A phase 1 study of 3 different schedules of the folic acid-tubulysin small-molecule drug conjugate EC1456 in pts with advanced solid tumors

Abstract

Background: The therapeutic target folate receptor (FR) is expressed in many epithelial tumors. EC1456, a potent small-molecule drug conjugate of folate and tubulysin B hydrazide (TubBH), is a cytotoxic agent that targets TubBH to FR-expressing cells. TubBH inhibits tubulin polymerization, causing metaphase cell arrest. Preclinical studies show good EC1456's antitumor activity with complete remissions seen in mice bearing FR-expressing xenografts, both as single-agent and in combination with different agents ( platinum/taxane/erubilin). Materials and Methods: Part A of the study (NCT01999738) in pts with advanced solid tumors assesses EC1456's MTD. Key inclusion criteria are age ≥18 years, ECOG PS 0-1, and adequate organ function. Patients must have failed standard therapy or not be a candidate for standard therapy. Part B evaluates EC1456's antitumor activity (at MTD) in pts with triple-negative breast, advanced non-small cell lung, or ovarian cancer in which all target lesions express FR as determined by 99mTc-etarfolatide imaging. EC1456 (start dose 0.5 mg/m2) is IV administered BIW on wks 1, 2 of a 3 or 4-week cycle and QWon wks 1, 2 of a 3-week cycle. The standard 3 + 3 dose escalation schema is used for the BIW, and continuous reassessment method (CRM) is used for the QW schedule. Cycle 1 dose-limiting toxicity (DLT) evaluation must be completed by all pts in a cohort before starting the next cohort. The primary study objective is to determine EC1456 MTD and recommended phase 2 dose for pts with solid tumors. Secondary objectives include evaluating EC1456 safety, pharmacokinetic profiles, and antitumor activity. Results: Fifteen patients have been enrolled into 8 dose levels, 11 in the BIW, and 4 in the QW schedule. The number of cycles administered ranged from 1 to 14, with no dose delay/omission due to drug-related AEs. No DLT was observed and only few TEAs, mostly of grade 1, were reported (e.g. fatigue, nausea, anemia). Two patients (mesothelioma and gastroesophageal) have durable stable disease of a year. Conclusions: Dose escalation is ongoing, currently at 2.0 mg/m2 for the BIW and 3.5 mg/m2 for the QW schedule. Durable stable disease was observed in mesothelioma and gastroesophageal cancer. Updated data will be presented at the conference.