Assessment of the biological and pharmacological effects of the alpha nu beta3 and alpha nu beta5 integrin receptor antagonist, cilengitide (EMD 121974), in patients with advanced solid tumors.

Background: Cilengitide, an antiangiogenic agent that inhibits the binding of integrins alpha(nu)beta(3) and alpha(nu)beta(5) to the extracellular matrix, was studied at two dose levels in cancer patients to determine the optimal biological dose.

Patients And Methods: The doses of cilengitide were 600 or 1200 mg/m(2) as a 1-h infusion twice weekly every 28 days. A novel dose escalation scheme was utilized that relied upon the biological activity rate.

Priorities in colorectal cancer research: recommendations from the Gastrointestinal Scientific Leadership Council of the Coalition of Cancer Cooperative Groups.

Emerging technologies have greatly expanded our ability to detect, characterize, and treat colorectal cancer. The Coalition of Cancer Cooperative Groups convened a multidisciplinary panel, the Scientific Leadership Council in GI cancer, to discuss and advise on the priorities and opportunities to advance current and future approaches into the clinical arena to impact most rapidly the morbidity and mortality from this disease. The Council's recommendations for research priorities are the result of engagement of community and academic oncologists, patient advocacy groups, and other stakeholders including the pharmaceutical industry and governmental agencies.

A physiologically based pharmacokinetic model of docetaxel disposition: from mouse to man.

Purpose: Docetaxel (Taxotere), an important chemotherapeutic agent with shown activity in a broad range of cancers, is being investigated for use in combination therapies and as an antiangiogenic agent. Docetaxel exhibits a complex pharmacologic profile with high interpatient variability. Pharmacokinetic models capable of predicting exposure under various dosing regimens would aid the rational development of clinical protocols.

A phase I pharmacokinetic and pharmacodynamic study of s-3304, a novel matrix metalloproteinase inhibitor, in patients with advanced and refractory solid tumors.

Purpose: Matrix metalloproteinases (MMP) play a fundamental role in cancer development and progression. S-3304 is a potent, orally active, noncytotoxic inhibitor of MMPs, primarily MMP-2 and MMP-9, that prolongs survival in mice xenografts and is well tolerated in healthy volunteers.

Experimental Design: The aims of this phase I clinical trial were to determine the maximum tolerated dose, dose-limiting toxicities, pharmacokinetic profile, and intratumoral MMP inhibitory activity of single-agent S-3304 in advanced and refractory solid tumors.

Sunitinib: from rational design to clinical efficacy.

Sunitinib (SU011248) is an oral small molecular tyrosine kinase inhibitor that exhibits potent antiangiogenic and antitumor activity. Tyrosine kinase inhibitors such as SU6668 and SU5416 (semaxanib) demonstrated poor pharmacologic properties and limited efficacy; therefore, sunitinib was rationally designed and chosen for its high bioavailability and its nanomolar-range potency against the antiangiogenic receptor tyrosine kinases (RTKs)--vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR). Sunitinib inhibits other tyrosine kinases including, KIT, FLT3, colony-stimulating factor 1 (CSF-1), and RET, which are involved in a number of malignancies including small-cell lung cancer, GI stromal tumors (GISTs), breast cancer, acute myelogenous leukemia, multiple endocrine neoplasia types 2A and 2B, and familial medullary thyroid carcinoma.

The farnesyl transferase inhibitor, tipifarnib, is a potent inhibitor of the MDR1 gene product, P-glycoprotein, and demonstrates significant cytotoxic synergism against human leukemia cell lines.

Farnesyl transferase inhibitors (FTIs) target signal-transduction pathways responsible for the proliferation and survival of hematologic malignancies, including acute myelogenous leukemias (AML). Lonafarnib has been shown to be a potent inhibitor of Pgp-mediated drug efflux. On the basis of these findings, we examined the Pgp-inhibitory properties of tipifarnib and assessed its activity when combined with anthracyclines.

Novel targets in solid tumors: MEK inhibitors.

