Cirmtuzumab is currently in a Phase 1/2 clinical trial in combination with ibrutinib as a treatment for chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). A separate investigator-initiated Phase 1 study of cirmtuzumab in combination with paclitaxel for women with metastatic breast cancer is also enrolling patients at UC San Diego.
Monoclonal Antibody Targeted to ROR1
Cirmtuzumab is a first-in-class humanized monoclonal antibody that binds with high affinity to a biologically important epitope on ROR1 (Receptor-tyrosine kinase-like Orphan Receptor 1). ROR1 is a type 1 transmembrane protein, essential for fetal development, that is expressed on the plasma membrane with an extracellular domain that is essential for ligand binding and signal transduction. Cirmtuzumab binds to many different types of cancer cells, but does not recognize most normal adult tissues.
ROR1 is a Survival Factor for Many Cancers
Tumor cells that express ROR1 have tumor-initiating features that are associated with a dedifferentiated oncogenic state. When expressed by hematologic malignancies such as mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL), ROR1 acts as a receptor for the tumor growth factor Wnt5a. When cirmtuzumab binds to ROR1, it blocks Wnt5a activation, induces differentiation of the tumor cells, and inhibits tumor cell proliferation, migration and survival. Early clinical data indicates that cirmtuzumab synergizes with ibrutinib (marketed as IMBRUVICA® with $2,968 million in U.S. revenues in 2018) as a potential combination treatment for CLL and MCL.
Unmet Need in CLL and MCL
CLL and MCL are cancers of B-cells that can cause disabling constitutional symptoms; lymph node and/or spleen/liver enlargement, and bone marrow infiltration, causing marrow failure, immune deficiency, morbidity, and early mortality. Approximately 21,000 and 4,200 persons respectively are diagnosed with CLL/SLL and MCL annually in the United States. There are currently no curative therapies. Patients with CLL or MCL generally require successive rounds of therapy and often develop refractory disease.
Ibrutinib (IMBRUVICA®) is an orally administered inhibitor of Bruton’s tyrosine kinase, that has become a standard of care in the modern treatment of CLL and MCL. However, most patients with CLL achieve only a partial response with ibrutinib, which then must be administered continuously, resulting in a greater potential for side effects, an enhanced health care burden for patients, and substantial therapeutic costs. The proportion of patients with CLL who achieve a complete response to ibrutinib after 12 months of therapy is below 10%. In previously treated patients with MCL, rates of complete response range from 12.5% to 23%, even with long-term, continuous therapy. Resistance to ibrutinib eventually develops in many patients with CLL and the great majority of patients with MCL. An agent that increases the complete response rate of CLL and MCL to ibrutinib is urgently needed.
Collaboration with University of California San Diego and CIRM
Cirmtuzumab was developed at the University of California in San Diego based on the pioneering scientific research of Thomas Kipps, MD, Ph.D., and his colleagues at the Moores Cancer Center. Oncternal holds an exclusive worldwide license to develop and commercialize antibodies recognizing ROR1. The development of cirmtuzumab has been supported by the California Institute for Regenerative Medicine (CIRM), in recognition of the role of ROR1 conferring stem cell-like properties to the cancer cells that express it.
We are enrolling patients:
- With B-Cell Lymphoid Malignancies (chronic lymphocytic leukemia and mantle cell lymphoma) for a Phase 1b/2 study of cirmtuzumab in combination with ibrutinib
- With HER2 negative, metastatic breast cancer for a Phase 1b study of cirmtuzumab in combination with paclitaxel
- With relapsed/refractory CLL for a Phase 2 clinical study of cirmtuzumab in combination with venetoclax, a Bcl-2 inhibitor
- With Ewing sarcoma for a Phase 1 study of TK216, our small-molecule inhibitor of ETS-family transcription factor oncoproteins, in combination with vincristine