187P - Phase 1/2 study of the oral CCR4 antagonist, FLX475, as monotherapy and in combination with pembrolizumab in advanced cancer

Background

Preclinical studies with oral CCR4 antagonists have demonstrated inhibition of suppressive regulatory T cell (T_reg) migration into the tumor microenvironment and antitumor efficacy. The FLX475-02 trial is a phase 1/2, open-label, dose-escalation and cohort expansion study to determine the safety and antitumor activity of the oral CCR4 antagonist FLX475 as monotherapy and in combination with pembrolizumab in subjects with several types of advanced cancer.

Methods

A standard 3+3 design was used in phase 1 testing FLX475 given orally once daily as monotherapy or in combination with pembrolizumab (200 mg IV Q3 weeks). In phase 2, expansion cohorts of subjects both naïve to and pretreated with checkpoint inhibitor with tumor types predicted to be enriched for T_eff, T_reg, and CCR4 ligand expression (i.e. “charged tumors”) – including EBV+ tumors and NSCLC– are being enrolled using a Simon 2-stage design.

Results

Phase 1 dose escalation has been completed and a recommended phase 2 dose of 100 mg once daily was selected for FLX475. The safety profile of FLX475 was consistent with that previously described in healthy volunteers, and there has been no evidence of increased severity or frequency of adverse events in combination therapy vs either FLX475 or pembrolizumab given alone. In phase 2 expansion, FLX475 monotherapy has induced complete responses in the first two subjects of five evaluable enrolled with EBV+ NK/T cell lymphoma. In addition, enrollment of the Stage 1 portion has been completed in several phase 2 expansion cohorts for the combination of FLX475 and pembrolizumab. In a cohort enrolling subjects with non-small-cell lung cancer (NSCLC) not previously treated with checkpoint inhibitor, 4/13 subjects (31%) have had confirmed partial responses (PRs), including several ongoing for over 6 months, meeting criteria to proceed to Stage 2 enrollment.

Conclusions

In this ongoing phase 1/2 trial of the oral CCR4 antagonist, FLX475, as monotherapy and in combination with pembrolizumab, antitumor activity including complete responses to FLX475 monotherapy and encouraging combination activity have been observed with an acceptable safety profile.

Clinical trial identification

NCT03674567.

Legal entity responsible for the study

RAPT Therapeutics, Inc.

Funding

RAPT Therapeutics, Inc.

Disclosure

M. Chisamore: Financial Interests, Personal, Full or part-time Employment: Merck. R. Goyal: Financial Interests, Personal, Full or part-time Employment: RAPT Therapeutics. N. Nasrah: Financial Interests, Personal, Full or part-time Employment: RAPT Therapeutics. W. Ho: Financial Interests, Personal, Leadership Role: RAPT Therapeutics. All other authors have declared no conflicts of interest.