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Purpose: Cabazitaxel has not been studied in patients with hepatic impairment (HI). This phase I study assessed cabazitaxel safety and pharmacokinetics in patients with HI., Methods: Patients with advanced, non-hematologic cancer, and normal hepatic function (Cohort 1: C-1), or mild (C-2), moderate (C-3), severe (C-4) HI received cabazitaxel starting doses of 25, 20, 10, and 10 mg/m 2 , respectively. Doses were escalated in patients with HI based on Cycle 1 dose-limiting toxicities (DLTs). Adverse events and the cabazitaxel pharmacokinetic profile were assessed., Results: In C-2, three patients receiving cabazitaxel 25 mg/m 2 experienced DLTs; maximum tolerated dose (MTD) was 20 mg/m 2 . In C-3, two patients receiving 20 mg/m 2 experienced DLTs; MTD was 15 mg/m 2 . C-4 was discontinued early due to DLTs. The most frequent cabazitaxel-related, grade 3-4 toxicity was neutropenia (42%). Cabazitaxel clearance normalized to body surface area (CL/BSA) was lower in C-1 (geometric mean [GM] 13.4 L/h/m 2 ) than expected (26.4 L/h/m 2 ), but similar in C-2 (23.5 L/h/m 2 ) and C-3 (27.9 L/h/m 2 ). CL/BSA in C-4 was 18.1 L/h/m 2 . Compared with C-2, CL/BSA increased 19% in C-3 (GM ratio 1.19; 90% CI 0.74-1.91), but decreased 23% in C-4 (0.77; 0.39-1.53). Cabazitaxel free fraction was unaltered. No significant correlation was found between grade 3-4 toxicities and pharmacokinetic parameters., Conclusions: Mild-moderate HI did not cause substantial decline in cabazitaxel clearance. Cabazitaxel dose reductions in patients with mild-moderate HI, and a contraindication in patients with severe HI, are justified based on safety data., Competing Interests: Compliance with ethical standardsConflict of interestJohn Sarantopoulos, Jimmy Hwang, James Mier, and Aiwu He have no conflicts of interest to disclose. Olivier Rixe has been a member of advisory boards for Areva Med and Sisene Oncology. John C. Morris has participated at speaker bureaus for Boehringer Ingelheim. Alain C. Mita has participated at speaker bureaus for Genentech. James L. Wade is a stockholder of Celgene and Seattle Genetics. A. Craig Lockhart has received research funding from Amgen, Bayer, Lilly, Novartis, Pfizer, and Genentech. David I. Quinn has received research funding and honoraria from Sanofi and has been a member of advisory boards for Sanofi. Chung-Tsen Hsueh has been a member of advisory boards for Bayer, Merrimack, and Onyx. Pierre-François Clot is an employee of Sanofi. Wenping Zhang, Claudine Wack, and Jian Yin are employees and stock holders of Sanofi.Ethical approvalAll procedures performed in studies involving human participants were in accordance with the ethical standards of the Institutional and/or National Research Committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

Purpose: First-in-human phase I trial to determine the safety, pharmacokinetics, and antitumor activity of BIND-014, a novel, tumor prostate-specific membrane antigen (PSMA)-targeted nanoparticle, containing docetaxel., Experimental Design: Patients with advanced solid tumors received BIND-014 every three weeks (n = 28) or weekly (n = 27), with dose levels ranging from 3.5 to 75 mg/m(2) and 15 to 45 mg/m(2), respectively., Results: BIND-014 was generally well tolerated, with no unexpected toxicities. The most common drug-related toxicities (>20% of patients) on either schedule included neutropenia, fatigue, anemia, alopecia, and diarrhea. BIND-014 demonstrated a dose-linear pharmacokinetic profile, distinct from docetaxel, with prolonged persistence of docetaxel-encapsulated circulating nanoparticles. Of the 52 patients evaluable for response, one had a complete response (cervical cancer on the every three week schedule) and five had partial responses (ampullary adenocarcinoma, non-small cell lung, and prostate cancers on the every-three-week schedule, and breast and gastroesophageal cancers on the weekly schedule). Responses were noted in both PSMA-detectable and -undetectable tumors., Conclusions: BIND-014 was generally well tolerated, with predictable and manageable toxicity and a unique pharmacokinetic profile compared with conventional docetaxel. Clinical activity was noted in multiple tumor types. The recommended phase II dose of BIND-014 is 60 mg/m(2) every three weeks or 40 mg/m(2) weekly. Clin Cancer Res; 22(13); 3157-63. ©2016 AACR., (©2016 American Association for Cancer Research.)

