Cirmtuzumab/Ibrutinib Combo Achieves 50% CR Rate in R/R MCL Cohort

Cirmtuzumab in combination with ibrutinib induced a clinical benefit rate of 100% in a small cohort of patients with relapsed or refractory mantle cell lymphoma, according to interim results of the phase I/II CIRLL trial.

Hun Ju Lee, MD

Cirmtuzumab in combination with ibrutinib (Imbruvica) induced a clinical benefit rate of 100% in a small cohort of patients with relapsed or refractory mantle cell lymphoma (MCL), according to interim results of the phase I/II CIRLL trial.

Additionally, complete responses (CRs) were seen in half of the 12 evaluable patients, according to a press release from Oncternal Therapeutics announcing the preliminary results.

“The reported complete response rate for patients with MCL treated with cirmtuzumab and ibrutinib is highly encouraging and is higher than previously reported for ibrutinib alone, particularly considering that some of these patients were heavily pretreated. Patients with relapsed MCL remain in dire need of well-tolerated treatment options that provide deeper and more durable responses,” said investigator Hun Ju Lee, MD, associate professor of medicine, Department of Lymphoma & Myeloma, The University of Texas MD Anderson Cancer Center, in the press release.

Cirmtuzumab is a potentially first-in-class ROR1-targeted monoclonal antibody. CIRLL was designed to explore the potential efficacy of cirmtuzumab in combination with Bruton’s tyrosine kinase inhibitor ibrutinib in patients with B-cell chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma.The trial was later expanded to include patients with MCL.

The study is broken down into 3 parts: part 1 is a dose-finding study, part 2 is a dose-expansion evaluation (phase I), and in part 3 the activity of the combination is compared with the use of ibrutinib alone (phase II).

In phase I, cirmtuzumab monotherapy was administered intravenously every 2 weeks for 5 administrations and then every 4 weeks thereafter, followed by the combination with ibrutinib given orally once a day and cirmtuzumab given every 2 weeks for 3 administrations and afterwards every 4 weeks.

The recommended dose for the combination was determined to be 600 mg of cirmtuzumab administered intravenously every 2 weeks for 3 doses, followed by dosing every 4 weeks, in combination with the approved dose of ibrutinib for patients with MCL, 560 mg once daily.

All patients in the relapsed/refractory MCL cohort had previously received a median of 2 prior therapies, including chemotherapy, stem cell transplant, chimeric antigen receptor T-cell therapy, and/or ibrutinib plus rituximab (Rituxan).

After a median follow-up of 6.4 months, the best objective response rate was 83% and the clinical benefit rate was 100%, consisting of 6 CRs, 4 partial responses, and 2 patients with stable disease.

All of the CRs are ongoing, with one patient remaining in CR for over 21 months. Four of the CRs were achieved within 4 months of initiating the doublet regimen.

“We are encouraged by the complete response rate for patients with MCL reported in the ongoing CIRLL clinical trial, and look forward to further developing cirmtuzumab in the ongoing clinical trials for patients with MCL, CLL, and breast cancer, as well as potentially for otherROR1-expressing solid tumors and hematological malignancies,” James Breitmeyer, MD, PhD, president and CEO of Oncternal, said in a statement.

The combination was considered to be well tolerated, and the safety profile was consistent with that of ibrutinib alone. No dose-limiting toxicities were reported nor any discontinuations or serious adverse events that could be attributed to cirmtuzumab alone.

Enrollment in the dose-expansion cohort for patients with relapsed/refractory MCL is ongoing as well as the phase II portion of the trial for patients with CLL.

Cirmtuzumab is also being studied in an investigator-initiated phase I study in combination with paclitaxel in women with metastatic breast cancer.

Reference:

Oncternal Therapeutics Announces Interim Clinical Data Update, Including 50% Complete Response Rate, for Cirmtuzumab in Combination with Ibrutinib in Patients with Mantle Cell Lymphoma [press release]. San Diego, CA: Oncternal Therapeutics; March 11, 2020. https://bwnews.pr/2vdChpH. Accessed March 11, 2020.Nat Med.doi:10.1038/nm.4118.