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Phase I dose escalation pharmacokinetic assessment of intravenous humanized anti-MUC1 antibody AS1402 in patients with advanced breast cancer.

ABSTRACT: MUC1 is a cell-surface glycoprotein that establishes a molecular barrier at the epithelial surface and engages in morphogenetic signal transduction. Alterations in MUC1 glycosylation accompany the development of cancer and influence cellular growth, differentiation, transformation, adhesion, invasion, and immune surveillance. A 20-amino-acid tandem repeat that forms the core protein of MUC1 is overexpressed and aberrantly glycosylated in the majority of epithelial tumors. AS1402 (formerly R1550) is a humanized IgG1k monoclonal antibody that binds to PDTR sequences within this tandem repeat that are not exposed in normal cells. AS1402 is a potent inducer of antibody-dependent cellular cytotoxicity (ADCC), specifically against MUC1-expressing tumor cells. The objective of this study was to determine the safety, tolerability, and pharmacokinetic (PK) characteristics of AS1402 monotherapy in patients with locally advanced or metastatic MUC1-positive breast cancer that had progressed after anthracyclines- and taxane-based therapy.Patients received AS1402 over a 1- to 3-hour intravenous (i.v.) infusion at doses between 1 and 16 mg/kg, with repeated dosing every 1 to 3 weeks (based on patient-individualized PK assessment) until disease progression. Serum AS1402 levels were measured at multiple times after i.v. administration. Human anti-human antibody (HAHA) responses were measured to determine the immunogenicity of AS1402. Noncompartmental pharmacokinetic parameters were determined and were used to assess dose dependency across the dose range studied.Twenty-six patients were treated. AS1402 was generally well tolerated. Two grade 3/4 drug-related adverse events were reported, both at the 3-mg/kg dose. Neither was observed in expanded or subsequent dosing cohorts. No anti-human antibodies were detected. Plasma concentrations of AS1402 appeared to be proportional to dose within the 1- to 16-mg/kg dose range assessed, with a mean terminal half-life of 115.4 +/- 37.1 hours.Repeated iv administration of AS1402 was well tolerated, with a maximum tolerated dose (MTD) exceeding 16 mg/kg, the highest dose administered in this study. The half-life and exposure of AS1402 were such that weekly dosing could achieve plasma concentrations corresponding to the maximal ADCC activity observed in vitro. A phase II study is ongoing to evaluate the clinical activity of AS1402 in patients with advanced breast cancer.ClinicalTrials.gov Identifier: NCT00096057.

SUBMITTER: Pegram MD

PROVIDER: S-EPMC2790853 | biostudies-literature | 2009

REPOSITORIES: biostudies-literature

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Phase I dose escalation pharmacokinetic assessment of intravenous humanized anti-MUC1 antibody AS1402 in patients with advanced breast cancer.

Pegram Mark D MD Borges Virginia F VF Ibrahim Nuhad N Fuloria Jyotsna J Shapiro Charles C Perez Susan S Wang Karen K Schaedli Stark Franziska F Courtenay Luck Nigel N

Breast cancer research : BCR 20090101 5

<h4>Introduction</h4>MUC1 is a cell-surface glycoprotein that establishes a molecular barrier at the epithelial surface and engages in morphogenetic signal transduction. Alterations in MUC1 glycosylation accompany the development of cancer and influence cellular growth, differentiation, transformation, adhesion, invasion, and immune surveillance. A 20-amino-acid tandem repeat that forms the core protein of MUC1 is overexpressed and aberrantly glycosylated in the majority of epithelial tumors. AS ...[more]

