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Phase I pharmacokinetics (PK) of humanized anti-MUC-1 antibody R1550


, : Phase I pharmacokinetics (PK) of humanized anti-MUC-1 antibody R1550. Journal of Clinical Oncology 24(18_suppl): 2533-2533

NlmCategory="UNASSIGNED">2533 Background: MUC-1 glycoprotein establishes a molecular barrier at the epithelial surface, and engages in morphogenetic signal transduction. A 20 amino acid MUC-1 core tandem repeat is aberrantly glycosylated in >90% of epithelial tumors, exposing peptide sequence PDTRP. Humanized IgG1 κ monoclonal antibody R1550 binds PDTRP (Kd∼1nM) and induces potent antibody-dependent cellular cytotoxicity. R1550 clinical tolerability and PK was determined in advanced, PDTRP-expressing (by IHC), breast cancer patients progressing after anthracyclines and taxanes. Key eligibility: informed consent, WHO PS 0-1, life expectancy >4 mos, non-inflammatory histology, and no CNS metastasis. R1550 was infused IV over 1-3 hrs: cohort 1 (N = 3) 1 mg/kg; cohort 2 (N = 9) 3 mg/kg; cohort 3 (N = 6) 9 mg/kg; cohort 4 (N=3) 16 mg/kg, with repeat dosing every 1-2 weeks (patient-individualized PK assessment) until disease progression. Plasma [R1550] was measured by quantitative ELISA. PK parameters were analyzed by a non-compartmental model, and a 2-compartment population PK model. 21 patients (mean age 54, median # of prior chemotherapy agents = 4) have been dosed. Safety data (n=18): R1550 is generally well tolerated with fatigue (28%), gastrointestinal symptoms (22%), skin rash (17%), pyrexia (11%), and elevated liver function tests (11%) as the most frequently reported adverse events (AEs). Two grade 4 AEs were reported: elevated AST, and hyperglycemia, both in cohort 2. Neither have been observed in expanded or subsequent cohorts. Median number of doses received per patient = 3 (range, 3-4), 4 (1-13) and 6 (4-21), in cohorts 1, 2, and 3, respectively. No anti-humanized antibodies were detected. PK parameters of cohorts 1-3 are shown below. R1550 is well tolerated, with MTD exceeding 9 mg/kg. PK parameters using non-compartmental, and 2-compartment population PK models are in agreement. R1550 half-life suggests weekly dosing. Plasma exposure and dose relationships are linear within 1-9 mg/kg dose range. Accrual to cohort 4 is ongoing. [Table: see text] [Table: see text].

US$29.90

PMID: 27954948


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