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Dose-escalation Study (dose-escalation + study)

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Medical Sciences	100%

Selected Abstracts

Phase 1 Dose-Escalation Study of CP-690 550 in Stable Renal Allograft Recipients: Preliminary Findings of Safety, Tolerability, Effects on Lymphocyte Subsets and Pharmacokinetics

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 8 2008
E. Van Gurp
CP-690 550 inhibits Janus kinase 3 with nanomolar potency. In this dose-escalation study, we assessed the safety, tolerability, effects on lymphocyte subsets, and pharmacokinetics of CP-690 550 when coadministered with mycophenolate mofetil in stable renal allograft recipients for 28 days. Twenty-eight patients were enrolled. Six patients received CP-690 550 5 mg twice daily (BID), 6 patients received 15 mg BID, 10 patients received 30 mg BID, and 6 patients received placebo. The most frequent adverse events were infections and gastrointestinal (abdominal pain, diarrhea, dyspepsia, and vomiting). CP-690 550 15 mg BID and 30 mg BID were associated with a mean decrease in hemoglobin from baseline of 11% and a mean decrease in absolute natural killer cell counts of 50%. CP-690 550 30 mg BID was also associated with a mean increase in absolute CD19+ B-lymphocytes of 130%. There were no changes in the number of neutrophils, total lymphocytes, platelets, or CD4+ or CD8+ T cells; clinical chemistry; vital signs; or electrocardiograms from the pretreatment baseline. Administration of CP-690 550 without a concomitant calcineurin inhibitor resulted in CP-690 550 exposures consistent with previous studies in nontransplant subjects. Additional dose-ranging studies are warranted to evaluate the safety and efficacy of CP-690 550 in renal transplant recipients over longer treatment duration. [source]

Novel tobramycin inhalation powder in cystic fibrosis subjects: Pharmacokinetics and safety

PEDIATRIC PULMONOLOGY, Issue 4 2007
David E. Geller MD
Abstract Aerosolized antibiotics are associated with a high treatment burden that can result in non-adherence to chronic therapy. We evaluated the pharmacokinetics (PK) and safety of tobramycin inhalation powder (TIP), a novel dry-powder formulation designed to deliver a high payload of tobramycin topically to the lungs for management of chronic Pseudomonas aeruginosa infections. This was a multi-center, open-label, sequential-cohort, single-dose, dose-escalation study using the standard 300 mg dose of tobramycin solution for inhalation (TSI) as an active control. Subjects were randomized to TIP or TSI in a 3:1 ratio in each of five cohorts. Measurements included serum and sputum tobramycin concentrations, administration time, serum chemistries, acute change in lung function, and adverse events (AEs). Out of 90 randomized subjects, 86 had data for safety analysis; and 84 had data for PK analysis. Serum tobramycin PK profiles were similar for TIP and TSI. Four capsules of 28 mg TIP (total tobramycin dose 112 mg) produced comparable systemic exposure to 300 mg TSI, in less than one-third the administration time. The most common AEs associated with TIP were cough (20%) and dysgeusia (17%). TIP allows for faster and more efficient pulmonary delivery of tobramycin than TSI and has a safety profile that supports continued clinical investigation. The increased rate of local respiratory tract irritation noted with TIP is not unexpected with a high-payload powder formulation. The development of dry powder inhaled antibiotics may represent an important advance in the treatment of chronic lung infections. Pediatr Pulmonol. 2007; 42:307,313. © 2007 Wiley-Liss, Inc. [source]

Phase 1 Dose-Escalation Study of CP-690 550 in Stable Renal Allograft Recipients: Preliminary Findings of Safety, Tolerability, Effects on Lymphocyte Subsets and Pharmacokinetics

Delayed memory B cell recovery in peripheral blood and lymphoid tissue in systemic lupus erythematosus after B cell depletion therapy

