Trial to assess ibrutinib-cirmtuzumab combination for B-cell malignancies

Researchers at University of California, San Diego, are investigating whether a the addition of the monoclonal antibody cirmtuzumab to standard therapy with ibrutinib benefits patients with B-cell malignancies.

Thomas Kipps, MD, PhD, distinguished professor of medicine and deputy director of research at UC San Diego Moores Cancer Center, and colleagues will conduct the phase 1b/phase 2 trial.

They will assess whether cirmtuzumab (Oncternal Therapeutics) — which targets the tumor cell surface protein ROR1 — could improve responses to ibrutinib (Imbruvica, Janssen), a Bruton tyrosine kinase inhibitor approved for treatment of B-cell diseases, including chronic lymphocytic leukemia and mantle cell lymphoma.

Investigators also will evaluate the safety of the combination.

The trial is funded by a $18.3 million grant from California’s stem cell agency.

H emOnc T oday spoke with Kipps about the challenges of developing treatments for this patient population, the study design and the potential implications of the results.

Question : Can you describe the unmet needs for this patient population?

Answer: We have come a long way in the development of new therapies for patients with CLL. Right now, we are exploiting what we have learned about the biology of this disease to target the distinctive features required for it to survive and grow. This has ushered in development of new therapies that are better tolerated than traditional chemotherapy. These drugs also have improved survival. One example is ibrutinib, a small molecule that can inhibit the signaling of the B-cell receptor; such signaling stimulates the leukemia cells, thereby enhancing their proliferation and survival. Ibrutinib also inhibits the migration of leukemia cells.

Despite the success we are having with drugs such as ibrutinib, challenges persist. Ibrutinib generally cannot by itself eradicate leukemia. As such, patients are required to take this drug for years. Even small side effects become compounded over time. Another problem is cost. This brings up the need to find ways to improve the efficacy of targeted therapies, such as ibrutinib, to eradicate the disease and eliminate the need for lifelong therapy.

Q : Why are patients not achieving complete responses ?

A : This has become somewhat of a problem in oncology in general. We are seeing it with the new drugs such as ibrutinib that fall within the kinase inhibitor class. These drugs adversely affect tumor cells by interfering with an important survival signaling pathway. However, such drugs generally cannot eradicate the cancer by themselves. Consequently, patients undergo continuous therapy until they develop intolerance or drug resistance. In CLL, we have found other survival pathways that are not blocked by ibrutinib that can serve as lifelines for the leukemia cells of patients undergoing therapy. One such pathway is triggered by the surface protein ROR1, which we found expressed on leukemia cells but not on normal B-cells or normal adult tissues. Cirmtuzumab, an antibody specific for ROR1, can effectively block the signaling pathways triggered by ROR1, as demonstrated in phase 1 clinical trials. Moreover, therapy with cirmtuzumab appears safe and well tolerated, with few — if any — side effects. In preclinical model systems, cirmtuzumab and ibrutinib had complementary effects. The combination puts leukemia cells in crisis, blocking the escape route provided by ROR1. This leads to enhanced clearance of leukemia cells and deeper remissions.

Q. Could you describe the trial design and methods?

A : There is a phase 1b portion and a phase 2 portion for treatment of patients with CLL or mantle cell lymphoma. The phase 1b portion is to determine what dose of cirmtuzumab to give with ibrutinib, and to find out whether the combination is safe. Patients receive a couple treatments of cirmtuzumab over a month’s time, then start on daily ibrutinib and monthly cirmtuzumab, which is given once each month for 6 months. Patients are observed for any problems or toxicities. They are also observed for whether treatment with cirmtuzumab effectively blocks the ROR1 signaling pathway in the leukemia cells of treated patients. Thus far, there have not been any added safety concerns observed when the two drugs are used together, even at higher doses of cirmtuzumab. I understand that patients already are experiencing faster remission rates, although it’s very early. The phase 2 portion of the study will use the most appropriate dose identified in the phase 1b portion.

Q : What is the timeline for trial completion and data availability?

A : The phase 1b accrued very rapidly. The hope was to have this completed by late summer, and it was gratifying to see that the principal investigators of this study met the accrual goals. The study involves a number of participants, including Oncternal — which is responsible for providing the antibody — and Pharmacyclics, which has reviewed the study and agreed to provide ibrutinib to enrolled patients.

Q : What are the potential clinical implications if this regimen is shown to be effective ?

A : It could shorten the duration of therapy with ibrutinib. It could allow patients to achieve a deeper remission and to be able to get off therapy altogether. – by Rob Volansky

For more information:

Thomas Kipps, MD, PhD, can be reached at University of California, San Diego, 9500 Gilman Drive #0820, La Jolla, CA 92093; email: tkipps@ucsd.edu.

Disclosure: Kipps developed cirmtuzumab, which was licensed to Oncternal Therapeutics by the University of California, which holds the patents for the antibody.