A randomized phase 1b trial of the active site polymerase inhibitor nucleotide ATI-2173 in patients with chronic hepatitis B virus infection.

ATI-2173 is an active site polymerase inhibitor nucleotide in development as part of a potentially curative regimen for chronic hepatitis B virus (HBV) infection. This study evaluated the safety, tolerability, pharmacokinetics (PK) and antiviral activity of ATI-2173. This was a phase 1b, randomized, double-blind, placebo-controlled trial in treatment-naive adults with chronic HBV infection conducted in the Republic of Moldova and Ukraine (ClinicalTrials.gov: NCT04248426). Patients positive for hepatitis B surface antigen were randomized 6:2 to receive once-daily oral doses of ATI-2173 10, 25, or 50 mg (n = 6 per dose) or placebo (n = 7) for 28 days, with off-treatment monitoring for 24 weeks. Endpoints included PK parameters of ATI-2173 and its metabolite clevudine, maximum reduction from baseline in HBV DNA, and safety and tolerability. Treatment-emergent adverse events occurred in eight patients (47%) receiving ATI-2173 and five (71%) receiving placebo; headache was the most common (n = 4). ATI-2173 PK was generally dose proportional. Systemic clevudine exposure with ATI-2173 dosing was substantially reduced compared with historical values observed with clevudine administration. On Day 28, mean changes from baseline in HBV DNA were -2.72 to -2.78 log10  IU/ml with ATI-2173 and +0.17 log10  IU/ml with placebo. Off-treatment sustained viral suppression and decreases in covalently closed circular DNA biomarkers were observed in most patients; one maintained undetectable HBV DNA at 24 weeks off treatment. In this 28-day monotherapy study, ATI-2173 demonstrated safety and antiviral activity, with sustained off-treatment effects and substantially reduced systemic clevudine exposure. These results support evaluation of ATI-2173 with tenofovir disoproxil fumarate in phase 2 studies.

Pharmacokinetic drug-drug interaction assessment of peptibody trebananib in combination with chemotherapies.

PURPOSE: To provide the first evaluation of pharmacokinetic (PK) drug-drug interactions (DDIs) between trebananib and chemotherapies across tumor types. METHODS: PK data of trebananib and chemotherapies (paclitaxel, carboplatin, pegylated liposomal doxorubicin, topotecan, capecitabine, lapatinib, 5-FU, irinotecan, or docetaxel) were collected from trials of ovarian cancer, metastatic breast cancer, colorectal carcinoma, and mixed solid tumor. A dedicated PK DDI study of trebananib and paclitaxel in patients with mixed solid tumors was also conducted. The geometric least squares mean (GLSM) ratios and corresponding 90 % confidence intervals (CI) of C max and AUC were estimated for DDI evaluations. RESULTS: In the PK DDI study of trebananib and paclitaxel, the GLSM ratio (90 % CI) was 1.17 (1.10-1.25) for paclitaxel AUC and 1.30 (1.15-1.48) for paclitaxel C max. The GLSM ratio (90 % CI) for the effect of paclitaxel on trebananib PK was 0.92 (0.87-0.97) for trebananib AUC and 0.98 (0.92-1.05) for trebananib C max. In the remaining studies, the GLSM ratios (90 % CI) of C max and AUC generally ranged from 0.8 to 1.25 or exhibited less than twofold PK variabilities across chemotherapeutic agents. No dose-dependent DDIs were evident. CONCLUSIONS: No PK DDI was deemed clinically meaningful between trebananib and the tested chemotherapeutic agents to warrant dose adjustments.

A phase 1b study of trebananib in combination with pegylated liposomal doxorubicin or topotecan in women with recurrent platinum-resistant or partially platinum-sensitive ovarian cancer.

OBJECTIVE: To examine the tolerability and antitumor activity of trebananib plus pegylated liposomal doxorubicin (PLD) or topotecan in recurrent platinum-resistant or partially platinum-sensitive ovarian cancer. METHODS: In this open-label phase 1b study, patients received trebananib 10 mg/kg or 15 mg/kg IV QW plus PLD 50 mg/m(2) (cohorts A1 and A3, respectively) or topotecan 4 mg/m(2) (cohorts B1 and B3, respectively). Endpoints were dose-limiting toxicity (DLT; primary); treatment-emergent adverse events (AEs), overall response rate, anti-trebananib antibodies, and pharmacokinetics (secondary). RESULTS: 103 patients were enrolled. One patient in A1 and B1 had DLTs. Across all cohorts, the most common AEs were nausea, fatigue, and peripheral edema. Across both trebananib plus PLD cohorts (A1/A3), grade 4 AEs were pulmonary embolism, disease progression, and anemia. Two patients had grade 5 intestinal perforation (n=1) and sudden death (n=1). Across both trebananib plus topotecan cohorts (B1/B3), grade 4 AEs were neutropenia, hypokalemia, decreased granulocyte count, chest pain, dyspnea, decreased neutrophil count, and pulmonary embolism. Two patients had grade 5 disease progression. One patient had grade 5 pleural effusion associated with progressive disease. Confirmed objective response rates were 36.0% (A1), 34.8% (A3), 16.7% (B1), and 0.0% (B3). Median progression-free survival duration (months) was 7.4 (A1), 7.1 (A3), 3.5 (B1), and 3.1 (B3), respectively. No drug-drug interactions were apparent. CONCLUSIONS: Trebananib 10mg/kg and 15 mg/kg IV QW plus PLD or topotecan appear to have acceptable toxicity profiles in recurrent platinum-resistant or partially platinum-sensitive ovarian cancer. Antitumor activity was evident across all cohorts.

