Impact of food and the proton pump inhibitor rabeprazole on the pharmacokinetics of GDC-0941 in healthy volunteers: bench to bedside investigation of pH-dependent solubility.

GDC-0941 is an orally administered potent, selective pan-inhibitor of phosphatidylinositol 3-kinases (PI3Ks) with good preclinical antitumor activity in xenograft models and favorable pharmacokinetics and tolerability in phase 1 trials, and it is currently being investigated in phase II clinical trials as an anti-cancer agent. In vitro solubility and dissolution studies suggested that GDC-0941, a weak base, displays significant pH-dependent solubility. Moreover, preclinical studies conducted in famotidine-induced hypochlorhydric dog suggested that the pharmacokinetics of GDC-0941 may be sensitive to pharmacologically induced hypochlorhydria.

Prevalence of acid-reducing agents (ARA) in cancer populations and ARA drug-drug interaction potential for molecular targeted agents in clinical development.

Acid-reducing agents (ARAs) are the most commonly prescribed medications in North America and Western Europe. There are currently no data describing the prevalence of their use among cancer patients. However, this is a paramount question due to the potential for significant drug-drug interactions (DDIs) between ARAs, most commonly proton pump inhibitors (PPIs), and orally administered cancer therapeutics that display pH-dependent solubility, which may lead to decreased drug absorption and decreased therapeutic benefit.

A phase 1 study of weekly dosing of trastuzumab emtansine (T-DM1) in patients with advanced human epidermal growth factor 2-positive breast cancer.

Background: We conducted a phase 1, multicenter, open-label, dose-escalation study (TDM3569g) to assess the safety, tolerability, and pharmacokinetics of single-agent trastuzumab emtansine (T-DM1) administered weekly and once every 3 weeks in patients with HER2-positive metastatic breast cancer previously treated with trastuzumab. The weekly dose results are described here.

Methods: Patients were administered escalating doses of T-DM1 weekly, starting at 1.

Trastuzumab emtansine (T-DM1): a novel agent for targeting HER2+ breast cancer.

Increased understanding of the molecular mechanisms of tumorigenesis has led to the development of novel agents that target tumor cells with minimal effects on normal cells. The success of this approach is exemplified by the development of monoclonal antibodies directed toward antigens expressed selectively by tumor cells. The conjugation of these monoclonal antibodies with potent cytotoxic drugs has the potential to further improve efficacy while retaining a favorable safety profile.

Phase I study of trastuzumab-DM1, an HER2 antibody-drug conjugate, given every 3 weeks to patients with HER2-positive metastatic breast cancer.

Purpose: Trastuzumab-DM1 (T-DM1) is an antibody-drug conjugate that uses trastuzumab to specifically deliver the maytansinoid antimicrotubule agent DM1 to HER2-positive cells. This first-in-human study of T-DM1 evaluated safety, pharmacokinetics, and preliminary activity of T-DM1 in patients with advanced HER2-positive breast cancer.

Patients And Methods: Successive cohorts of patients who had progressed on trastuzumab-based therapy received escalating doses of T-DM1.

A phase I study of gefitinib, capecitabine, and celecoxib in patients with advanced solid tumors.

This phase I study was designed to determine the maximum tolerated dose (MTD) and toxicity profile of the combination of gefitinib, capecitabine, and celecoxib in patients with advanced solid tumors. Patients were treated with escalating doses of gefitinib once daily, capecitabine twice daily (14 of 28 days), and celecoxib twice daily. Plasma samples for biomarkers were obtained at baseline and weekly for the first 2 cycles.

A phase I pharmacological and biological study of PI-88 and docetaxel in patients with advanced malignancies.

Purpose: This study evaluated the safety, toxicity, pharmacological properties and biological activity of PI-88, a heparanase endoglycosidase enzyme inhibitor, with fixed weekly docetaxel in patients with advanced solid malignancies.

Experimental Design: This was a phase I study to determine the maximal-tolerated dose of escalating doses of PI-88 administered subcutaneously for 4 days per week, along with docetaxel 30 mg/m(2) given on days 1, 8, 15 of a 28-day schedule.

Results: Sixteen patients received a total of 42 courses of therapy.

A phase I safety, tolerability, and pharmacokinetic study of enzastaurin combined with capecitabine in patients with advanced solid tumors.