Purpose: Cabazitaxel is primarily metabolized by CYP3A. This study evaluated the impact of moderate/strong CYP3A inhibitors [aprepitant (Study Part 2); ketoconazole (Study Part 3)] or strong CYP3A inducers [rifampin (Study Part 4)] on the pharmacokinetics of cabazitaxel., Methods: Adult patients received IV cabazitaxel/cisplatin 15/75 mg/m(2) on Day 1 of 3-week cycles (5/75 mg/m(2) in Cycles 1 and 2 of Part 3 to allow a safety margin to the cabazitaxel MTD). Patients received repeated oral doses of aprepitant, ketoconazole or rifampin before/during Cycle 2. Cabazitaxel clearance was the primary endpoint; clearance and area under the plasma concentration-time curve (AUC) were normalized to body surface area and dose, respectively., Results: The PK population included 13 (Part 2), 23 (Part 3) and 21 patients (Part 4). Repeated aprepitant administration did not affect cabazitaxel clearance [geometric mean ratio (GMR) 0.98; 90 % confidence interval (CI) 0.80-1.19]. Repeated ketoconazole administration resulted in 20 % decrease in cabazitaxel clearance (GMR 0.80; 90 % CI 0.55-1.15), associated with 25 % increase in AUC (GMR 1.25; 90 % CI 0.86-1.81). Repeated rifampin administration resulted in 21 % increase in cabazitaxel clearance (GMR 1.21; 90 % CI 0.95-1.53), associated with 17 % decrease in AUC (GMR 0.83; 90 % CI 0.65-1.05). The GMR of AUC0-24 with rifampin administration was 1.09 (90 % CI 0.9-1.33), suggesting that rifampin had a low impact during the initial phases of cabazitaxel elimination. Safety findings were consistent with previous results., Conclusions: Cabazitaxel pharmacokinetics are modified by drugs strongly affecting CYP3A. Co-administration of cabazitaxel with strong CYP3A inhibitors or inducers should be avoided.

Purpose: ATI-1123 is a liposomal formulation of docetaxel and may be administered without the premedications and hypersensitivity reactions. This Phase I study examines the safety, tolerability, pharmacokinetics (PKs), and antitumor activity of ATI-1123., Methods: Patients with advanced solid malignancies received escalating doses of ATI-1123 intravenously over 1-h every 3 weeks. The dosing commenced using an accelerated titration design and was followed by a modified 3 + 3 Fibonacci schema to determine maximally tolerated dose (MTD). Plasma was analyzed for encapsulated/non-encapsulated docetaxel; PK analyses were performed using model independent method. Response was assessed using RECIST criteria., Results: In total, 29 patients received doses ranging from 15 to 110 mg/m(2). At 110 mg/m(2), two of six patients experienced dose-limiting toxicities including grade 3 stomatitis and febrile neutropenia. The 90 mg/m(2) cohort was expanded to ten patients and identified as the MTD. The most common adverse events were fatigue, nausea, neutropenia, anemia, anorexia, and diarrhea. ATI-1123 exhibited linear and dose proportional PKs. One patient with lung cancer had confirmed partial response, and stable disease was observed in 75 % patients., Conclusions: ATI-1123 demonstrated an acceptable tolerability and favorable PK profile in patients with solid tumors. Our results provide support for Phase II trials to determine the antitumor activity of this drug.

The taxanes are recognized as a major class of chemotherapeutic agents; however, mechanisms of innate and acquired resistance can limit their usefulness. Cabazitaxel, a novel taxane with microtubule-stabilizing potency similar to docetaxel, exhibits activity against tumor cell lines resistant to paclitaxel and docetaxel. Cabazitaxel showed linear pharmacokinetics and a terminal elimination half-life comparable with that of docetaxel, findings which support dosing as a single infusion in three-week treatment cycles. Dose-ranging studies recommended doses of 20 or 25 mg/m(2) every three weeks. Antitumor activity was shown in patients with advanced cancer and chemotherapy failure (including taxane failure). Other early studies investigated the efficacy of cabazitaxel in pretreated metastatic breast cancer, either as a single agent or in combination with capecitabine. Objective antitumor response rates of up to 24% and sustained tumor stabilizations were also observed. The TROPIC phase III study, conducted in patients with metastatic castrate-resistant prostate cancer previously treated with docetaxel, established cabazitaxel as the first chemotherapeutic agent to offer a survival advantage in this patient population. Across these studies, the dose-limiting hematologic toxicity was neutropenia (including febrile neutropenia), usually controllable with colony-stimulating factor/granulocyte-colony stimulating factor support., (©2012 AACR.)

Purpose: To assess the feasibility of administering XRP6258, a new taxane with a low affinity for the multidrug resistance 1 protein, as a 1-hour i.v. infusion every 3 weeks. The study also sought to determine the maximum tolerated dose and the recommended dose, to describe the pharmacokinetic (PK) behavior of the compound, and to seek preliminary evidence of anticancer activity., Experimental Design: Twenty-five patients with advanced solid malignancies were treated with 102 courses of XRP6258 at four dose levels ranging from 10 to 25 mg/m(2). Dose escalation was based on the occurrence of dose-limiting toxicity (DLT) at each dose level, provided that PK variables were favorable. The maximum tolerated dose was defined as the dose at which at least two patients developed a DLT at the first course., Results: Neutropenia was the principal DLT, with one patient experiencing febrile neutropenia and two others showing prolonged grade 4 neutropenia at the 25 mg/m(2) dose level. Nonhematologic toxicities, including nausea, vomiting, diarrhea, neurotoxicity, and fatigue, were generally mild to moderate in severity. XRP6258 exhibited dose-proportional PK, a triphasic elimination profile, a long terminal half-life (77.3 hours), a high clearance (mean CL, 53.5 L/h), and a large volume of distribution (mean V(ss), 2,034 L/m(2)). Objective antitumor activity included partial responses in two patients with metastatic prostate carcinoma, one unconfirmed partial response, and two minor responses., Conclusion: The recommended phase II dose of XRP6258 on this schedule is 20 mg/m(2). The general tolerability and encouraging antitumor activity in taxane-refractory patients warrant further evaluations of XRP6258.