning of day 1 through the morning of day 10, and then lopinavir/ritonavir 500/125 mg bid was coadministered with efavirenz 600 mg every evening (qhs) from the evening of day 10 through day 20. Lopinavir and ritonavir exposures when administered alone versus with efavirenz were determined on days 10 and 20 and compared using point estimates and 90% confidence intervals. The point estimates for the ratios of lopinavir maximum observed plasma concentration (Cmax), plasma concentration prior to morning dosing (Ctrough), and area under the plasma concentration‐time curve over a dosing interval (AUC12) were 1.121, 0.954, and 1.060, respectively. The lopinavir/ritonavir dose of 500/125 mg bid administered with efavirenz most closely approximates the pharmacokinetic exposure of lopinavir/ritonavir 400/100 mg bid administered alone.

Assessment of the effect of ethnicity on linifanib tolerability and pharmacokinetics in patients with cancer.

e13082 Background: Linifanib is a novel orally active, potent and selective vascular endothelial growth factor receptor and platelet derived growth factor receptor kinase inhibitor. Linifanib activity as a monotherapy has been demonstrated in phase 1 and 2 trials in patients with a variety of advanced solid tumors. The aim of this assessment was to evaluate the impact of ethnicity on linifanib tolerability and pharmacokinetics (PK) in cancer patients. METHODS Linifanib tolerability and PK were compared across Chinese, Japanese and non-Asian cancer patients from 8 clinical trials. Data for the Chinese and Japanese analyses were obtained from 2 phase 1 and 3 phase 2 trials, and 3 phase 1, one phase 2, and one phase 3 trial, respectively. The impact of ethnicity on tolerability was assessed by evaluating significance of ethnicity on the exposure-safety relationship. Logistic regression analysis was conducted to construct the exposure-safety relationship for eight common adverse events (hypertension, asthenia, GI-abdominal disorder, diarrhea, skin toxicity 1, skin toxicity 2, proteinuria and anorexia). The steady-state linifanib PK exposure parameters, when not available from non-compartmental analysis, were estimated modeling the available phase 1 and 2 data using a population PK approach. RESULTS The exposure-safety response analysis showed that ethnicity was not a significant factor influencing the exposure-safety response relationship for any of the tested adverse events. In addition, linifanib exposures as dose-normalized (DN) AUC were similar between Chinese and non-Chinese patients (DN AUC: 0.36 ± 0.16 (N=106) and 0.32 ± 0.16 (N=160), respectively) and between Japanese and non-Japanese patients (DN AUC: 0.34 ± 0.11 [N=11] and 0.34 ± 0.15 [N=36), respectively). CONCLUSIONS There appears to be no meaningful ethnic differences in linifanib tolerability and PK across Chinese, Japanese and non-Asian cancer patients.

Abstract 1300: Evaluating the relative bioavailability of a new formulation of navitoclax (ABT-263) in both cancer patients and healthy volunteers

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL INTRODUCTION: Navitoclax (ABT-263) is a novel, orally bioavailable small molecule that inhibits Bcl-2 family proteins and promotes apoptosis. The current Phase 1 formulation is a lipid solution, which has a short shelf-life. A new lipid solution with improved shelf-life was developed to support Phase 2/3 clinical development. Relative bioavailability studies in patients were expected to have large variability, which would make the interpretation challenging. Meanwhile, the toxicity profile of navitoclax limited an evaluation at the recommended phase II dose in healthy volunteers. Therefore, relative bioavailability studies for the new formulation were conducted in both healthy volunteers (at doses with minimal safety risk) and cancer patients (at therapeutic doses). METHODS: Two randomized, crossover studies were conducted to evaluate the bioavailability of the new formulation relative to that of the Phase 1 formulation. Study I was conducted in 12 healthy female subjects with non-childbearing potential at a single dose of 25 mg navitoclax. Study II was conducted in 12 cancer patients at a single dose of 250 mg navitoclax. Both studies were conducted under low-fat conditions. RESULTS: The new lipid solution was bioequivalent to the Phase 1 formulation in healthy subjects. In patients, the point estimates of the bioavailability of the new lipid solution were 30% higher than the Phase 1 formulation; nevertheless, the point estimates were associated with wide 90% confidence intervals indicating high uncertainty in the point estimate. The percent coefficient of variation for navitoclax exposure in patients (49%) was markedly higher than that in healthy subjects (25%). CONCLUSION: Relative bioavailability assessment in healthy volunteers had substantially lower variability compared to that in cancer patients, therefore served as the primary basis for decision making. However, results from patients provided supportive information at the therapeutic dose levels. Overall results from both studies in healthy subjects and patients provided strong evidence that the new lipid solution has comparable bioavailability as the Phase 1 formulation under low-fat conditions at therapeutic doses, and enabled a decision to select the new lipid formulation without dose modification for Phase 2/3 studies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1300. doi:10.1158/1538-7445.AM2011-1300

