Phase 1 study of the PSMA-targeted tubulysin small-molecule drug conjugate EC1169 in patients with metastatic castrate-resistant prostate cancer (mCRPC): Study update

Background

Prostate-specific membrane antigen (PSMA) is overexpressed by most prostate cancers. EC1169 is a conjugate of a PSMA targeting moiety linked to the cytotoxic agent tubulysin B hydrazide (TubBH). Following internalization of EC1169 by targeted cancer cells, intracellular release of TubBH results in inhibition of tubulin polymerization. In PSMA-positive LNCaP and MDA PCa 2b xenografts, complete responses and cures have been observed following EC1169 treatment. EC1169 does not show activity in PSMA-negative models, demonstrating its specificity. EC0652 is a companion radiodiagnostic conjugate of a ^99mTc chelator and a PSMA-targeting moiety designed to characterize PSMA-expressing disease in real time. Rapid tumor uptake of ^99mTc-EC0652 and rapid normal tissue clearance result in enhanced tumor: background ratios with SPECT imaging.

Methods

Key inclusion criteria are age ≥18 years, ECOG PS 0–1, and adequate organ function. Patients (pts) must have failed androgen-deprivation therapy, progressed on abiraterone or enzalutamide, and have been previously treated with a taxane unless contraindicated. Patients are to undergo a ^99mTc-EC0652 SPECT scan prior to therapy. PSMA positivity is not a requirement for study entry. EC1169 is administered as an intravenous bolus on Days (D) 1, 8 (QW) every 21 D. Dose escalation is based upon the “3 + 3” method. Study objectives include determination of EC1169 MTD and recommended phase II dose, safety, pharmacokinetics, antitumor activity and its correlation with PSMA expression as identified on ^99mTc-EC0652 SPECT imaging.

Results

23 pts have been treated on the QW schedule. Median age is 70 (range: 57-82). The median number of administered EC1169 cycles is 2 (range: 1-11). 12 (52%) treatment related AEs have been reported. Most common Grade 3/4 AEs were anaemia (2; 8.7%) and lymphopenia (2; 8.7%). No DLT, related SAEs or toxicity requiring dose reductions occurred. PSA response (≥50% max decline) has been observed in 2 pts. Data will be updated at the meeting.

Conclusions

To date, EC1169 has been well tolerated. There are promising signs of early efficacy in this heavily pre-treated population.

Clinical trial identification

ClinicalTrials.gov NCT02202447

Legal entity responsible for the study

Endocyte, Inc.

Funding

Endocyte, Inc.

Disclosure

M.J. Morris: MSKCC receives funding from Endocyte for the conduct of this study. I've received funding for advisory boards from Progenics, Tokai, & Millennium Pharmaceuticals. I'm an uncompensated advisor for Bayer, which my institution also receives funding. O. Sartor, D. Petrylak: Endocyte: consultancy fees.

A. Armour: Alison Armour is an employee of Endocyte. H.M. Babiker: Endocyte: consultancy fees. Celgene: Consultant/Advisory Board. SirTex: Honorarium. All other authors have declared no conflicts of interest.