244MO A phase II trial targeting disseminated dormant tumor cells with hydroxychloroquine, everolimus or the combination to prevent recurrent breast cancer (“CLEVER”)

Breast cancer (BC) recurrence may follow a dormant phase in which quiescent cells reside in niches such as bone marrow (BM). Dormant BM disseminated tumor cells (DTCs) are independently associated with BC recurrence/death. We investigated whether targeting dormancy through autophagy inhibition (hydroxychloroquine (HCQ), and/or mTOR signaling (everolimus (EVE) in DTC+ BC survivors was feasible, reduced DTCs and/or prevented recurrence. The CLEVER trial (NCT03032406) is a randomized, phase II trial in patients (pts) diagnosed within 5 years, with positive nodes, triple-negative disease, high-risk Oncotype/Mammaprint, and/or residual disease post-neoadjuvant therapy who completed all treatment except endocrine therapy. DTCs were detected in BM aspirate (BMA) by IHC with pan-CK antibody AE1/AE3. DTC+ pts were randomized to six 28-day cycles (C) of HCQ (600 mg BID), EVE (10 mg daily) or both (+/- 3-month (m0) observation period). If DTC+ persisted after C6, pts received another 6C HCQ+EVE. DTC assessment was done after C3, C6, C12 (if applicable) and 6-mo after end of treatment. Adverse events (AE) were assessed by CTCAEv4. Primary endpoint was feasibility, defined as >75% completion of C6C without G3/G4 AE. Secondary endpoints were safety, DTC response rate (RR) and 3-year RFS. DTC RR was analyzed with Bayesian Poisson regression models. 184/197 eligible pts had baseline BMA, 55 (30%) were DTC+, 53 were randomized: HCQ (n=15), EVE (n=15), and HCQ+EVE (n=23). 13 patients had repeat after 3-mo observation. Feasibility endpoint was met. There were no G4/5 toxicities. At a median follow up of 42 mo (range 7-60), 1 pt recurred in lung (after 2 cycles EVE), 1 pt developed new contralateral breast cancer. The posterior probabilities that HCQ, EVE, and HCQ+EVE reduced DTCs by at least 80% after C3 vs observation alone are 99.1%, 98.2%, and 99.9%, respectively. The CLEVER trial provides proof-of-principle that therapeutic targeting of dormant BC is feasible and active in eliminating DTCs by targeting dormancy-specific mechanisms. Follow up for recurrence and survival is ongoing.