Abstract C37: A Phase 1 open‐label study evaluating pharmacokinetics, safety, and tolerability of linifanib in Japanese patients with solid tumors

Background: Linifanib (ABT‐869) is a novel orally active and selective inhibitor of vascular endothelial growth factor and platelet derived growth factor families of receptor tyrosine kinases. Linifanib demonstrated antitumor activity in a variety of advanced solid tumor pts enrolled in early‐phase clinical trials. Preliminary data from an international phase 1 multicenter study (M04‐710) showed specific single‐agent antitumor activity with a recommended tolerated dose of 0.25 mg/kg and a maximum tolerated dose of 0.30 mg/kg. Efficacy was observed in 3 phase 2 studies in pts with hepatocellular carcinoma, non‐small cell lung cancer and renal cell carcinoma. Methods: This is a phase 1, open‐label, dose‐escalating study evaluating the PK, safety/tolerability of linifanib in Japanese pts with solid tumors. Pts were assigned to 4 dosing cohorts (0.05, 0.10, 0.20 and 0.25 mg/kg) of linifanib given orally once daily (QD) on Cycle (C) 1 Day (D) 1 under fasting conditions for 21 days. PK samples were collected at various time points after single dose on C1D1 and multiple doses on C1D15. CT scans were performed at baseline and at D1 of every second cycle; efficacy was evaluated using RECIST criteria. Adverse events (AEs) were graded by NCI CTCAE V3.0. Results: As of August 2009, 15 pts have received linifanib in this study: 3 at 0.05 mg/kg; 6 at 0.10 mg/kg; 3 at 0.20 mg/kg and 3 at 0.25 mg/kg. Pts had NSCLC (5), lung carcinoid (1) sarcoma (4), breast cancer (3), thymic carcinoma (1) and angioendothelioma (1). Partial response was noted in 1 breast cancer pt in the 0.20 mg/kg cohort (32% reduction from baseline). 15 pts had ≥ Grade 2 AEs; hypertension (12); neutropenia (4), thrombocytopenia (3) and hand foot syndrome (2). Among all pts, 2 experienced a dose limiting toxicity; 1 each at 0.10 mg/kg (Grade 3 ALT increase) and at 0.25 mg/kg (ECG T wave inversion). 4 pts had AEs leading to dose interruptions (3 pts at C3 and 1pt at C1) and 1 pt had an AE leading to dose reduction in C5. 5 pts have discontinued study at the time of this analysis; 2 due to radiographic progressive disease (PD), 1 due to clinical PD and 2 due to AEs. At 0.25 mg/kg dose, the exposures (AUC 24 ) after single and multiple doses were 6.2±1.2 µg*hr/mL (mean±SD) and 10.7±3.1 µg*hr/mL, respectively. These multiple dose exposures are approximately 2‐fold higher than efficacious exposures predicted based on observed results in preclinical animal models. The estimation of effective half‐life based on observed accumulation was approximately 1 day. Conclusion: Preliminary ongoing results show that linifanib is tolerated in Japanese pts at ≤ 0.25 mg/kg and has antitumor activity as a single‐agent in 1 pt with breast cancer. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C37.