Abstract CT056: A Phase Ia/IIa trial of AVID100, an anti-EGFR antibody-drug conjugate

Background AVID100, a rationally designed anti-EGFR-DM1 conjugate, showed potent activity in preclinical models, including cancer cell lines resistant to approved anti-EGFR monoclonal antibodies. In addition, AVID100 showed increased toxicity on tumor cells compared to the unconjugated antibody. There was no increased AVID100-mediated toxicity on keratinocytes. Methods In the completed Phase Ia segment, 24 patients with advanced or metastatic epithelial malignancies without available standard of care therapy and likely to express EGFR were enrolled into sequential dose-escalation cohorts to assess safety, tolerability, pharmacokinetic (PK) parameters, and to identify the recommended Phase II dose (R2PD) of 2 hour infusions on an every 3 week schedule. In the ongoing Phase IIa segment, preliminary antitumor activity is being assessed in expansion cohorts of patients with high EGFR expression, including triple-negative breast cancer (TNBC) (2+ expression in ≥75% or 3+ in ≥50% of tumor cells) or either squamous cell carcinoma of the head and neck (SCCHN) or squamous non-small cell lung carcinoma (sqNSCLC) (3+ expression in ≥ 50% of tumor cells). The DAKO PharmDx assay was validated and used for screening intensity of EGFR protein expression. Results During Phase Ia, no Cycle 1 dose limiting toxicities (DLTs) were observed in Cohorts 1-6 at doses (N) of 20 (1), 40 (1), 80 (3), 120 (3), 180 (3), and 220 (6) mg/m2. In Cohort 7 (6) (270 mg/m2; ~ 7.3 mg/kg) two patients experienced Cycle 1 DLTs (G3 asymptomatic lipase elevation, G4 reversible thrombocytopenia), exceeding the maximally tolerated dose. A third patient developed G3 reversible pneumonitis. As a result, 220 mg/m2 (~6 mg/kg) was selected as the R2PD. Tumor types in greater than one patient included: colorectal (13), breast (4), and ovarian (2). Preliminary PK results at the R2PD revealed exposure exceeding preclinically predicted therapeutic levels. Cmax increased proportionally with dose, plasma half-life was ~50 hours at the R2PD, and clearance decreased with increasing doses with saturation observed between 180-270 mg/m2. Safety and tolerability were acceptable. Other treatment-related adverse events included: infusion-related reactions that were ameliorated by premedication and infusion prolongation, rash, nausea, vomiting, fatigue, headache, anorexia, mucositis, punctate keratitis, diarrhea, elevated amylase, reversible transaminase and alkaline phosphatase elevations without other evidence of hepa