No abstract

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.

No abstract

3099 Background: The MCT inhibitor CYT-0851 blocks lactate transport resulting in glycolytic cancer cell death. Monotherapy clinical activity has been previously reported in lymphoma and solid tumors. Preclinical studies assessing CYT-0851 with chemotherapy identified enhanced growth inhibition when combined with 5-FU or gem supporting clinical evaluation. Methods: Patients (pts) with solid tumors were treated with CYT-0851 + standard dosing of cape or gem in 21- and 28-day cycles, respectively, following a 3+3 design. The primary objective was to determine the MTD. Secondary objectives included: safety, PK, and anti-tumor activity by RECIST. Results: As of Feb 1, 2023, 14 pts (pancreatic n=9; ovarian n=5) were treated in 4 cohorts (100 - 400 mg QD) with cape. No DLTs occurred, and 400 mg QD was selected as the RP2D. 8 pts (57%) experienced a treatment-related adverse event (TRAE), including 2 (14%) with a G3/4 AE. The most common related AEs were primarily G1/2 and included fatigue (21%), nausea, decreased appetite, dry skin, mucosal inflammation and maculopapular rash (all 14%). 10 pts (sarcoma n=6; HNSCC n=1; ovarian n=1; pancreatic n=2) were treated in 2 cohorts (100, 200 mg QD) with gem. No DLTs occurred. Escalation is ongoing with up to 2 further cohorts. 9 pts (90%) experienced a TRAE, including 5 (50%) with a G3/4 AE which were primarily cytopenias. The most common TRAEs were fatigue (50%), anemia (50%), neutropenia (40%), thrombocytopenia (30%), nausea, pruritus, ALT/AST increased, neutrophil decreased and WBC decreased (all 20%). CYT-0851 exposure was similar between combination therapy and monotherapy. 8 pts in the cape cohorts were response-evaluable, including 3 with ovarian cancer. 1 pt with platinum-resistant ovarian cancer had a confirmed PR with treatment ongoing at 174 days. 7 pts had SD. 6 pts in the gem cohorts were response-evaluable. 1 pt with sarcoma had a confirmed PR, 4 pts had SD and 1 had PD. Conclusions: 400 mg QD was selected as the RP2D in combination with cape as no MTD was identified. Escalation of gem + CYT-0851 is ongoing to identify the MTD. Both combinations have demonstrated an acceptable safety and tolerability profile with no unanticipated toxicities at clinically active doses. Encouraging antitumor activity has been observed in heavily pre-treated pts with both regimens including pts with ovarian cancer in the cape combo. The cape cohort is being expanded with additional pts with ovarian cancer and will be presented. Clinical trial information: NCT03997968 .

No abstract