PMID: 19811637

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Project description:ImportanceWe assessed feasibility of monthly subcutaneous administration of PF-06801591, a humanized immunoglobulin G4 monoclonal antibody that binds to the programmed cell death (PD-1) receptor and blocks its interaction with PD-1 ligands.ObjectiveTo evaluate the safety, efficacy, and pharmacokinetics of PF-06801591 administered intravenously vs subcutaneously.Design, setting, and participantsOngoing phase 1, open-label, multicenter, dose-escalation study of 40 patients, 18 years or older, with locally advanced or metastatic solid tumors, enrolled between March 8, 2016, and March 5, 2018, from 4 US medical centers.InterventionsAn intravenous dose of 0.5, 1, 3, or 10 mg/kg of PF-06801591 was administered every 3 weeks or a subcutaneous dose of 300 mg was administered every 4 weeks. Dose escalation occurred after 2 to 4 patients were enrolled per dose level, with additional patients enrolled in each cohort for further assessment.Main outcomes and measuresThe primary end points were dose-limiting toxic effects and safety. Secondary end points included pharmacokinetics, immunogenicity, PD-1 receptor occupancy, and efficacy.ResultsOf 40 enrolled patients (12 men and 28 women; mean [SD] age, 61 [13] years) in this phase 1 dose-escalation trial, 25 received PF-06801591 intravenously at escalating dose levels (0.5, 1, 3, or 10 mg/kg) and 15 patients received the monoclonal antibody subcutaneously at a single dose level. No dose-limiting toxic effects were observed. Grade 3 or higher treatment-related adverse events occurred in 4 (16%) patients treated intravenously and 1 (6.7%) patient treated subcutaneously. Immune-related adverse events occurred in 10 (40%) patients treated intravenously and 3 (20%) treated subcutaneously. No dose-adverse event associations were observed during intravenous dose escalation, and no serious skin toxic effects occurred with subcutaneous delivery. Responses were seen in 5 patients receiving PF-06801591 intravenously and in 2 patients treated subcutaneously for an overall objective response rate of 18.4%. Median overall survival was not reached with intravenous dosing vs 10.7 months with subcutaneous administration. Exposure to PF-06801591 increased in a dose-proportional manner over the range of intravenous doses. Median time to maximum observed serum concentration was 8 days after subcutaneous administration. Full PD-1 receptor occupancy was seen in all dose cohorts.Conclusions and relevanceAnti-PD-1 antibody PF-06801591 was tolerable and showed antitumor activity in a variety of tumor types across all dose levels of intravenous and subcutaneous administration. Monthly subcutaneous administration of PF-06801591 offers a convenient, effective alternative to currently available intravenously administered checkpoint inhibitors.Trial registrationClinicalTrials.gov identifier: NCT02573259.

Project description:BackgroundErythropoietin-producing hepatocellular receptor A2 (EPHA2) is overexpressed on the cell surface in many cancers and predicts poor prognosis. DS-8895a is a humanized anti-EPHA2 IgG1 monoclonal antibody afucosylated to enhance antibody-dependent cellular cytotoxicity activity. We conducted a two-step, phase I, multicenter, open-label study to determine the safety, tolerability, and pharmacokinetics of DS-8895a in patients with advanced solid tumors.MethodsStep 1 was a dose escalation cohort in advanced solid tumor patients (six dose levels, 0.1-20 mg/kg) to determine Step 2 dosing. Step 2 was a dose expansion cohort in EPHA2-positive esophageal and gastric cancer patients. DS-8895a was intravenously administered every 2 weeks for the duration of the study, with a 28-day period to assess dose-limiting toxicity (DLT). Safety, pharmacokinetics, tumor response, and potential biomarkers were evaluated.ResultsThirty-seven patients (Step 1: 22, Step 2: 15 [9: gastric cancer, 6: esophageal cancer]) were enrolled. Although one DLT (Grade 4 platelet count decreased) was observed in Step 1 (dose level 6, 20 mg/kg), the maximum tolerated dose was not reached; the highest dose (20 mg/kg) was used in Step 2. Of the 37 patients, 24 (64.9%) experienced drug-related adverse events (AEs) including three (8.1%) with Grade ≥ 3 AEs. Infusion-related reactions occurred in 19 patients (51.4%) but were manageable. All patients discontinued the study (evident disease progression, 33; AEs, 4). Maximum and trough serum DS-8895a concentrations increased dose-dependently. One gastric cancer patient achieved partial response and 13 patients achieved stable disease. Serum inflammatory cytokines transiently increased at completion of and 4 h after the start of DS-8895a administration. The proportion of CD16-positive natural killer (NK) cells (CD3-CD56+CD16+) decreased 4 h after the start of DS-8895a administration, and the ratio of CD3-CD56+CD137+ to CD3-CD56+CD16+ cells increased on day 3.ConclusionsTwenty mg/kg DS-8895a infused intravenously every 2 weeks was generally safe and well tolerated in patients (n = 21) with advanced solid tumors. The exposure of DS-8895a seemed to increase dose-dependently and induce activated NK cells.Trial registrationPhase 1 Study of DS-8895a in patients with advanced solid tumors ( NCT02004717 ; 7 November 2013 to 2 February 2017); retrospectively registered on 9 December 2013.

Dataset Information

Phase I dose escalation pharmacokinetic assessment of intravenous humanized anti-MUC1 antibody AS1402 in patients with advanced breast cancer.

Publications

Phase I dose escalation pharmacokinetic assessment of intravenous humanized anti-MUC1 antibody AS1402 in patients with advanced breast cancer.

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