P1.05A ph 1 study of 2 different schedules of the PSMA-tubulysin small-molecule drug conjugate EC1169 in pts with rec Met Cast-Resist PC (MCRPC)

ABSTRACT Background: EC1169 is a conjugate of a prostate-specific membrane antigen (PSMA) targeting moiety linked to tubulysin B hydrazide (TubBH) that specifically binds to PSMA-expressing tumor cells to exert its anti-tumor effect in vivo. The PSMA “target” that binds EC1169 is overexpressed on a majority of prostate cancer (PCa) cells. TubBH, a member of the tubulysin class of anti-neoplastic agents, exerts an anti-tumor effect by inhibiting the polymerization of tubulin into microtubules, thus blocking spindle formation and arresting cells in metaphase. Xenograft studies demonstrated good EC1169's antitumor activity with complete remissions and cures observed in mice bearing PSMA-positive LNCaP and MDA PCa 2b tumors. 99mTc-EC0652 has a 99mTc binding moiety linked to a DUPA moiety, which binds to PSMA on the surface of target cells, and has displayed more sustained retention in PCa masses than any previously described PCa imaging agent. Materials and Methods: Key inclusion criteria are age ≥18 years, ECOG performance status 0–1, and adequate organ function. Patients must have failed prior or ongoing androgen-deprivation therapy, progressed on abiraterone or enzalutamide, and previously treated with a taxane unless contraindicated. All patients undergo a 99mTc-EC0652 scan, and EC1169 is IV bolus administered TIW or QW on wks 1, 2 of a 3-week cycle, with the continuous reassessment method (CRM) used for dose escalations. The primary study objective is to determine EC1169 MTD and recommended phase 2 dose. Secondary objectives include evaluating EC1169 safety, pharmacokinetic profiles, antitumor activity, and its correlation with PSMA expression as measured by 99mTc-EC0652. Results: Five patients had been enrolled into 5 dose levels, 3 in the TIW, and 2 in the QIW schedule. The number of cycles administered ranged from 1 to 4, with no dose delay or omission due to toxicity. No DLT was observed and only TEAEs of grade 1, were reported (e.g. dysgeusia, arthralgia and anorexia). One pt had SD for 4 cycles, and four pts are still on study. Conclusions: Dose escalation is ongoing, currently at 0.45 mg/m2 for both the TIW and QIW schedules. Updated data will be presented at the conference.