First-in-human phase I/II study of CYT-0851, a first-in-class inhibitor of RAD51-mediated homologous recombination in patients with advanced solid and hematologic cancers.
Authors: Lynch Ryan C , Bendell Johanna C. , Advani Ranjana H. , Falchook Gerald Steven , Munster Pamela N. , Patel Manish R. , Gutierrez Martin , Burness Monika Leigh , Palmisiano Neil , Hamadani Mehdi , Bradley William D , O'Shea Thomas J , Doleman Susan , Renschler Markus Frederic , Englert Judson M. , Yap Timothy A. 
Published: June 2021

3006 Background: Homologous recombination (HR) is an essential, high-fidelity mechanism to repair DNA double strand breaks (DSBs). Inhibition of HR in cancer cells leads to accumulation of unrepaired DSBs and tumor cell death. This is the first reporting of the first-in-human study of CYT-0851, an oral, first-in-class, small molecule inhibitor of RAD51-mediated DNA repair. Methods: Patients (pts) with advanced hematologic and solid tumors were treated with continuous 28-day cycles of increasing doses of CYT-0851 with an accelerated titration and 3+3 trial design. Primary objectives included safety, maximum tolerated dose (MTD), recommended Phase 2 dose (RP2D) (Phase 1), and antitumor activity (Phase 2). Secondary and exploratory objectives included pharmacokinetics (PK), pharmacodynamics (PD) and predictive biomarkers of response. Results: As of an 8 Dec 2020 data cutoff (DCO), 23 pts with advanced cancers (Sarcoma n = 8, Breast n = 4, Non-Hodgkin’s Lymphoma n = 5; Pancreas n = 3; Ovarian n = 2; mucoepidermoid carcinoma n = 1) were enrolled in 6 cohorts (15 mg, 20 mg, 30 mg, and 45 mg BID; 90 mg and 130 mg QD). No pts experienced a dose-limiting toxicity and escalation continues per protocol to identify the MTD. 6 pts (26.1%) experienced a CYT-0851-related adverse event with only Gr 1/2 nausea (n = 3, 13%) and constipation (n = 2, 8.7%) occurring in > 1 pt. There has been no reported CYT-0851-related myelosuppression, serious adverse events, study discontinuation, or death. Preliminary PK analyses showed dose proportional systemic exposure with a half-life of ̃3 days supporting transition from BID to QD dosing. PD effects were observed with increases in ɣH2AX in on-treatment circulating tumor cells compared to baseline at exposures associated with preclinical anti-tumor activity. Ten pts were response evaluable prior to the DCO. Two partial responses by Lugano and RECIST v1.1 criterion were achieved in pts with DLBCL (-74%) and myxofibrosarcoma (-30%) at 45 mg BID with treatment ongoing at 126+ and 250+ days. An additional two pts, with pancreatic cancer (-19%) and follicular lymphoma (-42%) had stable disease with tumor shrinkage at 45 mg BID for 111 and 99+ days. Conclusions: CYT-0851, a first-in-class inhibitor of RAD51-mediated HR, is well tolerated, with linear PK, target-directed PD effects and promising antitumor activity across different tumor types. CYT-0851 is the first DNA-damage repair (DDR) therapeutic with demonstrated clinical activity in both hematologic malignancies and solid tumors. Dose escalation continues to establish the RP2D, with planned expansion in 7 disease-specific cohorts in hematologic and solid cancers. Clinical trial information: NCT03997968.