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Gupta M.,Genentech | Lorusso P.M.,Barbara Ann Karmanos Cancer Institute | Wang B.,Genentech | Yi J.-H.,Genentech | And 8 more authors.
Journal of Clinical Pharmacology | Year: 2012

Trastuzumab emtansine (T-DM1) is a HER2-targeted antibody-drug conjugate in development for treatment of HER2-positive cancers. T-DM1 has been tested as a single agent in a phase I and 2 phase II studies of patients with heavily pretreated metastatic breast cancer (MBC), with the maximum tolerated dose established at 3.6 mg/kg intravenously for every-3-week dosing. The authors present results from the population pharmacokinetics analysis for T-DM1. Population pharmacokinetics for T-DM1 were characterized using a clinical database of 273 patients from the 3 studies. Pharmacokinetics was best described by a linear 2-compartment model. Population estimates (interindividual variability [IIV]) for pharmacokinetic parameters were clearance, 0.7 L/d (21.0%); central compartment volume (Vc), 3.33 L (13.2%); peripheral compartment volume (Vp), 0.89 L (50.4%); and intercompartmental clearance, 0.78 L/d. Body weight, albumin, tumor burden, and aspartate aminotransferase levels were identified as statistically significant covariates accounting for interindividual variability in T-DM1 pharmacokinetics, with body weight having a greater effect on IIV of clearance and Vc than other covariates. T-DM1 exposure was relatively consistent across the weight range following body weight-based dosing. This analysis suggests no further T-DM1 dose adjustments are necessary in heavily pretreated patients with MBC. © 2012 The Author(s). Source


Raez L.E.,University of Miami | Papadopoulos K.,Institute for Drug Development | Ricart A.D.,Institute for Drug Development | Chiorean E.G.,Indiana University | And 11 more authors.
Cancer Chemotherapy and Pharmacology | Year: 2013

Purpose: This phase I trial was initiated to evaluate the safety, pharmacokinetics (PK) and maximum tolerated dose (MTD) of the glycolytic inhibitor, 2-deoxy-d-glucose (2DG) in combination with docetaxel, in patients with advanced solid tumors. Methods: A modified accelerated titration design was used. 2DG was administered orally once daily for 7 days every other week starting at a dose of 2 mg/kg and docetaxel was administered intravenously at 30 mg/m2 for 3 of every 4 weeks beginning on day 1 of week 2. Following the completion of dose escalation, cohorts of patients were then treated with 2DG for 21 days or every day of each 4-week cycle for up to 12 cycles. Results: Thirty-four patients were enrolled: 21 on every other week, 6 on a 21 of 28-day cycle and 7 on the continuous 2DG dosing schedule. There were no dose-limiting toxicities which met the MTD criteria. The most common adverse events were fatigue, sweating, dizziness and nausea mimicking the hypoglycemic symptoms expected from 2DG administration. Therefore, 63 mg/kg was selected as the clinically tolerable dose. The most significant adverse effects noted at 63-88 mg/kg doses were reversible hyperglycemia (100 %), gastrointestinal bleeding (6 %) and reversible grade 3 QTc prolongation (22 %). Eleven patients (32 %) had stable disease, 1 patient (3 %) partial response and 22 patients (66 %) progressive disease as their best response. There was no PK interaction between 2DG and docetaxel. Conclusion: The recommended dose of 2DG in combination with weekly docetaxel is 63 mg/kg/day with tolerable adverse effects. © 2012 Springer-Verlag Berlin Heidelberg. Source


Mita M.M.,Institute for Drug Development | Spear M.A.,Nereus Pharmaceuticals | Mita A.C.,Institute for Drug Development | Heath E.I.,Barbara Ann Karmanos Cancer Institute | And 11 more authors.
Clinical Cancer Research | Year: 2010

Purpose: Plinabulin (NPI-2358) is a vascular disrupting agent that elicits tumor vascular endothelial architectural destabilization leading to selective collapse of established tumor vasculature. Preclinical data indicated plinabulin has favorable safety and antitumor activity profiles, leading to initiation of this clinical trial to determine the recommended phase 2 dose (RP2D) and assess the safety, pharmacokinetics, and biologic activity of plinabulin in patients with advanced malignancies. Experimental Design: Patients received a weekly infusion of plinabulin for 3 of every 4 weeks. A dynamic accelerated dose titration method was used to escalate the dose from 2 mg/m2 to the RP2D, followed by enrollment of an RP2D cohort. Safety, pharmacokinetic, and cardiovascular assessments were conducted, and Dynamic contrast-enhanced MRI (DCE-MRI) scans were performed to estimate changes in tumor blood flow. Results: Thirty-eight patients were enrolled. A dose of 30 mg/m2 was selected as the RP2D based on the adverse events of nausea, vomiting, fatigue, fever, tumor pain, and transient blood pressure elevations, with DCE-MRI indicating decreases in tumor blood flow (Ktrans) from 13.5 mg/m2 (defining a biologically effective dose) with a 16% to 82% decrease in patients evaluated at 30 mg/m2. Half-life was 6.06 ± 3.03 hours, clearance was 30.50 ± 22.88 L/h, and distributive volume was 211 ± 67.9 L. Conclusions: At the RP2D of 30 mg/m2, plinabulin showed a favorable safety profile, while eliciting biological effects as evidenced by decreases in tumor blood flow, tumor pain, and other mechanistically relevant adverse events. On the basis of these results additional clinical trials were initiated with plinabulin in combination with standard chemotherapy agents. ©2010 AACR. Source


Kurzrock R.,University of Texas M. D. Anderson Cancer Center | Patnaik A.,Institute for Drug Development | Aisner J.,Cancer Institute of New Jersey | Warren T.,University of Texas M. D. Anderson Cancer Center | And 8 more authors.
Clinical Cancer Research | Year: 2010

Purpose: A phase I study was conducted to evaluate the pharmacokinetics, pharmacodynamics, safety, and tolerability of R1507 - a fully human IgG1 type monoclonal antibody directed against the human insulin-like growth factor-I receptor. Experimental design: Patients with advanced solid tumors were assigned to receive i.v. R1507 weekly (qW), starting with 1 mg/kg. Subsequent cohorts were dosed at 3 and then 9 mg/kg. An additional 12 patients received 9 mg/kg R1507 qW. Patients remained on the study until the development of a dose-limiting toxicity or progressive disease. Results: In total, 37 patients were treated with R1507 qW. No dose-limiting toxicities were identified and the maximum tolerated dose was not reached. The pharmacokinetics of R1507 were characterized by a slow clearance and limited volume of distribution, with an estimated elimination half-life justifying weekly administration. Serum IGF-I ligand levels increased proportionally to dose during the first 72 hours in all cohorts. R1507 was well tolerated. Two patients diagnosed with Ewing's sarcoma had partial responses of 11.5 and >26 months (ongoing at time of submission); 13 patients had stable disease; and 16 had progressive disease as best response by the Response Evaluation Criteria in Solid Tumors. Conclusion: R1507 is well tolerated and shows antitumor activity in patients with solid neoplasms, in particular Ewing's sarcoma. The recommended dose for the weekly schedule is 9 mg/kg qW. ©2010 AACR. Source

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