Updated phase I/Ib trial data on ublituximab, a glycoengineered anti-CD20 monoclonal antibody, in combination with umbralisib (an oral, next generation PI3K delta inhibitor) and bendamustine in patients with follicular lymphoma were recently presented at the International Conference on Malignant Lymphoma (Abstract 277).
Recognizing an unmet need among patients with relapsed/refractory indolent non-Hodgkin lymphoma, specifically those who are unable to tolerate high-dose chemotherapy or transplant, as well as the proven activity of bendamustine in the treatment of non-Hodgkin lymphoma, researchers sought to determine if they could “safely enhance the benefit of the ublituximab + umbralisib regimen through combination treatment with bendamustine.”
The phase I/Ib UTX-TGR-103 study (NCT02006485) analyzed the combination of ublituximab and umbralisib in patients with relapsed or refractory non-Hodgkin lymphoma and chronic lymphocytic leukemia.
Researchers found that the combination of ublituximab and umbralisib is a safe and efficacious backbone regimen on which to build novel multi-drug combinations.
Following the evaluation of the doublet therapy, a triplet cohort was opened evaluating the combination of ublituximab, umbralisib, and bendamustine restricted to enrollment for follicular lymphoma and diffuse large B-cell lymphoma (DLBCL) patients, which included patients refractory to any prior agent, and those not able to tolerate aggressive chemotherapy, stem-cell transplant, or CD19 CAR-T directed therapy.
This poster presentation includes data from patients with relapsed or refractory follicular lymphoma or DLBCL treated with the triple combination of ublituximab, umbralisib, and bendamustine.
Thirty-three patients were evaluable for safety of which 24 were evaluable for efficacy (nine patients were note evaluable; seven were too early to evaluate, and two patients were off study prior to an efficacy assessment: one non-related adverse event (AE) and one investigator decision).
The primary objective of the study was to determine the safety and maximum tolerated dose of the combination therapy. The secondary objectives included overall response rate, time to response, duration of response, and progression-free survival.
Key eligibility requirements included:
- confirmed diagnosis of follicular lymphoma or DLBCL;
- ECOG Performance Status ≤ 2;
- relapse after or refractory to at least one prior treatment regimen (no limit on prior therapies); and
- patients who relapsed from a prior autologous stem cell transplant after 90 days.
The triple combination appears well-tolerated with no discontinuations for a treatment-related AE. No events of pneumonitis and no grade 3/4 transaminitis were reported. Twenty-one patients (64%) were refractory to prior treatment. Mean time on study was approximately 6 months.
Efficacy highlights from this presentation included:
- eighty-eight percent (7 of 8) ORR, including a 50 percent complete response (CR) rate, observed in patients with relapsed or refractory follicular lymphoma;
- one-hundred percent (4 of 4) ORR, including a 50 percent CR rate, observed in patients with relapsed DLBCL; and
- fifty percent (6 of 12) ORR, including a 42 percent CR rate, observed in patients with refractory DLBCL with durable CR and PR responses observed (PR ongoing for >16+ months).
This data supports the use of this triplet therapy, which is “well-tolerated and highly active in patients with advanced indolent and aggressive NHL, including those not eligible for HD/SCT or CD19 CAR-T therapy,” according to study authors.
Given these results, the triple combination of ublituximab, umbralisib, and bendamustine is being study in additional trials. The phase IIb UNITY-NHL study is currently enrolling patients with previously treated follicular lymphoma, DLBCL, small lymphocytic lymphoma, and marginal zone lymphoma.
“I am extremely pleased with the durable responses seen with this novel triplet regimen, especially in patients with aggressive DLBCL who may not have been candidates for more intensive chemotherapy, transplantation, or CAR-T therapy, due to poor performance status or need for urgent therapy, a truly unmet medical need,” stated Matthew Lunning, DO, of the University of Nebraska Medical Center. “Many patients had high-risk molecular features and some have obtained sustained responses.
“In addition to being highly active, the triplet regimen of [ublituximab, umbralisib, and bendamustine] was very well-tolerated, with a low incidence of grade 3 or greater adverse events, particularly those that have been associated with the PI3K-delta class,” he concluded. “I look forward to the possibility of testing this regimen earlier in relapsed and refractory [disease] and am excited to see it advance into registration directed studies.”