PK/PD modeling of FXI antisense oligonucleotides to bridge the dose-FXI activity relation from healthy volunteers to end-stage renal disease patients.

IONIS-FXI (BAY2306001) is an antisense oligonucleotide that inhibits the synthesis of coagulation factor XI (FXI) and has been investigated in healthy volunteers and patients with end-stage renal disease (ESRD). FXI-LICA (BAY2976217) shares the same RNA sequence as IONIS-FXI but contains a GalNAc-conjugation that facilitates asialoglycoprotein receptor (ASGPR)-mediated uptake into hepatocytes. FXI-LICA has been studied in healthy volunteers and is currently investigated in patients with ESRD on hemodialysis.

Effect of Diet on Serum Creatinine in Healthy Subjects During a Phase I Study.

Creatinine is widely used as an indirect marker of renal function. However, interfering factors such as diet, exercise and problems with the assay can generate false results and misinterpretation of real kidney function. In this article, we report the dietary effects on serum creatinine during a phase I single dose escalation study and discuss the reasons why serum creatinine should be measured under fasting conditions.

SEARCH: a phase III, randomized, double-blind, placebo-controlled trial of sorafenib plus erlotinib in patients with advanced hepatocellular carcinoma.

Purpose: To compare the clinical outcomes of sorafenib plus either erlotinib or placebo in patients with advanced hepatocellular carcinoma (HCC) in a multicenter, multinational, randomized, phase III trial.

Patients And Methods: Patients with advanced HCC and underlying Child-Pugh class A cirrhosis, who were naive to systemic treatment (N = 720), were randomly assigned to sorafenib plus either erlotinib (n = 362) or placebo (n = 358). The primary end point was overall survival (OS).

The novel chimeric anti-NCAM (neural cell adhesion molecule) antibody ch.MK1 displays antitumor activity in SCID mice but does not activate complement-dependent cytolysis (CDC).

A monoclonal chimeric antibody ch.MK1 was generated by immunizing F004 mice expressing human instead of murine IgG1/kappa immunoglobulin constant regions. The novel antibody specifically binds cell surface-expressed human neural cell adhesion molecule (NCAM) as shown by immunoprecipitation, flow cytometry and cytospins.

Seventy-five years of Resochin in the fight against malaria.

The four different forms of human malaria have threatened humanity since time immemorial and to this day, they exact a death toll of one to three million people annually. Synthetic anti-malarial agents have been in development since early 1900. Perhaps the most successful and widely used drug, Resochin (chloroquine), was discovered 75 years ago; for a long time, it was the drug of choice and to this day, it is still used in many regions of the world as a reliable treatment against simpler forms of malaria.

Phase I study of a novel pro-apoptotic drug R-etodolac in patients with B-cell chronic lymphocytic leukemia.

R-etodolac is a novel pro-apoptotic agent with potential antitumor activity against B-cell chronic lymphocytic leukemia (B-CLL). This phase I clinical trial was conducted to determine the tolerability, safety, and maximum tolerated dose (MTD) of R-etodolac, administered orally twice a day (BID), in patients with B-CLL. Secondary objectives included evaluating clinical response, pharmacodynamic activity (reduction of lymphocytes), and pharmacokinetic (PK) profile.

Targeting the neural cell adhesion molecule in cancer.

NCAM is a tumour associated antigen expressed on small cell lung cancer, neuroblastoma, rhabdomyosarkoma, brain tumours, multiple myelomas and acute myeloid leukaemia. Constant and strong expression of NCAM is a prerequisite for the development of antibody-based immunotherapies. From the spectrum of existing anti-NCAM compounds, radioimmunoconjugates and immunotoxins represent the clinically most advanced and successful strategies.

One step generation of fully chimeric antibodies using Cgamma1- and Ckappa mutant mice.

Humanized antibodies (Abs) are effective drugs against a variety of diseases such as cancer, autoimmune diseases, transplant rejection and others. The most powerful technology to develop humanized Abs is the use of mice that produce humanized Abs. By modifying the genetic background of F004 mice a new mouse substrain was developed for optimized "one step" generation of chimeric humanized monoclonal Abs.

Prolonged remission in a patient with relapsed follicular lymphoma after a single course of rituximab.

Background: Rituximab monotherapy can achieve remissions of up to 80% in follicular lymphoma. As the antibody has only been on the market since 1997, long-term observations are still rare.

Case Report: We report about a patient with follicular lymphoma who received a single treatment of 4 x 375 mg/m(2) of the monoclonal antibody rituximab without chemotherapy and has been in complete remission (CR) for 8 years.

Localization of 131I-labelled monoclonal antibody ERIC1 in a subcutaneous xenograft model of neuroblastoma in SCID mice.

Purpose: To evaluate a novel strategy of immunolocalization of human neuroblastoma by targeting the neural cell adhesion molecule (NCAM), which is over-expressed on neuroblastoma.

Methods: NCAM expression on the cell surface of established neuroblastoma cells was shown by flow cytometry. A SCID mouse model using IMR5-75 neuroblastoma cells to induce subcutaneous tumour growth was established.

Implementation and evaluation of a central coordination office for clinical trials in a tertiary care hospital.

Background: Controlled clinical trials are essential tools for establishing new standards in patient care. Nevertheless, the majority of cancer patients are not treated within clinical trials. We report about a project now running for 7 years that was started in order to enhance the recruitment of patients into clinical trials, to improve trial-related quality, and to comply with the regulatory issues related to these studies.

Fludarabine in combination with alemtuzumab is effective and feasible in patients with relapsed or refractory B-cell chronic lymphocytic leukemia: results of a phase II trial.

Purpose: To determine the efficacy and safety of a newly developed concomitant administration of fludarabine and alemtuzumab (FluCam) in patients with relapsed or refractory B-cell chronic lymphocytic leukemia (B-CLL).

Patients And Methods: A total of 36 patients were treated in this phase II study (median age, 61.47 years; mean number of prior chemotherapies, 2.

Reduced frequencies and suppressive function of CD4+CD25hi regulatory T cells in patients with chronic lymphocytic leukemia after therapy with fludarabine.

Globally suppressed T-cell function has been described in many patients with cancer to be a major hurdle for the development of clinically efficient cancer immunotherapy. Inhibition of antitumor immune responses has been mainly linked to inhibitory factors present in cancer patients. More recently, increased frequencies of CD4+CD25hi regulatory T cells (Treg cells) have been described as an additional mechanism reducing immunity.

NK cell depletion diminish tumour-specific B cell responses.

Natural killer (NK) cells can exercise immediate cytotoxicity against malignant cells and thus far modulate the development of tumour directed T cell immunity. To investigate the impact of NK cells on the development of tumour directed B cell immunity mice were immunised with IMR5-75 human neuroblastoma cells with or without prior in vivo NK cell depletion. Flow cytometry analyses gave evidence for an impaired IgG response against the cells immunised with.