Enzastaurin, an oral inhibitor of protein kinase Cbeta, affects signal transduction associated with angiogenesis, proliferation, and survival. Capecitabine is converted to 5-fluoruracil by thymidine phosphorylase, a putative angiogenic factor. The all-oral combination of the two drugs offers the potential for targeting angiogenesis in capecitabine-sensitive tumors with nonoverlapping toxicities.

Arterial thromboembolic events in patients with metastatic carcinoma treated with chemotherapy and bevacizumab.

Background: Although combination treatment with bevacizumab (humanized monoclonal antibody against vascular endothelial growth factor) and chemotherapy improves survival of patients with various metastatic carcinomas, an increased risk of arterial thromboembolic events has been observed in some trials. We characterized this risk by performing post hoc analyses of randomized controlled trials that evaluated combination treatment with bevacizumab and chemotherapy versus chemotherapy alone. Low-dose aspirin was permitted in these trials, and its safety was also analyzed.

Impact of vascular endothelial growth factor-A expression, thrombospondin-2 expression, and microvessel density on the treatment effect of bevacizumab in metastatic colorectal cancer.

Purpose: Bevacizumab is a monoclonal antibody to vascular endothelial growth factor-A (VEGF). In the pivotal trial in metastatic colorectal cancer (mCRC), addition of bevacizumab to first-line irinotecan, fluorouracil, and leucovorin (IFL) significantly prolonged median survival. The aim of these retrospective subset analyses was to evaluate VEGF, thrombospondin-2 (THBS-2), and microvessel density (MVD) as prognostic factors and/or predictors of benefit from bevacizumab.

Association of k-ras, b-raf, and p53 status with the treatment effect of bevacizumab.

Background: A recent phase III trial showed that the addition of bevacizumab, a monoclonal antibody to vascular endothelial growth factor-A, to first-line irinotecan, 5-fluorouracil, and leucovorin (IFL) prolonged median survival in patients with metastatic colorectal cancer. We carried out a retrospective analysis of patients in the trial to evaluate whether mutation status of k-ras, b-raf, or p53 or P53 expression could predict which patients were more likely to respond to bevacizumab.

Methods: Microdissected tumors from 295 patients (274 primary tumors, 21 metastases) were subject to DNA sequence analysis to identify mutations in k-ras, b-raf, and p53.

Safety and pharmacokinetic study of RPI.4610 (ANGIOZYME), an anti-VEGFR-1 ribozyme, in combination with carboplatin and paclitaxel in patients with advanced solid tumors.

Purpose: RPI.4610 (ANGIOZYME) is a chemically stabilized ribozyme targeting vascular endothelial growth factor receptor 1. The purpose of this study was to evaluate the safety and pharmacokinetics of RPI.

A phase I and pharmacokinetic study of exisulind and docetaxel in patients with advanced solid tumors.

Purpose: Exisulind (sulindac sulfone, FGN-1, Aptosyn) is a sulindac metabolite that induces apoptosis via inhibition of cyclic GMP-phosphodiesterase. This agent demonstrated tumor growth inhibition in rodent models of colon, breast, prostate, and lung carcinogenesis. In an orthotopic model of human non-small-cell lung cancer, the combination of exisulind and docetaxel prolonged survival in athymic nude rats, forming the basis of this phase I combination study.

Analysis of docetaxel pharmacokinetics in humans with the inclusion of later sampling time-points afforded by the use of a sensitive tandem LCMS assay.

Purpose: Docetaxel is a semisynthetic taxane derived from the needles of the European yew ( Taxus baccata) and it is an important chemotherapeutic agent in the treatment of recurrent ovarian, breast and non-small-cell lung cancers. Traditional dosing regimens with docetaxel involve doses of 60-100 mg/m(2) by infusion every 3 weeks. Now weekly low-dose (30-36 mg/m(2)) regimens are being evaluated in phase I trials.

Angiogenesis inhibitors in clinical development for lung cancer.

The use of tumor angiogenesis as a therapeutic target is based on extensive literature showing the dependence of tumors on the process of angiogenesis for growth, invasion, and metastasis. Seminal work performed by Folkman three decades ago determined that tumors beyond the size of approximately 2 mm require angiogenesis for subsequent growth and development. This basic hypothesis stimulated research in the field of angiogenesis and has resulted in the identification of factors that both enhance and inhibit this "angiogenic switch.