Combination therapy with the investigational treatment cirmtuzumab plus Imbruvica (ibrutinib) led to “highly encouraging” response rates among patients with mantle cell lymphoma (MCL), a type of B-cell cancer, according to the latest clinical results announced by Oncternal Therapeutics.
Cirmtuzumab, developed by Oncternal, is an investigational antibody that blocks ROR1, or receptor tyrosine kinase-like orphan receptor 1. Normally, this receptor is not produced in healthy adult tissue, but many different cancers can reactivate its expression. This helps cancer cells to survive and grow. Preclinical studies have shown that by binding to ROR1, cirmtuzumab is able to inhibit tumor cell proliferation, migration, and survival.
Imbruvica, developed by Janssen and AbbVie, is an oral therapy for people with MCL who have received at least one prior therapy. It is a Bruton’s tyrosine kinase (BTK) inhibitor that helps kill and reduce the number of cancerous B-cells.
Imbruvica and cirmtuzumab are both targeted therapies that are designed to kill or prevent cancer cells from growing and spreading. A study has suggested that a combination of both offers superior results than either agent alone.
In the CIRLL Phase 1b/2 trial (NCT03088878), researchers have been testing a combination of both treatments in patients with B-cell lymphoid malignancies, including MCL and chronic lymphocytic leukemia/small lymphocytic leukemia (CLL/SLL), who have been previously treated and never received treatment with a BTK inhibitor.
The study, which is currently recruiting, is taking place at U.S. sites in New York, Texas, Connecticut, Ohio, and California, and aims to enroll 156 patients, 18 and older. More information about contacts and locations is available here.
CIRLL’s primary objectives are to determine the best dosing regimen and compare the percentage of patients achieving a complete response with cirmtuzumab-Imbruvica versus Imbruvica alone.
The trial has three parts. In part 1 (dose-finding group), participants received ascending doses of cirmtuzumab alone, followed by a combination of cirmtuzumab and Imbruvica. The goal was to determine the recommended dosing regimen to be used for additional studies.
In part 2 (dose-expansion group), the dose found in the previous part was further tested for safety and pharmacological properties. In total, 66 patients were included in these two parts of the trial (Phase 1b).
Based on these studies, the best dosing for MCL was considered to be 600 mg of cirmtuzumab given into the vein (intravenously) every two weeks, followed by dosing every four weeks, in combination with 560 mg daily of Imbruvica tablets.
The third part (Phase 2) of the study will enroll approximately 90 people with MCL who will be randomized to receive cirmtuzumab plus Imbruvica at the recommended dose, or Imbruvica alone.
Enrollment in part 1 is fully completed, while enrollment in part 2 has been completed for CLL patients only. Enrollment is still ongoing for MCL patients in part 2 and CLL patients in Phase 2.
Results from the trial’s first part, with a median follow-up of 6.4 months (data cutoff March 6, 2020), have now been released.
They show that 50% of the patients with MCL who were given cirmtuzumab plus Imbruvica (6 of 12 patients) had a complete response, which means their tumors significantly reduced while their bone marrow was clear of detectable cancer.
All six patients have maintained a complete response, including one patient who remains on a complete response for more than 21 months. Four patients reached complete responses within four months of treatment. One patient had a complete response by positron emission tomography (PET scan), but was awaiting marrow biopsy results.
The remaining patients either reached a partial response (33% or four patients) or stable disease (17% or two patients).
Overall, 83% of the patients taking cirmtuzumab-Imbruvica responded completely or partially, and 100% of them had a clinical benefit from the double combo (complete or partial response, or stable disease).
Of note, some of the patients included were heavily pre-treated. They received a median of two prior therapies before participating in this study including chemotherapy, autologous stem cell transplant (SCT), CAR-T therapy, allogeneic SCT, and Imbruvica plus Rituxan (rituximab).
Cirmtuzumab-Imbruvica was well-tolerated, with adverse events comparable to those of Imbruvica alone. There were no dose-limiting toxicities, study drop-outs, or serious adverse events associated with cirmtuzumab.
“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 pre-treated,” Hun Ju Lee, MD, one of the trial investigators and associate professor at the University of Texas MD Anderson Cancer Center, said in a press release. “Patients with relapsed MCL remain in dire need of well-tolerated treatment options that provide deeper and more durable responses.”
The CIRLL clinical trial is supported by a grant from the California Institute for Regenerative Medicine and is being conducted in collaboration with the University of California San Diego.
“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, chronic lymphocytic leukemia (CLL) and breast cancer, as well as potentially for other ROR1-expressing solid tumors and hematological malignancies,” said James Breitmeyer, MD, PhD, Oncternal’s president and CEO.