ARTHRITIS & RHEUMATISM, Issue 9 2007
Jennifer H. Anolik
Objective Recent data suggest that the reconstituting peripheral B cell compartment after B cell depletion therapy may be functionally immature, with a preponderance of transitional B cells and a paucity of memory B cells. This study was undertaken to determine the magnitude, duration, and cause of these defects in rituximab-treated systemic lupus erythematosus (SLE) patients. Methods Fifteen patients with SLE previously treated with rituximab as part of a phase I/II dose-escalation study were evaluated during a long-term followup (mean followup period 41 months). B cells from peripheral blood and tonsils were assessed using multicolor flow cytometry, and their developmental pathway was classified based on the expression of defined surface markers. Results Reconstitution of peripheral blood CD27+ memory B cells was delayed for several years after B cell depletion therapy in a subset of patients with prolonged clinical responses and autoantibody normalization. This delay correlated with the degree of expansion of B cells of a transitional phenotype during the B cell reconstitution phase (P = 0.005) and the absence of baseline autoantibodies directed against extractable nuclear antigens (RNP, Sm, Ro antigen, La antigen). Despite the paucity of peripheral blood memory cells and the prolonged expansion of functionally immature transitional B cells, tonsil biopsy tissues revealed active germinal center (GC) reactions, but with decreased Fc receptor homolog 4,positive memory B cells. Conclusion These results suggest heterogeneity in the B cell depletion and reconstitution process that impacts clinical and immunologic outcomes in SLE. The presence of GC reactions, but with altered memory B cell subpopulations in tonsils, suggests that peripheral blood memory cell reconstitution lags behind a slow secondary lymphoid tissue recovery, with important implications for immunologic competence and tolerance. [source]

Determining the Optimal Dose of Intravenous Fat Emulsion for the Treatment of Severe Verapamil Toxicity in a Rodent Model

ACADEMIC EMERGENCY MEDICINE, Issue 12 2008
Eric Perez MD
Abstract Objectives:, Recent animal studies have shown that intravenous fat emulsion (IFE) increases survival and hemodynamics in severe verapamil toxicity. However, the optimal dose of IFE is unknown. The primary objective was to determine the optimal dose of IFE based on survival in severe verapamil toxicity. Secondary objectives were to determine the effects on hemodynamic and metabolic parameters. The hypothesis was that there is a dose-dependent effect of IFE on survival until a maximum dose is reached. Methods:, This was a controlled dose-escalation study. Thirty male rats were anesthetized, ventilated, and instrumented to record mean arterial pressure (MAP) and heart rate (HR). Verapamil toxicity was achieved by a constant infusion of 15 mg/kg/hr. After 5 minutes, a bolus of 20% IFE was given. Animals were divided into six groups based on differing doses of IFE. Arterial base excess (ABE) was measured every 30 minutes. Data were analyzed with analysis of variance. Results:, The mean survival time for each dose of IFE was 0 mL/kg = 34 minutes, 6.2 mL/kg = 58 minutes, 12.4 mL/kg = 63 minutes, 18.6 mL/kg = 143.8 minutes, 24.8 mL/kg = 125.6 minutes, and 37.6 mL/kg = 130 minutes. Post hoc testing determined that the 18.6 mL/kg dose resulted in the greatest survival when compared to other doses. It increased survival 107.2 minutes (p = 0.004), 91.2 minutes (p = 0.001), and 80.8 minutes (p = 0.023) when compared to the lower doses of 0, 6.2, and 12.4 mL/kg, respectively. There was no added benefit to survival for doses greater than 18.6 mL/kg. The secondary outcomes of HR, MAP, and ABE showed the most benefit with 24.8 mL/kg of IFE at both 30 and 60 minutes. Conclusions:, The greatest benefit to survival occurs with 18.6 mL/kg IFE, while the greatest benefit to HR, MAP, and BE occurs at 24.8 mL/kg IFE. The optimal dose for the treatment of severe verapamil toxicity in this murine model was 18.6 mL/kg. [source]

A pilot dose-escalation study of the effects of nordihydroguareacetic acid on hormone and prostate specific antigen levels in patients with relapsed prostate cancer

