2576 Background: The folate receptor (FR) is highly expressed in a variety of cancers including adenocarcinoma of the lung, but is expressed at low levels in most normal tissues, making it a potential target for therapeutic intervention. EC1456 is an FR-targeted small molecule drug conjugate (SMDC) consisting of folic acid chemically attached through a bio-releasable linker system to a potent microtubule inhibitor, tubulysin B hydrazide (TubBH). EC1456 binds to, and is endocytosed by the FR-expressing cancer cell to deliver TubBH. Following endocytosis, the FR recycles back to the membrane surface every 18-24 hours. Therefore alternative EC1456 schedules will be evaluated for safety, pharmacokinetics, and therapeutic benefit. Methods: Part A (dose escalation) is being evaluated in unselected patients (pts) with advanced solid tumors. 4 schedules (3-week cycle) are being evaluated: BIW (twice weekly); QW (once weekly); CWD (continuously weekly); QIW (four times a week). The primary objective of Part A is to determine the RP2 dose and schedule of EC1456. Part B (expansion) will confirm the MTD and RP2 dose and evaluate efficacy of EC1456 in 99mTc-etarfolatide-selected NSCLC patients in up to three schedules. Results: 74 Part A pts are evaluable for toxicity. Median age is 68 (range: 26-88); 53 pts are female. Toxicities are primarily Grade (Gr) 1 and 2. Common treatment-related adverse events (TRAE) are gastrointestinal, fatigue, metabolic changes, alopecia, and headache. 5 Gr 3 DLTs have been observed: infusion reaction (4.5 mg/m2 QW), headache (10.0 mg/m2 QW), and abdominal pain (7.5 mg/m2 BIW, 12.5 mg/m2 QW and 10.0 mg/m2CWD). TRAEs are summarized in the table for each schedule. Durable stable disease of 12 wks or longer has been observed in 12 pts (6 BIW and 6 QW). Conclusions: All Part A EC1456 schedules have been well tolerated. RP2 dose for BIW is 6.0 mg/m2 and QW is 12.5 mg/m2; dose escalation is ongoing for CWD and QIW. Early signs of efficacy in an unselected pt population may be suggested by durable stable disease. Safety and efficacy evaluation in the 99mTc-etarfolatide-selected NSCLC population (Part B) is ongoing. Clinical trial information: NCT01999738. [Table: see text]
Phase 1 Dose-Escalation Study of the Folic Acid-Tubulysin Small-Molecule Drug Conjugate Ec1456 in Patients (Pts) with Advanced Solid Tumors