FDA Grants Orphan Drug Designation to Cirmtuzumab in MCL and CLL

The FDA has granted an Orphan Drug designation to the ROR1 antibody cirmtuzumab (UC-961) for the treatment of patients with mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL).

“We are pleased to receive orphan drug designations for cirmtuzumab, our potentially first-in-class investigational ROR1 antibody,” said James Breitmeyer, MD, PhD, president and chief executive officer, Oncternal, in a statement. “We are excited about cirmtuzumab’s potential for the treatment of patients with ROR1-expressing cancers, including MCL, CLL, HER2-negative breast cancer, and other solid tumors, and look forward to further advancing its development to benefit patients with significant unmet medical needs.”

Oncternal echoed statistics around MCL and SLL. For MCL, the figures show a median survival of roughly 2 to 5 years and a 10-year survival rate of 5% to 10%. For CLL, the most common form of leukemia in adults, there is are no curable drug in existence.

The agent is currently being researched in the phase 1/2 clinical trial (NCT03088878) led by the University of California (UC), San Diego, in collaboration with the California Institute for Regenerative Medicine and Oncternal Therapeutics, Inc. The multi-arm study is evaluating cirmtuzumab in combination with ibrutinib (Imbruvica) in the dose-finding and dose-expansion phases. In phase 2, the study will evaluate the safety efficacy cirmtuzumab plus ibrutinib compared with ibrutinib alone.

The primary end point of the phase 2 portion of the trial is complete response rate. The secondary end points include plasma concentration, ROR1 cell surface expression, duration of response, progression-free survival, time to treatment failure, and overall survival.

Recruitment is ongoing with key inclusion criteria such as an ECOG performance status of 0 to 2, histologically confirmed diagnosis of CLL/SLL or MCL, and adequate renal and bone marrow function. The study excludes individuals with a histological transformation to an aggressive lymphoma, known central nervous system involvement, and other conditions that may interfere with cirmtuzumab or ibrutinib treatment.

The rationale for this study lies with preclinical evidence from UC San Diego School of Medicine, suggesting that targeting a critical epitope on ROR1 was important for targeted ROR1 expressing tumors. Researchers hypothesized that such an agent could lead to a survival and fitness advantage. Cirmtuzumab was developed based on this hypothesis and demonstrated Wnt5a signaling blockage, tumor cell proliferation inhibition, migration, and survival in a preclinical study. Cirmtuzumab also induced differentiation of the tumor cells.

Aside from B-cell malignancies, cirmtuzumab in combination with paclitaxel is also under investigation in a phase 1 study of female patients with HER2-positive metastatic breast cancer, which is also being conducted by the UC San Diego School of Medicine.

_Reference:

_{Oncternal Therapeutics Announces Orphan Drug Designations of Cirmtuzumab ROR1 Antibody for Treatment of Mantle Cell Lymphoma and for Treatment of Chronic Lymphocytic Leukemia. News release. Oncternal Therapeutics, Inc. https://bwnews.pr/2NMiaV6}