Estimation of Variance for Harmonic Mean Half-Lives

Purpose: BMS-214662 is a nonsedating benzodiazepine derivative that exhibits broad spectrum cytotoxicity against human solid tumor cell lines and potently inhibits farnesylation of the H-ras and K-ras oncogenic proteins. This report describes the initial Phase I clinical trial of the compound. The main objective of the study was to determine the doselimiting toxicities and the maximum tolerated dose of BMS-214662 when administered as a single dose i.v. over 1 h every 21 days to patients with advanced solid tumors.Experimental Design: Patients with advanced solid tumors and adequate organ function were eligible for the study. The dose was escalated according to a modified Fibonacci schedule after evaluating groups of at least three patients for toxicity during the first cycle of therapy at each dose level. Pharmacokinetic and pharmacodynamic studies were performed after administration of the two initial doses.Results

Section: Methodsmentioning

confidence: 99%

Phase I Clinical Trial of the Farnesyltransferase Inhibitor BMS-214662 Given as a 1-Hour Intravenous Infusion in Patients with Advanced Solid Tumors

Ryan

Eder

Puchlaski

et al. 2004

“…All group results are expressed as arithmetic mean and SD with the exception of T max and T 1/2 . T max is expressed as the median and range and T 1/2 is reported as the harmonic mean and pseudo SD based on the jackknife variance technique (32).…”

Section: Pharmacokineticsmentioning

confidence: 99%

Pharmacokinetics and Tolerability of a Single Dose of DN-101, a New Formulation of Calcitriol, in Patients with Cancer

Beer

Javle²,

Lam

et al. 2005

Background: Intermittent administration allows substantial dose escalation of calcitriol but limited bioavailability of the commercially available formulations at high doses is limiting. In this dose escalation study, we sought to evaluate the tolerability and pharmacokinetics of a single oral dose of DN-101, a high-dose calcitriol formulation. Methods: DN-101 doses were escalated in sequential groups of three to six patients with advanced solid tumors. Dose-limiting toxicity was defined as grade z2 hypercalcemia or grade z3 persistent treatment-related toxicities. Single-dose administration of 15,30, 60, 75, 90, 105, 135, and 165 Ag was tested. Results: Thirty-eight patients were enrolled in 2002 and 2003. The median age was 70 years (range, 44-91 years). Dose escalation was stopped at the 165 Ag level when the number of capsules required at one time reached 11. No dose-limiting toxicities occurred. Transient and selflimited grade 3 toxicities were hyponatremia (2) and proteinuria (1). A dose-proportional increase in peak concentration (C max ) and area under the concentration curve (AUC) was seen across the full range of DN-101doses tested. At the 165 Ag dose, C max was 6.21 F1.99 ng/mL, AUC(0-24) was 41.3 F 9.77 ng h/mL, AUC(0-1) was 55.4 F 8.44, and half-life (T 1/2 ) was 16.2 hours. Conclusions: At doses between 15 and 165 Ag, DN-101 exhibits linear pharmacokinetics. At 165 Ag, DN-101 achieves systemic exposure that is 5-to 8-fold higher than that achieved with commercial formulations of calcitriol, which makes DN-101 comparable to that required for antitumor activity in vivo in a murine squamous cell carcinoma model.Numerous studies have shown that calcitriol, the natural ligand of the vitamin D receptor, potently inhibits cell proliferation in vitro and in vivo in many cell types, including carcinomas of the breast, prostate, colon, skin, and brain, myeloid leukemia cells, and others (1, 2). Recently, calcitriol has also been shown to induce apoptosis and to inhibit angiogenesis, tumor invasion, and metastases (reviewed in ref. 3). Calcitriol or its analogues have been shown to produce additive or synergistic antineoplastic activity with a broad range of agents including dexamethasone (4, 5), retinoids (6, 7), tamoxifen (8 -10), and radiation (11, 12), and several cytotoxic chemotherapy drugs, including docetaxel (13), paclitaxel (14), platinum compounds (15, 16), mitoxantrone (17), doxorubicin (18), and etoposide (19), are enhanced by calcitriol or its analogues. These preclinical data have stimulated interest in developing calcitriol for cancer treatment. Antineoplastic effects of calcitriol occur at supraphysiologic concentrations. In in vitro models of human prostate (LNCaP and DU145), pancreas (CaPAN-1), lung (MV522), breast (MCF-7), myeloma (H929), leukemia (HL-60), rat prostate (Dunning), and murine squamous cell carcinoma (SCC), IC 50 values of 1 to 50 nmol/L have been reported (14, 20 -22). Johnson and Trump also confirm these findings.5 Kumagai et al. found that the 1,25 dihydroxychole...

“…Instead, only the following pharmacokinetic variables for free camptothecin in plasma are presented: AUC, C max , T max , and apparent t 1/2 . Mean values and SDs were determined for all variables except t 1/2 's for which harmonic means and pseudo-SDs are presented (16).…”

Section: Methodsmentioning

confidence: 99%

Phase 1 Study of Weekly Polyethylene Glycol-Camptothecin in Patients with Advanced Solid Tumors and Lymphomas

Posey

Saif

Carlisle

et al. 2005

Purpose:To determine the maximal tolerated dose and dose-limiting toxicities (DLT) of pegamotecan (polyethylene glycol-camptothecin) in patients with advanced malignancies when administered in cycles of once weekly for 3 of 4 weeks. Experimental Design: Eligible patients had advanced solid tumors that failed to respond to standard therapy or for which no standard therapy was available, including also the following criteria: measurable disease, Eastern Cooperative Oncology Group performance status of V2, and acceptable organ function. Pegamotecan was administered as a 60-minute infusion, with successive patient cohorts receiving escalating doses from 800 to 4,300 mg/m 2 . The primary end point was to determine the maximal tolerated dose. Other end points were toxicity, pharmacokinetics, pharmacodynamics, and efficacy. Pharmacokinetic analysis measured free camptothecin. Pharmacodynamic analysis correlated drug effects with pegamotecan dose and pharmacokinetic variables. Results: Twenty-seven patients were enrolled. The maximal tolerated dose was 3,240 mg/m 2 . Grade 4 neutropenia, the DLT, was noted in two of four patients treated at 4,300 mg/m 2 . Other grade 3 and 4 toxicities were anemia, thrombocytopenia, fatigue, prolonged partial thromboplastin time, hemorrhagic cystitis, dysuria, and urinary frequency. Pharmacokinetic analysis showed the apparent terminal elimination half-life to be 46 F 12.8 hours. Pharmacodynamic analysis showed that hematuria occurred in 8 of 15 patients with an area under the curve extrapolated to infinity (AUC 0-1 ) > 20 ng h/mL and 0 of10 patients with an AUC 0-1 V 20 ng h/mL. Unconfirmed partial responses were observed in two patients, one with metastatic small bowel adenocarcinoma and the other with metastatic esophageal cancer. Conclusions: The maximal tolerated dose of pegamotecan when administered weekly for 3 of 4 weeks is 3,240 mg/m 2 . The DLT was neutropenia. Among nonhematologic toxicities, the incidence of gastrointestinal toxicity was low, but genitourinary toxicity seems to occur in the same effective dose range as noted with native camptothecin in earlier trials (27-43 mg/m 2 ). The observed antitumor activity suggests that pegamotecan has single-agent activity and merits further investigation in phase 2 studies.