Purpose Pertuzumab is a humanized monoclonal antibody inhibiting human epidermal growth factor receptor 2 (HER2) dimerization. The aim of this phase II trial was to assess the antitumor activity and safety profile of pertuzumab monotherapy in patients with HER2-negative metastatic breast cancer. The utility of biomarkers detected in paraffin-embedded tissue as predictors of response was also explored. Patients and Methods This was an international, multicenter, open-label, randomized phase II study. Patients (n = 79) with centrally confirmed HER2-negative metastatic breast cancer were randomly assigned to receive pertuzumab once every 3 weeks with a loading dose of 840 mg followed thereafter by either 420 mg (arm A) or 1,050 mg (arm B). Patients were stratified by country and prior taxane therapy. Results Of 79 patients who were randomly assigned, 78 were included in the intent-to-treat population. In arm A (n = 41), two patients had partial responses, and 18 patients (44%) experienced stable disease (SD)...

Open-Label, Phase II, Multicenter, Randomized Study of the Efficacy and Safety of Two Dose Levels of Pertuzumab, a Human Epidermal Growth Factor Receptor 2 Dimerization Inhibitor, in Patients With Human Epidermal Growth Factor Receptor 2–Negative Metastatic Breast Cancer

Catumaxomab is a trifunctional monoclonal antibody with binding sites directed to human EpCAM and the human T cell antigen CD3 (anti-EpCAM × anti-CD3). Catumaxomab demonstrated efficacy when administered intraperitoneally in patients with EpCAM positive malignant ascites from ovarian cancer in terms of tumor cell killing and reduction of ascites generation. As EpCAM is also overexpressed in NSCLC, the present study was conducted in order to evaluate safety and tolerability of intravenous treatment with catumaxomab. UICC stage IB–IV NSCLC patients were eligible, if they had at least one prior therapy. Other inclusion criteria were: age 18–75 years, adequate bone marrow function and AST or gamma-GT ≤ 2.5 ULN. Escalating doses of catumaxomab were administered over 8 h as a continuous intravenous infusion. Dose escalation started at 2 μg and was increased to 7.5 μg. In addition various doses of dexamethasone as premedication were investigated. All patients were pretreated with antihistamines. Dose limiting toxicity (DLT) was a grade 3 and 4 elevation of ALT, AST and gamma-GT, which was observed in dose level IV (10 mg dexamethasone premedication, 5 μg catumaxomab) and V (40 mg dexamethasone followed by 7.5 μg catumaxomab). Elevated liver enzymes decreased to grade 2 within 3–7 days and were at baseline level within 14 days after infusion. The maximum tolerated dose (MTD) was defined in dose level III (40 mg of dexamethasone followed by 5 μg of catumaxomab). Five micrograms of catumaxomab with a pre-medication of 40 mg dexamethasone and antihistamines can be recommended as first dose for i.v. therapy consisting of multiple catumaxomab infusions for patients with NSCLC.

Treatment of non-small cell lung cancer patients with the trifunctional monoclonal antibody catumaxomab (anti-EpCAM x anti-CD3): a phase I study.

The invention relates to tumors expressing HER2 and EGFR, using HER2-dimerization inhibitors (HDIs) and EGFR inhibitors.

Combination therapy of her expressing tumors

PROBLEM TO BE SOLVED: To provide a method for treating cancer comprising administering one or more fixed doses of HER antibodies to a human patient in an amount effective to treat the cancer.SOLUTION: A method of treating cancer in a human patient comprises administering at least one fixed dose of pertuzumab to the patient, where the fixed dose is selected from a group consisting of approximately 420 mg, approximately 525 mg, approximately 840 mg, and approximately 1,050 mg of pertuzumab. An article of manufacture comprises a vial containing a fixed dose of HER antibodies, where the fixed dose is selected from a group consisting of approximately 420 mg, approximately 525 mg, approximately 840 mg, and approximately 1,050 mg of the HER antibodies.

Fixed dosing of her antibodies

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

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

2532 Background: Pertuzumab, a humanized HER2-targeted antibody, represents the first in a new class of targeted therapeutic agents known as HER2 dimerization inhibitors (HDIs). Pertuzumab blocks ligand-associated HER2 dimerization with HER kinase family members (EGFR, HER3, HER4), thereby inhibiting intracellular signaling through MAP and PI3 kinases. Pertuzumab is currently being evaluated in phase II studies as a single-agent in ovarian, breast, prostate, and lung cancers. Interim pertuzumab PK data from the phase II studies is presented. Methods: Pertuzumab was administered once every 3 weeks (q3 week) as an IV infusion at a fixed dose of either 420 mg following an initial 840 mg loading dose (LD), or 1050 mg with no LD. PK data from four phase II studies were pooled for analysis by both descriptive and population PK (PopPK) modeling Methods: Results: PopPK modeling of the data from ovarian and breast cancer studies showed that a linear 2-compartment model best described the concentration-time profile...

V. Jimenez

Papers

Pharmacokinetics (PK) of pertuzumab (rhuMAb 2C4) in phase II studies of ovarian, breast, prostate, and lung cancers