BJU INTERNATIONAL, Issue 4 2008
Charles J. Ryan
OBJECTIVE To assess the tolerability of the effects of nordihydroguareacetic acid (NDGA) and its effect on prostate-specific antigen (PSA) kinetics in patients with relapsed prostate cancer, as among the many biological effects of NDGA is the inhibition of the insulin-like growth factor 1 receptor (IGF-1R) tyrosine kinase. PATIENTS AND METHODS Eligible patients were those with an increasing PSA level after definitive local therapy, in either the non-castrate (androgen-dependent prostate cancer, ADPC) or the castrate state (castration-resistant prostate cancer, CRPC) with no evidence of metastatic disease by bone scan or computed tomography of the abdomen or pelvis. Treatment consisted of continuous oral daily dosing according to a planned dose escalation of 750, 1250, 1750, 2250 and 2500 mg of NDGA. PSA levels were measured every 28 days. Serial levels of testosterone, dihydrotestosterone, oestradiol and sex hormone-binding globulin were measured at baseline and monthly while on study therapy. RESULTS Fifteen patients were enrolled, including 11 with ADPC and four with CRPC. There were asymptomatic increases in transaminase in six patients, two of which were grade 3, all occurring at ,3 months. The increases in transaminase resolved after stopping NDGA but recurred with repeated dosing. Doses of NDGA up to 2500 mg/day caused no other toxicities. A median (range) of 5.5 (1,13) cycles were delivered. Of the 11 patients with ADPC, one had a decline in PSA level of >50% of the baseline value and one a decline of <50%. Three patients with ADPC had a greater than three-fold increase in PSA doubling time while on therapy, one from 11 to 46 months (750 mg), one from 9.5 to 49.5 months (1750 mg), and one from 5.9 to 46.2 months (2500 mg). There were no reductions in PSA level in patients with CRPC. There were no significant effects on levels of testosterone, dihydrotestosterone, oestradiol or sex hormone-binding globulin. CONCLUSIONS Continuous daily dosing with NDGA is reasonably well tolerated but is associated with transaminitis in some patients, that occurs after several months on therapy. There were apparent effects on the rate of increase in PSA. Further study is required to determine the optimum pharmacokinetics and antitumour effects of this therapy. [source]

Phase 1 study of INNO-406, a dual Abl/Lyn kinase inhibitor, in Philadelphia chromosome-positive leukemias after imatinib resistance or intolerance

CANCER, Issue 11 2010
Hagop Kantarjian MD
Abstract BACKGROUND: INNO-406, a dual v-abl Abelson murine leukemia viral oncogene homolog (Abl)/v-yes-1 Yamaguchi sarcoma viral-related oncogene homolog (Lyn) tyrosine kinase inhibitor (TKI), has demonstrated specific Lyn kinase inhibitory activity with no or limited activity against other sarcoma (Src) family member kinases. Several breakpoint cluster region (Bcr)-Abl kinase domain mutations are sensitive to INNO-406 in vitro, including mutations that involve a phenylalanine-to-leucine or phenylalanine-to-valine substitution at codon 317 (F317L and F317V, respectively). In the current study, the authors evaluated the use of INNO-406 in patients with Philadelphia (Ph) chromosome-positive chronic myelogenous leukemia (CML) or acute lymphocytic leukemia (ALL) after imatinib resistance or intolerance. METHODS: A dose-escalation study was conducted at a starting dose of oral INNO-406 30 mg once daily. Cohorts of at least 3 patients were treated at each dose level until the maximum tolerated dose (MTD) was reached. Twice-daily dosing also was evaluated. Therapy was allowed to continue for a maximum of 24 months. RESULTS: INNO-406 was administered to 56 patients with imatinib resistance (n = 40) or intolerance (n = 16). Other previous treatments included nilotinib (n = 20 patients), dasatinib (n = 26 patients), and dasatinib/nilotinib (n = 9 patients). Common mutations at the time of study entry included a tyrosine-to-histidine substitution at codon 253 (Y253H) (n = 6 patients), a glycine-to-glutamic acid substitution at codon 250 (G250E) (n = 4 patients), a threonine-to-isoleucine substitution at codon 315 (T315I) (n = 4 patients), and F317L (n = 3 patients). Of 31 patients with CML in chronic phase who received INNO-406, the major cytogenetic response rate was 19%. No responses were observed in patients who had CML in accelerated phase, CML in blastic phase, or Ph-positive ALL. The dose-limiting toxicities (DLTs) at an INNO-406 dose of 480 mg twice daily were liver function abnormalities and thrombocytopenia. CONCLUSIONS: INNO-406 had anti-CML efficacy in a heavily pretreated study population. On the basis of the classic determinations of both DLT and MTD, the recommended phase 2 dose of oral INNO-406 was 240 mg twice daily. Lower doses of INNO-406 may be equally effective and should be explored. Cancer 2010. © 2010 American Cancer Society. [source]

