The folate receptor (FR) is highly expressed in certain cancers such as adenocarcinoma-NSCLC, but is expressed at low levels in most normal tissues. FR constitutively cycles from the plasma membrane surface to the cytoplasm. In vitro and in vivo studies show the average FR recycling time to be about 18 hours. EC1456 is a potent second generation small molecule drug conjugate (SMDC) of folic acid and the cytotoxic tubulysin B hydrazide (TubBH). EC1456 targets FR-expressing (FR+) cancers for intracellular delivery of TubBH which inhibits tubulin polymerization in tumors.
The primary objective is to determine the MTD of EC1456 and optimize the dosing schedule. Key inclusion criteria: age ≥18 years, ECOG PS 0–1, and adequate end-organ function. Dose escalation follows the “3 + 3” protocol for all schedules. Patients are scanned using the diagnostic imaging agent 99mTc-EC20, however a positive scan is not required for enrollment.
In an unselected population, 55 patients (pts) are evaluable for cycle 1 toxicity. The median age is 69.5 (range: 39-88); 36 patients are female. Toxicities are primarily Grade (Gr) 1 and 2. Common adverse events (AE) are gastrointestinal, general fatigue, and metabolic changes. Two DLT's have been observed: Gr 3 infusion reaction (4.5 mg/m2 D 1, 8) and G3 headache (10.0 mg/m2 D 1, 8). Drug safety is summarized in the table below. Durable stable disease of 12 wks or longer has been observed in 10 pts.
|BIW (n = 29)||BIW (n = 29)||QW (n = 26)||QW (n = 26)|
|All AEs||TRAE||All AEs||TRAE|
|AE||28 (96.6%)||21 (72.4%)||26 (100.0%)||20 (76.9%)|
|SAE||9 (31.0%)||1 (3.4%)||12 (46.2%)||3 (11.5%)|
|Gr 3/4 AE||16 (55.2%)||5 (17.2%)||13 (50.0%)||4 (15.4%)|
|Dose Reduction||1 (3.4%)||1 (3.4%)||1 (3.8%)||1 (3.8%)|
|Discontinuation||0 (0.0%)||0 (0.0%)||2 (7.7%)||2 (7.7%)|
To date, all EC1456 schedules have been well tolerated. Dose escalation is ongoing. Anti-tumor activity of EC1456 is suggested by durable stable disease. Updated pharmacokinetic, safety, and efficacy analyses will be available for the conference.
Clinical trial identification
Legal entity responsible for the study
Sponsor is Endocyte, Inc.
A. Armour: Employee of Endocyte, Inc. All other authors have declared no conflicts of interest.