MAPK/ERK kinase (MEK) inhibitors constitute a promising class of novel targeted therapies. Although some of the initial clinical results with these compounds were disappointing, newer agents with more advantageous pharmacokinetic and pharmacodynamic properties have entered clinical trials. Partial responses have been seen in patients with advanced melanoma and pancreatic cancer, along with prolonged stable disease in several tumor types.

Randomized phase III study of exatecan and gemcitabine compared with gemcitabine alone in untreated advanced pancreatic cancer.

Purpose: Exatecan mesylate is a hexacyclic, water-soluble, topoisomerase-1 inhibitor. Exatecan has single-agent and combination activity with gemcitabine in advanced pancreatic cancer. A multicenter, randomized, phase III trial comparing exatecan plus gemcitabine versus gemcitabine alone in advanced pancreatic cancer was conducted.

A phase I safety, pharmacological and biological study of the farnesyl protein transferase inhibitor, tipifarnib and capecitabine in advanced solid tumors.

Background: To evaluate the toxicity and pharmacological and biological properties of the farnesyl protein transferase (FPTase) inhibitor, tipifarnib (R115777, ZARNESTRAtrade mark) and capecitabine administered for 14 days every 3 weeks.

Patients And Methods: Patients with advanced cancers received twice daily tipifarnib (100-500 mg) and capecitabine (1000-1125 mg/m(2)) for 14 days every 3 weeks. Pharmacokinetics of tipifarnib, capecitabine and 5-fluorouracil (5-FU) were determined.

Sequence-dependent inhibition of human colon cancer cell growth and of prosurvival pathways by oxaliplatin in combination with ZD6474 (Zactima), an inhibitor of VEGFR and EGFR tyrosine kinases.

To date, clinical studies combining the new generation of targeted therapies and chemotherapy have had mixed results. Preclinical studies can be used to identify potential antagonism/synergy between certain agents, with the potential to predict the most efficacious combinations for further investigation in the clinical setting. In this study, we investigated the sequence-dependent interactions of ZD6474 with oxaliplatin in two human colon cell lines in vitro.

Development and validation of a drug activity biomarker that shows target inhibition in cancer patients receiving enzastaurin, a novel protein kinase C-beta inhibitor.

Purpose: To evaluate the effects of the novel protein kinase C (PKC) inhibitor enzastaurin on intracellular phosphoprotein signaling using flow cytometry and to use this approach to measure enzastaurin effects on surrogate target cells taken from cancer patients that were orally dosed with this agent.

Experimental Design: The activity of PKC was assayed in intact cells using a modification of published techniques. The U937 cell line and peripheral blood mononuclear cells were stimulated with phorbol ester, fixed, permeabilized, and reacted with an antibody specific for the phosphorylated forms of PKC substrates.

Phase II trial of bevacizumab in combination with weekly docetaxel in metastatic breast cancer patients.

Purpose: To evaluate the safety and efficacy of bevacizumab and weekly docetaxel as first- or second-line therapy in patients with metastatic breast cancer (MBC).

Patients And Methods: Twenty-seven MBC patients received i.v.

Anti-tumor activity of the combination of cetuximab, an anti-EGFR blocking monoclonal antibody and ZD6474, an inhibitor of VEGFR and EGFR tyrosine kinases.

Purpose: The epidermal growth factor receptor (EGFR) autocrine pathway plays an important role in cancer cell growth. Vascular endothelial growth factor A (VEGF-A) is a key regulator of tumor-induced endothelial cell proliferation and vascular permeability. ZD6474 is an orally available, small molecule inhibitor of VEGF receptor-2 (VEGFR-2), EGFR and RET tyrosine kinase activity.

Phase I, pharmacokinetic, and pharmacodynamic study of intravenously administered Ad5CMV-p53, an adenoviral vector containing the wild-type p53 gene, in patients with advanced cancer.

