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The ongoing, phase 1/2 PrE0404 trial is evaluating the combination of ixazomib and ibrutinib in patients with relapsed/refractory mantle cell lymphoma with the goal of improving upon single-agent BTK inhibitor therapy in this patient population.
The ongoing, phase 1/2 PrE0404 trial (NCT03323151) is evaluating the combination of ixazomib (Ninlaro) and ibrutinib (Imbruvica) in patients with relapsed/refractory mantle cell lymphoma (MCL) with the goal of improving upon single-agent BTK inhibitor therapy in this patient population.1
“This is an important study to consider for any patient where you are thinking about using a BTK inhibitor,” said study chair, Jonathon B. Cohen, MD, MS, an assistant professor in the Department of Hematology and Medical Oncology at Emory University School of Medicine.2 “We know that single-agent BTK inhibitors are quite effective, but unfortunately, after about 18 to 24 months, most patients will start to progress. Our goal is to try to limit those early progressions and, hopefully, deepen responses.”
MCL is a rare subtype of non-Hodgkin lymphoma that is currently considered incurable with available therapeutic options, such as ibrutinib, lenalidomide (Revlimid), and bortezomib (Velcade). As such, novel therapies or combination regimens are needed for this patient population.
Ibrutinib, a BTK inhibitor, was approved by the FDA in November 2013 for use in patients with MCL who have received at least 1 prior therapy.
Ixazomib, an oral proteasome inhibitor (PI) that was FDA approved in 2015 for use in combination with lenalidomide and dexamethasone to treat patients with relapsed/refractory multiple myeloma, may enhance the anti-cancer effects of ibrutinib monotherapy in relapsed/refractory MCL.
The phase 1 portion of the open-label study was completed in November 2019 and reported that dose level 2 (4 mg of ixazomib plus 560 mg of ibrutinib) should be used as the recommended phase 2 dose in the study. In the phase 1 study, patients could have received prior ibrutinib if it was for less than 3 months.
The phase 2 portion of the study is further evaluating the efficacy and safety of the combination, with complete response rate serving as the primary end point. Secondary end points include treatment-related adverse effects, overall response rate, progression-free survival, and overall survival.
Patients will enroll onto 2 cohorts based on prior ibrutinib treatment. The first cohort will comprise patients with BTK inhibitor–naïve MCL, and the second cohort will comprise patients with BTK inhibitor–pretreated disease.
The estimated clinical trial enrollment is 43 patients. Eligible participants have to have pathologically confirmed, relapsed/refractory MCL with available current or prior tissue samples that show cyclin D1 positivity by immunohistochemistry or translocation (11;14) positivity by fluorescence in situ hybridization or cytogenetics. Patients have to have been refractory to or relapsed/progressed on at least 1 prior therapy.
“Patients are eligible for this trial as long as they have relapsed mantle cell lymphoma,” said Cohen, who is also co-director of the Lymphoma Program, medical director of Infusion Services, and chair of the Data and Safety Monitoring Committee at Winship Cancer Institute of Emory University. “There are some laboratory requirements, and [patients] have to be able to obtain ibrutinib. In addition, patients who are felt to be ineligible for ibrutinib due to other comorbidities would not be eligible for this study.”
Patients who underwent autologous or allogeneic stem cell transplant are eligible for enrollment as long as they do not have active grade 2 to 4 acute graft-vs-host disease (GVHD) or moderate/severe chronic GVHD. Patients cannot require immunosuppressive medications or corticosteroids for GVHD management.
Additionally, prior PIs are allowed, but patients could not have received the combination of a PI plus a BTK inhibitor.
Other criteria state that patients have to have ECOG performance scores of 0 to 2, adequate organ function, and no current or active central nervous system involvement, among other eligibility requirements.
Regarding patient recruitment, the BTK inhibitor–naïve cohort is still open for enrollment; however, the BTK inhibitor–pretreated cohort was closed for enrollment as of August 2020.
Eligible patients will receive 4 mg of oral ixazomib on days 1, 8, and 15 of 28-day cycles plus 560 mg of oral ibrutinib daily until disease progression or unacceptable toxicity. Tumor assessments will be performed approximately every 3 months during the first year of treatment and every 6 months thereafter until disease progression.
As of August 2020, a total of 2 patients were enrolled to the study. The estimated primary completion date of the study is January 2024, and the estimated study completion date is December 2024.
“This is a study that could ultimately impact patient care by identifying a safe and effective combination partner for BTK inhibition,” concluded Cohen.