481P - Phase 1 dose-escalation study of the folic acid-tubulysin small-molecule drug conjugate EC1456 in patients (pts) with advanced solid tumors

Date 27 September 2014
Event ESMO 2014
Session Poster Display session
Topics Drug Development
Translational Research
Presenter Edward Sausville
Citation Annals of Oncology (2014) 25 (suppl_4): iv146-iv164. 10.1093/annonc/mdu331
Authors E. Sausville1, W. Harb2, R. Ramanathan3, C.P. Leamon4, J.A. Reddy5, R. Clark6, D.E. Matei7
  • 1Greenebaum Cancer Center, University of Maryland, 21201 - Baltimore/US
  • 2Inc., Horizon Oncology Center, Lafayette/US
  • 3Clinical Trials, Virginia G. Piper Cancer Center/TGen, Scottsdale/US
  • 4Research, Endocyte, Inc., West Lafayette/US
  • 5Biology, Endocyte, Inc., West Lafayette/US
  • 6Medical Affairs, Endocyte, Inc., West Lafayette/US
  • 7Medicine, Indiana University, Indianapolis/US

Abstract

Aim

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 demonstrated EC1456's antitumor activity as it induced complete remissions in mice bearing FR-expressing xenografts (≤750 mm3), in absence of weight loss or major organ tissue degeneration (Reddy JA. AACR 2014; abstr 832). EC1456 can also be safely combined with chemotherapeutics (platinum-based agents/topoisomerase inhibitors/taxanes) to enhance antitumor effects and showed to be highly active against both paclitaxel- and cisplatin-resistant FR-expressing cell lines. These findings support EC1456's clinical evaluation.

Methods

Part A of the multicenter dose-escalation study (NCT01999738) in pts with advanced histologically confirmed solid tumors assesses EC1456's maximum tolerated dose (MTD). Key inclusion criteria are age ≥18 years, ECOG performance status 0–1, and adequate organ function. Part B evaluates EC1456's antitumor activity (at MTD) in pts with triple-negative breast, advanced non-small cell lung, ovarian, or hepatocellular cancer in which all target lesions (RECIST 1.1. criteria) express FR as determined by 99mTc-etarfolatide imaging. EC1456 (start dose 0.5 mg/m2) is intravenously administered on days 1/4/8/11 of a 4-week cycle per standard 3 + 3 dose-escalation schema (3–6 pts/dose level). Cycle 1 dose-limiting toxicity (DLT) evaluation must be completed by all pts in a cohort before dosing is initiated in 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 in selected pts.

Results

Up until April 2014, enrolled pts did not experience grade ≥3 toxicity after ≥4 cycles and had stable disease.

Conclusions

Study enrollment is ongoing and no DLTs have been observed by April 2014. Preliminary efficacy data will be presented at ESMO.

Disclosure

E.A. Sausville: Corporate-sponsored research: research sponsored by Endocyte, Inc.; W.A. Harb: Corporate-sponsored research: Endocyte sponsored participation in EC1456 study; R.K. Ramanathan: Corporate-sponsored research: Clinical trial with Endocyte; R. Clark: Ownership: Endocyte stock Corporate-sponsored research: Employee of Endocyte: All other authors have declared no conflicts of interest.