By Richard Simoneaux
ORLANDO—The transmembrane protein ROR1 is one member of the receptor tyrosine kinase-like orphan receptor family (the other member is ROR2). This embryonic protein, which is not normally expressed in postpartem tissues, has been observed in several different malignancies, including chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) or mantle cell lymphoma (MCL) (Protein & Cell 2014;5(7):496-502). Because of the differing expression between healthy adult and cancer cells, this has been employed as a therapeutic strategy.
In particular, the ROR1-targeting monoclonal antibody cirmtuzumab is currently being evaluated in a clinical setting among patients with a variety of malignancies. One particularly interesting clinical study is a phase I/II trial (NCT03088878) that is evaluating the combination of the Bruton's tyrosine kinase inhibitor ibrutinib plus cirmtuzumab in patients with CLL/SLL or MCL. One of the lead clinicians on this study is Michael Choi, MD, hematologist and medical oncologist at University of California San Diego School of Medicine and Moores Cancer Center. Regarding their safety findings, Choi stated, "We were pleased to see there were no new safety signals with this particular combination; no dose-limiting toxicities were observed."
Choi presented results from parts 1 and 2 of this 3-part study at the 2019 ASH Annual Meeting (Abstract 1755).
Cirmtuzumab & Ibrutinib Combination
When asked about why this particular combination of therapies was being evaluated for these malignancies, Choi replied, "Cirmtuzumab displayed the ability to block Wnt5a-ROR1-based survival signaling in CLL or MCL cells of patients taking ibrutinib (Oncotarget 2018; 9:24731-24736). Additionally, synergistic anti-tumor activity between cirmtuzumab and ibrutinib was noted in preclinical animal studies" (Leukemia 2017;31(6):1333-1339).
In a first-in-human phase I clinical study (NCT02222688), cirmtuzumab was evaluated in patients with relapsed or refractory CLL. The main objectives of this open-label, single-institution, dose-escalation study were to assess the maximum tolerated dose of cirmtuzumab and the rate of dose-limiting toxicities (DLTs), as well as evaluate the pharmacokinetics for administration (Cell Stem Cell 2018; 22(6):951-959).
A total of 26 patients participated in the study and received four infusions over a 2-month period. Of these, 22 were deemed evaluable for response evaluation. The four patients who enrolled but were not considered evaluable discontinued cirmtuzumab without achieving progressive disease. The response data for the 22 evaluable patients were as follows: complete remission–0; partial remission–0; stable disease–17; progressive disease–5. For the five patients experiencing progressive disease, three received cirmtuzumab at a dose of 240 µg/kg or less, and one each received 8 mg/kg and 20 mg/kg.
No DLTs were observed with the administration of cirmtuzumab. Potential drug-dependent toxicities such as hyperglycemia, weight loss, or pancreatitis were not observed in the participants, thus supporting the contention that cirmtuzumab lacked off-target reactivity with normal tissues. In addition, cirmtuzumab was shown to effectively inhibit ROR1-based signaling in a dose-dependent fashion in vivo.
An important finding in this study was that cirmtuzumab reversed the cancer cell stemness transcriptome signatures, which have been associated with aggressive malignancies. This observation may have broader implications, since ROR1 is also a biomarker for cancer stem cells and stemness in solid tumors. In previous preclinical studies, treating ovarian cancer-based patient-derived xenograft mice with cirmtuzumab was shown to reduce the capacity of the implanted tumors to metastasize or re-engraft immunodeficient mice, thus implying that targeting ROR1 can affect cancer stem cell self-renewal (PNAS 2014;111(48):17266-17271). The favorable safety profile of cirmtuzumab obtained in the phase I study may permit the antibody to be combined with other agents or immunotherapies which do not target cancer stem cells.
The 3-part clinical trial NCT03088878 was divided into the following segments: Part 1 was a dose-escalation phase that assessed increasing doses of cirmtuzumab with ibrutinib for safety, with the aim of determining the recommended dose regimen (RDR); Part 2 evaluated patients who were treated at the RDR of cirmtuzumab at 600 mg IV on days 1, 14, and 28 and then once every 28 days thereafter plus ibrutinib daily; Part 3, which has not yet completed, will see randomization of the patients to either cirmtuzumab plus ibrutinib or ibrutinib alone, based on the efficacy data obtained in parts 1 and 2 of the study.
In Parts 1 and 2 of this study, there were a total of 40 patients who were treated: 34 with CLL (23 of whom had relapsed or refractory CLL), and six with relapsed or refractory MCL.
"The safety profile obtained in part 2 of this study, in which we did not observe any serious adverse events, was generally consistent with that of ibrutinib monotherapy; no new adverse events were attributed to cirmtuzumab," Choi noted. Correlative studies showed that when given at the RDR, cirmtuzumab reduced the expression of NF-kB-target genes induced by ROR1 signaling, while also reversing the cancer cell stemness transcriptome signatures in treated patients' CLL cells.
"The overall response rate (ORR) was 100 percent for the six CLL patients who were treated at or below the RDR and had 24 weeks or more of evaluable data; this included one patient with a confirmed complete response (CR) with clearance of CLL in the marrow by histology," Choi observed. An additional 15 patients with CLL had 12 or more weeks of evaluable data; in these patients, an ORR of 87 percent was obtained. "One particularly promising observation," Choi added, "was that no patient with CLL experienced progressive disease while on therapy, though most patients are still in the first year of treatment."
Regarding the six heavily pre-treated MCL patients had 12 weeks or more of evaluable data, "Two experienced a CR (one of which was sustained for more than 9 months), two attained a partial response, and two had PD," Choi noted. "The two MCL patients displaying progressive disease had aggressive disease progression before therapy, which subsided for 3-6 months while they were on therapy."
"Taken together, these data demonstrate that the combination of ibrutinib and cirmtuzumab is biologically active, well-tolerated, safe, and effective," Choi stated. "We have initiated part 3 of the trial, which will allow for direct comparison between the activities of the cirmtuzumab plus ibrutinib combination and ibrutinib monotherapy, and hopefully continue the amazing improvements we have seen in the treatment of patients with CLL."
Richard Simoneaux is a contributing writer.