Treatment of malignant pleural effusion with the trifunctional antibody catumaxomab (Removab) (anti-EpCAM x Anti-CD3): results of a phase 1/2 study.

Catumaxomab is a trifunctional monoclonal antibody consisting of a mouse immunoglobulin G2a part and a rat immunoglobulin G2b part with 2 different antigen binding sites binding the epithelial cell adhesion molecule antigen on tumor cells and CD3 on T lymphocytes. The intact Fc region provides a third functional binding site, binding and activating selectively Fcgamma receptor I, IIa, and III-positive accessory cells. These binding properties lead to specific tumor cell killing. As catumaxomab demonstrated efficacy in patients with malignant ascites, we performed this phase 1/2 trial in patients with malignant pleural effusion (MPE). We investigated a series of 3 escalating doses of 5 to 200 microg catumaxomab administered intrapleurally to patients with MPE containing epithelial cell adhesion molecule -positive cells. Primary objectives were determination of dose-limiting toxicity, safety, and tolerability. Secondary objectives were efficacy and pharmacodynamics. Twenty-four patients were treated with catumaxomab. Most frequent adverse events were pyrexia, elevated liver enzymes, nausea, and decreased lymphocytes. Dose-limiting toxicities were observed in 2 patients: One had pleural empyema and fatal sepsis and 1 had grade 3 erythema and hepatobiliary disorder. Five patients with breast cancer out of 7 evaluable patients had a response to treatment. Intrapleural administration of catumaxomab is feasible although the substantial number of drop-outs and deaths in short proximity to study treatment raise questions whether MPE is the right indication for catumaxomab or whether the patient population should be defined different. Safety profile was as expected reflecting catumaxomab's mode of action. Preliminary efficacy showed a suggestion of improvement in some patients.

Clinical benefit in NSCLC: advanced-stage patients require symptom-improving palliation. Experiences from the 'Iressa' expanded access program.

BACKGROUND: The molecular genesis of lung cancer and its treatment remain hot spots of medical research because of the high mortality rates especially associated with non-small-cell lung cancer (NSCLC). New agents are required. The epidermal growth factor receptor (EGFR) pathway inhibitor gefitinib (Iressa) has been the first approved drug for NSCLC within this new therapeutic class. PATIENTS AND METHODS: The anti-tumor activity of gefitinib in a monocentric and prospective case series of 72 patients with refractory NSCLC is analyzed. Patients who had histologically confirmed NSCLC with one or more previous chemotherapies were eligible for enrollment. Patients received 250 mg gefitinib orally once daily for at least 28 days. RESULTS: An 8% response rate (PR) and an additional 42% rate of disease stabilizations (SD) have been found in our patient collective. The median survival of all patients was 8.6 weeks (95% CI 5.9-11.2). Comparing responders, patients with stable disease, and progressive patients it becomes evident that patients sensitive to gefitinib get a clinical benefit in terms of palliation and overall survival. Adenocarcinoma histology and former nicotine abstention seem to favor sensitivity to gefitinib. CTC grade 3/4 toxicities were observed in only one patient in form of skin reactions. Mild toxicities (CTC grade 1/2) were diarrhea, conjunctivitis and elevation of transaminases. CONCLUSION: These prospective data suggest an activity of gefitinib in pre-treated NSCLC patients without relevant toxicities. They are in agreement with other published data.

Density functional theory study of the d(10) series (H3P)3M(eta 1-SO2) and (MenPh(3-n)P)3M(eta 1-SO2) (M = Ni, Pd, Pt; n = 0-3): SO2 pyramidality and M-S bond dissociation energies.

Quantum mechanical density functional theory (DFT) and coupled DFT/molecular mechanics (QMMM) studies of the compounds (H(3)P)(3)M(eta(1)-SO(2)) and (Me(n)Ph(3-n)P)(3)M(eta(1)-SO(2)) (M = Ni, Pd, Pt; n = 0-3) model the experimental data well, particularly the planar/pyramidal geometries at sulfur. Bond dissociation energy (BDE) calculations confirm that Pd/Pt systems with pyramidal SO(2) ligands exhibit M-S BDEs smaller by 30-50% than Ni systems with planar SO(2). However, scans of the potential energy surfaces show that flexing the planar/pyramidal torsion angle within ranges of 20-30 degrees requires little energy. Bond energy decomposition calculations indicate that the electrostatic Delta E(elstat) term determines the BDE for Pd/Pt molecules where the sulfur is pyramidal, whereas all three terms matter when the sulfur is planar, as for Ni compounds. However, this accounts only for a fraction of the BDE differences; orbital energy matching accounts for the balance.