Phase 1b dose-finding study of motesanib with docetaxel or paclitaxel in patients with metastatic breast cancer.

The purpose of this study was to investigate the safety, tolerability, and pharmacokinetics of motesanib when combined with docetaxel or paclitaxel in patients with metastatic breast cancer. In this open-label, dose-finding, phase 1b study, patients received motesanib 50 or 125-mg orally once daily (QD), beginning day 3 of cycle 1 of chemotherapy, continuously in combination with either paclitaxel 90 mg/m(2) on days 1, 8, and 15 every 28-day cycle (Arm A) or docetaxel 100 mg/m(2) on day 1 every 21-day cycle (Arm B). Dose escalation to motesanib 125 mg QD occurred if the incidence of dose-limiting toxicities (DLTs, primary endpoint) was ≤ 33 %. If the maximum tolerated dose (MTD) of motesanib was established in Arm B, additional patients could receive motesanib at the MTD plus docetaxel 75 mg/m(2). Forty-six patients were enrolled and 45 received ≥ 1 dose of motesanib. The incidence of DLTs was <33 % in all cohorts; thus, motesanib 125 mg QD was established as the MTD. Seven patients (16 %) had grade 3 motesanib-related adverse events including cholecystitis (2 patients) and hypertension (2 patients). Pharmacokinetic parameters of motesanib were similar to those reported in previous studies. The objective response rate was 56 % among patients with measurable disease at baseline who received motesanib in combination with taxane-based chemotherapy. The addition of motesanib to either paclitaxel or docetaxel was generally tolerable up to the 125-mg QD dose of motesanib. The objective response rate of 56 % suggests a potential benefit of motesanib in combination with taxane-based chemotherapy.

Exposure-response relationship of AMG 386 in combination with weekly paclitaxel in recurrent ovarian cancer and its implication for dose selection.

PURPOSE: To characterize exposure-response relationships of AMG 386 in a phase 2 study in advanced ovarian cancer for the facilitation of dose selection in future studies. METHODS: A population pharmacokinetic model of AMG 386 (N = 141) was developed and applied in an exposure-response analysis using data from patients (N = 160) with recurrent ovarian cancer who received paclitaxel plus AMG 386 (3 or 10 mg/kg once weekly) or placebo. Reduction in the risk of progression or death with increasing exposure (steady-state area under the concentration-versus-time curve [AUC(ss)]) was assessed using Cox regression analyses. Confounding factors were tested in multivariate analysis. Alternative AMG 386 doses were explored with Monte Carlo simulations using population pharmacokinetic and parametric survival models. RESULTS: There was a trend toward increased PFS with increased AUC(ss) (hazard ratio [HR] for each one-unit increment in AUC(ss), 0.97; P = 0.097), suggesting that the maximum effect on prolonging PFS was not achieved at the highest dose tested (10 mg/kg). Among patients with AUC(ss) ≥ 9.6 mg h/mL, PFS was 8.1 months versus 5.7 months for AUC(ss) < 9.6 mg h/mL and 4.6 months for placebo. No relationship between AUC(ss) and grade ≥ 3 adverse events was observed. Simulations predicted that AMG 386 15 mg/kg once weekly would result in an AUC(ss) ≥ 9.6 mg h/mL in > 90% of patients with median PFS of 8.2 months versus 5.0 months for placebo (HR [15 mg/kg vs. placebo], 0.56). CONCLUSIONS: Increased exposure to AMG 386 was associated with improved clinical outcomes in recurrent ovarian cancer, supporting the evaluation of a higher dose in future studies.

Investigation of the pharmacokinetics of romiplostim in rodents with a focus on the clearance mechanism.