Phase 1/2 dose-escalation study of a GM-CSF-secreting, allogeneic, cellular immunotherapy for metastatic hormone-refractory prostate cancer,

CANCER, Issue 5 2008
Celestia S. Higano MD
Abstract BACKGROUND This open-label, multicenter, dose-escalation study evaluated multiple dose levels of immunotherapy in patients with metastatic hormone-refractory prostate cancer (HRPC). The immunotherapy, based on the GVAX platform, consisted of 2 allogeneic prostate-carcinoma cell lines modified to secrete granulocyte-macrophage-colony-stimulating factor (GM-CSF). METHODS Dose levels ranged from 100 × 106 cells q28d × 6 to 500 × 106 cells prime/300 × 106 cells boost q14d × 11. Endpoints included safety, immunogenicity, overall survival, radiologic response, prostate-specific antigen (PSA) kinetics, and serum GM-CSF pharmacokinetics. RESULTS Eighty men, median age 69 years (range, 49-90 years), were treated. The most common adverse effect was injection-site erythema. Overall, the immunotherapy was well tolerated. A maximal tolerated dose was not established. The median survival time was 35.0 months in the high-dose group, 20.0 months in the mid-dose, group, and 23.1 months in the low-dose group. PSA stabilization occurred in 15 (19%) patients, and a >50% decline in PSA was seen in 1 patient. The proportion of patients who generated an antibody response to 1 or both cell lines increased with dose and included 10 of 23 (43%) in the low-dose group, 13 of 18 (72%) in the mid-dose group, and 16 of 18 (89%) in the high-dose group (P = .002; Cochran-Armitage trend test). CONCLUSIONS This immunotherapy was well tolerated. Immunogenicity and overall survival varied by dose. Two phase 3 trials in patients with metastatic HRPC are underway. Cancer 2008. © 2008 American Cancer Society. [source]

Phase I/II and pharmacokinetic study of cladribine with 2-h infusion in Japanese patients with relapsed indolent B-cell lymphoma mostly pretreated with rituximab

CANCER SCIENCE, Issue 7 2009
Kensei Tobinai
We conducted a phase I/II study to investigate the toxicity, pharmacokinetics, and efficacy profiles of cladribine with 2-h intravenous infusion for five consecutive days every four weeks in Japanese patients with relapsed indolent B-cell lymphoma. This was a dose-escalation study to confirm the safety of the doses which have been recommended for Caucasian patients (phase I), and to further evaluate the efficacy and safety (phase II). In the phase I portion for nine patients, no dose-limiting toxicities were observed at levels 1 (0.09 mg/kg/day, n = 3) and 2 (0.12 mg/kg/day, n = 6). No appreciable accumulation of plasma cladribine concentration was suggested. We enrolled a total of 20 patients, and an additional 14 patients in the phase II portion at level 2 (0.12 mg/kg/day). Eighteen patients, including 13 with follicular lymphoma, were eligible for efficacy evaluation, and 15 (83%) were pretreated with rituximab. The overall response rate was 50% (9/18; 80% confidence interval, 35,65%), with 11% (2/18) complete response. With a median follow-up of 296 days, the estimated median time to progression for 18 eligible patients was 382 days. The most frequent adverse events were hematologic toxicities, including grade 4 neutropenia. Non-hematologic toxicities were mild. In conclusion, cladribine with 2-h intravenous infusion for five consecutive days every four weeks is effective with acceptable toxicities for Japanese patients with relapsed indolent B-cell lymphoma, including those pretreated with rituximab. (Cancer Sci 2009; 100: 1344,1350) [source]