A Phase 1a/2a trial of AVID100, an anti-EGFR antibody-drug conjugate

Abstract

Background: AVID100, an anti-EGFR-DM1 conjugate, showed potent activity in preclinical models in vitro and in vivo including in cell lines resistant to approved anti- EGFR mAbs. Methods: Patients with advanced or metastatic epithelial malignancies without available therapy and likely to express EGFR are being enrolled into sequential dose escalation cohorts (Phase 1a) to assess safety, tolerability, and PK parameters to identify the recommended Phase 2 dose (R2PD) of 1-hour infusions on an every 3 week schedule. In the Phase 2a segment preliminary antitumor activity will be assessed in expansion cohorts of patients with breast cancer (BC) and squamous cell carcinoma of the head and neck (SCCHN) with EGFR overexpression (3+ in≥50% of tumor cells). Results: No cycle 1 dose limiting toxicities (DLTs) have been observed in Cohorts 1-6 (dose (N); 20 (1), 40 (1), 80 (3), 120 (3), 180 (3), and 220 (3) mg/m2 every 3 weeks). Currently, patients are being evaluated in Cohort 7 (270 mg/ m2; approximately 6.9 mg/ kg). Preliminary clinical PK results show exposure levels of AVID100 have been achieved that exceed therapeutic levels predicted from preclinical studies. Safety and tolerability have been acceptable with G2-3 lipase elevations without clinical sequelae, infusion-related reactions ameliorated by premedication and infusion prolongation, reversible thrombocytopenia, and reversible transaminase elevations without other evidence of hepatic toxicity. Other G1-2 treatment-related adverse events reported include: rash, nausea, vomiting, fatigue, headache, anorexia, mucositis, diarrhea, elevated amylase, elevated alkaline phosphatase, hypomagnesemia, and hypokalemia. Patients entered to the Phase 1a segment were not screened for EGFR overexpression and included patients with: colorectal cancer (9); breast cancer (2); and single cases of ovarian, pancreatic, urothelial, and cervical cancer. Prolonged disease stabilization has been observed in 3 of these unselected patients (colorectal, ovarian, cervical). Conclusions: AVID100 is a well-tolerated anti-EGFR-DM1 conjugate with evidence for exposure levels at or above those observed for cetuximab and ado-trastuzumab emtansine. Antitumor activity will be evaluated in EGFR-overexpressing patients with BC and SCCHN.