Purpose: The purpose of this study was to assess the feasibility of administering Ad5CMV-p53, an adenoviral vector containing the wild-type p53 gene to patients with advanced malignancies, characterize the pertinent pharmacokinetic parameters, identify evidence of viral uptake in both normal and tumor tissue, and seek evidence of antitumor activity.

Methods: Patients were treated with escalating doses of Ad5CMV-p53 intravenously over 30 minutes on days 1, 2, and 3, every 28 days. The clearance of circulating Ad5CMV-p53 (INGN 201) DNA was characterized in the plasma and paired tumor and skin biopsies were performed in patients treated at the two highest dose levels to assess vector uptake into tissues.

Molecular targeted therapy: a strategy of disillusions or optimism?

Cytotoxic drugs were designed to kill tumor cells, whereas agents of molecular targeted therapy inhibit various molecular functions of the tumor cell. Consequently, their toxicity profiles also differ. Molecular targeted agents, except for monoclonal antibodies, are enumerated here in three classes: compounds active extracellularly, extra/intracellularly, and intracellularly.

Pallister-Killian syndrome: an unusual cause of epileptic spasms.

Pallister-Killian syndrome (PKS) is a rare, sporadic, genetic disorder characterized by dysmorphic features, learning disability, and epilepsy. It is caused by a mosaic supernumerary isochromosome 12p (i[12p]). The i(12p) is rarely found in peripheral blood but it is present in skin fibroblasts.

A Phase II study of intravenous exatecan administered daily for 5 days, every 3 weeks to patients with biliary tract cancers.

Purpose: Exatecan is a hexacyclic topoisomerase-1 inhibitor that has broad in vitro and in vivo activity. A multicenter phase II study to determine the antitumor activity of exatecan was conducted in patients with advanced cholangiocarcinoma and gallbladder carcinoma.

Methods: Patients with 0 to 1 prior chemotherapy regimens, adequate major organ function, and metastatic disease were eligible.

Sequence-dependent antiproliferative effects of cytotoxic drugs and epidermal growth factor receptor inhibitors.

Background: Epidermal growth factor receptor (EGFR) inhibitors are in clinical development in cancer treatment. Preclinical studies have shown potential antitumor efficacy of these agents in combination with chemotherapy or with radiotherapy. However, controversial results have been obtained in different clinical trials.

[Clinical studies with imatinib in 2004].

The successful period of targeted molecular therapy of malignancies started with the beneficial clinical application of trastuzumab and imatinib. Imatinib is a targeted molecule capable to inhibit tyrosine kinase active in the production of abl-bcr protein responsible for the translocation of 9 and 22 chromosome in chronic myeloid leukemia. Simultaneously the drug may be active against C-kit PDGFRalpha and beta, COL 1a1 and FIPI-LI gene mutations as well.

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.

Clinical evaluation of ZD6474, an orally active inhibitor of VEGF and EGF receptor signaling, in patients with solid, malignant tumors.

Background: ZD6474 selectively inhibits the tyrosine kinase activity of vascular endothelial growth factor receptor and epidermal growth factor receptor. The safety, tolerability and pharmacokinetics of ZD6474 were assessed in a phase I dose-escalation study of patients with advanced solid tumors.

Patients And Methods: Adult patients with tumors refractory to standard treatments received once-daily oral ZD6474 (50-600 mg) in 28-day cycles, until disease progression or unacceptable toxicity was observed.

A phase I and pharmacokinetic study of BAY59: a novel taxane.

Purpose: To determine the maximum tolerated dose (MTD), the dose limiting toxicities (DLT) and the pharmacokinetics of BAY59, a novel taxane given as a 1-hour intravenous infusion every 3 weeks in patients with advanced refractory solid tumors.

Experimental Design: Initially, 15 patients with previously treated (median of 4 prior chemotherapy regimens) refractory cancers, but with normal marrow, hepatic and renal function were treated with BAY59 at doses of 15, 30, 50, 75 and 100 mg/m2 using a standard dose escalation design. Subsequently, 11 patients were treated, 5 at 90 mg/m2 and 6 who had had prior oxaliplatin at 75 mg/m2.

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.