Cirmtuzumab, a ROR1 Targeted Mab, Reverses Cancer Stemness, and Its Combination with Ibrutinib Is Safe and Effective: Planned Analysis of the Cirll Phase 1/2 Trial for CLL and MCL

Cirmtuzumab (Cirm) is a novel humanized mAb specific for ROR1, which is expressed primarily during embryogenesis and in many cancers, including chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), but generally not on normal post-partum tissues. A Phase I study involving patients (pts) with CLL showed Cirm was safe and effective in blocking ROR1-signaling and in reversing cancer-cell-stemness transcriptome signatures associated with aggressive malignancies (Choi et al., Cell Stem Cell, 2018; Malta et al., Cell, 2018). Cirm also was shown to block Wnt5a-ROR1 survival-signaling in CLL or MCL cells of pts taking ibrutinib (Ibr), and had synergistic anti-tumor activity with Ibr in animal models (Yu et al., Leukemia, 2016; Yu et al., Oncotarget, 2018), forming the rationale for testing Cirm+Ibr in pts with CLL or MCL in the CIRLL study (Cirmtuzumab plus Ibrutinib in Relapsed Leukemia and Lymphoma), a 3-part clinical trial: Part 1 (P1)evaluated increasing doses of Cirm with Ibr for safety and to determine the recommended dose regimen (RDR); Part 2(P2) evaluated pts treated with the RDR (Ibr plus Cirm at 600 mg IV on day 1, 14, 28 and then q28 days thereafter). For P1 and P2, we treated 34 pts with CLL (23 with relapsed/refractory (R/R) CLL) and 6 pts with R/R MCL who required therapy. Part 3(P3) will randomize patients to receive Cirm+Ibr versus Ibr alone based on the efficacy analysis of data collected in P1 and P2. We did not observe any serious adverse events in pts treated in P2, which had an overall safety profile consistent with that of ibr alone; no new adverse events were attributed to Cirm. Correlative studies showed that Cirm at the RDR suppressed expression of NF-kB-target genes induced by ROR1-signaling and reversed cancer-cell-stemness transcriptome signatures in the CLL cells of treated pts. Of 6 CLL pts treated at or below the RDR with ≥24 wks. of evaluable data, the overall response rate (ORR) was 100%, including 1 patient with a confirmed complete response (CR) with clearance of CLL in the marrow by histology. Another 15 CLL pts with ≥12 wks. of evaluable data had an ORR of 87%. No pt with CLL had progressive disease (PD) on therapy. Of the 6 heavily-pre-treated MCL pts with ≥12 wks. of evaluable data, 2 had a CR (one sustained for 9+ mos.), 2 had a partial response (PR), and 2 had PD. The 2 pts with PD had aggressive disease progression prior to therapy that subsided for 3 to 6 mos. on therapy. Taken together, these data demonstrate that Cirm+Ibr is biologically active, well tolerated, safe, and effective. Moreover, the data from the CLL pts in P1 and P2 of the study support initiation of P3 of the study, which will allow for comparison of the activity of Cirm+Ibr versus Ibr alone for patients with CLL.