Background: ROR1 is an onco-embryonic tyrosine kinase receptor that is re-expressed at high levels on many hematologic and solid cancers but not on normal adult tissues. ROR1 binds Wnt5a, resulting in increased tumor growth and survival, cancer cell stemness and epithelial mesenchymal transition. Cirmtuzumab (Cirm) is a humanized monoclonal antibody designed to inhibit the tumor promoting activity of ROR1. In this study, we examined the safety and efficacy of Cirm in combination with ibrutinib (Ibr) in MCL or CLL. Methods: As of Jan 29, 2020, 12 pts with relapsed refractory (RR) MCL were enrolled into Part 1 Dose Escalation (DE). All MCL pts had stage 3/ 4 at original diagnosis, 25% had bulky tumor at study entry, 58% had intermediate/high risk MIPI scores and the majority (83%) had ≥ 2 prior regimens. 34 pts with CLL [12 treatment naïve (TN) and 22 RR pts] enrolled into Part 1 DE (n = 18) or Part 2 Expansion (n = 16). At least 79% of CLL pts were high risk as determined by unmutated IGHV, 17p/p53 loss, and/or del 11q. DE pts received Cirm IV q2wks x 3-5 doses then q4wks plus Ibr (starting D28). Following DE, Cirm 600mg IV q2wks x3 then q4wks plus Ibr (420mg/day CLL or 560mg/day MCL) was chosen for Expansion. Results:Safety: only grade 1/ 2 AEs were reported as possibly related to Cirm alone, whereas the safety profile attributed to Ibr or Ibr / Cirm was similar to published data, with no new or unexpected events. Efficacy for MCL: 83% ORR, 33% (4) CR, 50% (6) PR, 17% (2) SD. CRs were achieved at a median of 3.6 mos in heavily pretreated pts, including 2 with bulky disease > 5cm. Prior therapy of the 4 CR pts: 2 pts failed R-Ibr (7-10 mos) and R-hyperCVAD, 1 pt, auto-SCT and allo-SCT, 1 pt, auto-SCT and CAR-T. Efficacy for CLL: 88% ORR (92% TN, 86% RR), 3% (1) CR, 85% (22) PR/ (7) PR-L, 12% (4) SD. In addition, 3 PR pts with CLL met criteria for “Clinical CR, bone marrow biopsy not performed”. The pt achieving a CR had RR disease with del 11q; this pt remains in remission > 6 mos after stopping all therapy. At a median follow-up of 9.9 mos, 100% of CLL pts are free of disease progression and > 82% remain on study. Conclusions: Cirm in combination with Ibr is a well-tolerated and active regimen for RR MCL and TN or RR CLL. In this evaluation of 46 pts, the ORR and PFS continue to improve with longer follow-up and additional pts, supporting continued investigation of this regimen in ROR1 expressing tumors. This study is ongoing and enrolling an Expansion arm for MCL pts and an open-label randomized Phase 2 in CLL pts comparing Ibr alone to Cirm /Ibr. Clinical trial information: NCT03088878.