PURPOSE: Romiplostim, a treatment for adults with immune thrombocytopenia (ITP), is a novel thrombopoietin mimetic agent with a similar mechanism of action as thrombopoietin with no sequence homology. Structurally, it is a peptibody containing thrombopoietin mimetic peptides and the Fc portion of human IgG(1). We investigated romiplostim pharmacokinetics in rodents with a focus on the clearance mechanism. METHODS: Studies with appropriate controls were conducted in four models: FcRn knockout mice, thrombocytopenic mice, splenectomized rats, and bilateral nephrectomized rats. Catabolic breakdown of romiplostim was investigated in normal rats. The primary analytical method determines the intact/active romiplostim concentration, and the secondary method determines the sum of romiplostim and its catabolic degradants. RESULTS: FcRn interaction results in prolonged exposure. Platelets are involved in the target-mediated elimination, a saturable process and more prominent at low dose. Splenectomy does not affect the romiplostim pharmacokinetics in rats, an observation not unexpected. Nephrectomy in rats results in a greater increase of romiplostim exposure at a higher romiplostim dose, a nonlinearity likely due to saturation of competing pathway. Catabolism plays a major role in romiplostim elimination. CONCLUSION: Romiplostim clearance involves multiple mechanisms, including a nonlinear pathway. Consequently, the relative contribution of different mechanisms appears to be dose dependent.

Population pharmacokinetic/pharmacodynamic modeling for the time course of tumor shrinkage by motesanib in thyroid cancer patients.

OBJECTIVE: To develop a population pharmacokinetic/pharmacodynamic model describing the relationship between motesanib exposure and tumor response in a phase 2 study of motesanib in patients with advanced differentiated thyroid cancer or medullary thyroid cancer. METHODS: Data from patients (n = 184) who received motesanib 125 mg once daily were used for population pharmacokinetic/pharmacodynamic modeling. Motesanib concentrations were fitted to a 2-compartment population pharmacokinetic model. Observed change in tumor size was the drug response measure for the pharmacodynamic model. Exposure measures in the pharmacokinetic/pharmacodynamic model included dose, plasma concentration profile, or steady-state area under the concentration versus time curve (AUC( ss )). A longitudinal exposure-tumor response model of drug effect on tumor growth dynamics was used. RESULTS: Motesanib oral clearance in patients with medullary thyroid cancer was 67% higher than in patients with differentiated thyroid cancer patients (73.7 vs. 44 L/h). Patients' disease type (medullary thyroid cancer vs. differentiated thyroid cancer) was the most important covariate for explaining interpatient variability in clearance. The objective response rates were 14 versus 2% for differentiated thyroid cancer and medullary thyroid cancer, respectively. Motesanib exposure measures (AUC( ss ) or concentration profile) were better predictors of tumor response than motesanib dose. The estimated motesanib concentration yielding tumor stasis (1.9 ng/mL) was lower than the observed trough concentrations in differentiated thyroid cancer and medullary thyroid cancer patients. CONCLUSIONS: Differences in motesanib pharmacokinetics likely explain the difference in tumor response observed between differentiated thyroid cancer and medullary thyroid cancer patients. The population pharmacokinetic/pharmacodynamic model provides a tool for predicting tumor response to the drug to support the dosing regimen of motesanib in thyroid cancer patients.

Effect of coadministration of ketoconazole, a strong CYP3A4 inhibitor, on pharmacokinetics and tolerability of motesanib diphosphate (AMG 706) in patients with advanced solid tumors.

Motesanib diphosphate is a novel angiogenesis inhibitor selectively targeting vascular endothelial growth factor receptors 1, 2, and 3; platelet-derived growth factor receptor and stem cell factor receptor. The purpose of this phase 1b, drug-drug interaction study was to investigate the effect of ketoconazole, a strong inhibitor of the cytochrome P450 3A4 isoenzyme, on the pharmacokinetics and tolerability of motesanib diphosphate. Fourteen patients with advanced solid tumors refractory to standard treatment were enrolled and received motesanib diphosphate 50 mg once daily from day 1 through 15. Patients were randomized to receive a single oral dose of ketoconazole 400 mg either on day 8 (Sequence 1; n = 7) or day 15 (Sequence 2; n = 7), while pharmacokinetic samples were collected. After completion of this part (day 16), 13 patients received an escalated once-daily dose of motesanib diphosphate 125 mg. Evaluable pharmacokinetic data (n = 12) suggest that ketoconazole modestly increased motesanib exposure. The motesanib area under the concentration-time curve (AUC) from 0 to 24 h increased by 86% (90% CI, 1.50-2.29; P < 0.001) and the maximum plasma concentration (C (max)) by 35% (90% CI, 1.12-1.64; P = 0.02), compared with motesanib diphosphate administration alone. The tolerability profile (with or without ketoconazole coadministration) was consistent with that from other motesanib diphosphate monotherapy studies. Treatment-related adverse events were mild to moderate and commonly included fatigue (50% of patients), hypertension (43%), diarrhea (21%), dizziness (14%), paresthesia (14%), and vomiting (14%). Hypertension was the most common related grade 3 event (21%). No grade 4 or 5 treatment-related adverse events occurred.