Novel CD19-Targeted Antibody Moves Toward Regulatory Filing in DLBCL

A novel Fc-enhanced CD19-targeted antibody, MOR208, is generating interest for the treatment of patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who are not eligible for high-dose chemotherapy and autologous stem cell transplantation and is making its way toward a future regulatory filing, according to a news release from the manufacturer MorphoSys AG.¹

MOR208is currently being investigated in 2 ongoing clinical trials of patients with relapsed/refractory DLBCL. The L-MIND study, a single-arm, open-label phase II study is investigating the combination of MOR208 and lenalidomide (Revlimid) for patients who have received 1 to 3 prior systemic treatment regimens (NCT02399085). Results from the ongoing study were presented at the 2018 American Society of Hematology (ASH) Annual Meeting in December.²

In L-MIND, 81 patients were treated with 12 mg/kg of MOR208 by intravenous infusion weekly for the first 3 cycles followed by every other week in cycle 4 and beyond until disease progression, unacceptable toxicity, or discontinuation. Lenalidomide was administered daily at 25 mg for 3 of the 4 weeks of each cycle for up to 12 cycles or until disease progression or unacceptable toxicity.

In preliminary findings presented at the ASH meeting, the overall response rate was 58%, consisting of complete responses in 33% of patients (n = 27) and partial responses in 25% (n = 20). After a median follow-up of 12 months, patients treated with the combination had a median progression-free survival of 16.2 months (95% CI, 6.3-not reached). The median duration of response and median overall survival were both not met at the time of data cutoff, yet the 1-year OS rate was 73% (95% CI, 63%-85%) and 70% of responding patients had not progressed after a year. As of data cutoff, almost half of the patients were still receiving the study regimen.

The most common any-grade treatment-emergent adverse events observed were neutropenia in 48%, thrombocytopenia in 32%, anemia in 31%, diarrhea in 30%, pyrexia in 22%, and asthenia in 20%. Common grade ≥3 treatment-emergent adverse events included neutropenia in 43%, thrombocytopenia in 17%, and anemia in 9%. Forty-two percent of patients required a dose reduction of lenalidomide.

The L-MIND trial has completed enrollment and the company has announced that topline results will be presented at a medical conference mid-year. These results will serve as the basis for regulatory filings to the FDA, which are expected to be completed by the end of 2019.

In addition, MorphoSys AG is already in talks with the National European Medicines Agency regarding a potential marketing authorization application for the agent in Europe based off the results of the L-MIND trial.

"Our L-MIND trial continues as planned and we are on track to completing our regulatory submission to the FDA this year,” Malte Peters, MD, chief development officer of Morphosys AG, said in a statement. "Further, we are having early conversations with European regulators about the possibility of using L-MIND as the basis for a filing in Europe. We hope to have a clearer picture of the regulatory path in Europe within the next several months.”

The pivotal trial for MOR208 is the randomized, open-label, multicenter phase II/III B-MIND trial (NCT02763319), which is investigating the combination of MOR208 with bendamustine in comparison with rituximab (Rituxan) plus bendamustine in patients with relapsed/refractory DLBCL. The trial is expected to enroll approximately 330 patients across up to 180 centers in the United States, Europe, and Asia Pacific.

Treatment in the investigational arm consists of 6 cycles of 12 mg/kg of intravenous MOR208 and 90 mg/m²of intravenous bendamustine. Those who had achieved a response after the 6 cycles will continue to receive MOR208 for up to 18 more cycles.

The primary endpoint of the study is progression-free survival with secondary endpoints including objective response rate, overall survival, duration of response, disease control rate, time to progression, time to next treatment, safety, quality of life, immunogenicity, and pharmacokinetics.

In order to be eligible for the trial, patients had to have received 1 to 3 prior systemic therapies, 1 of which must have been a CD20-targeted agent, and they must have failed or not have been eligible for high-dose chemotherapy and autologous stem cell transplantation.

In the first quarter of the year, in agreement with the FDA, the company made an amendment to the study to include a new co-primary endpoint of response based on the presence of a particular biomarker.

“Following discussions with the FDA, we have introduced a co-primary endpoint into the B-MIND trial based on preclinical data that suggest the involvement of a certain biomarker. The amended B-MIND trial enables us to test the hypothesis that MOR208 shows enhanced activity in patients who can be identified using the biomarker, while in addition allowing us to test efficacy in the unselected patient population as originally planned,” Peters said.

Interim results from the B-MIND trial are expected in the second half of the year and could result in the trial increasing its enrollment to up to 450 patients.

If conditional approval is granted to MOR208 based on the results of the L-MIND study, then the B-MIND trial could serve as confirmatory findings.

References:

1. MorphoSys Provides Updates on L-MIND and B-MIND Clinical Trials of MOR208 in Relapsed/Refractory DLBCL. MorphoSys. Posted March 7, 2019. https://bit.ly/2IYLR5T. Accessed March 8, 2019.
2. Salles GA, Guell J, González-Barca E, et al. Single-arm phase II study of MOR208 combined with lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphoma: L-mind.Blood.2018;132(suppl 1; abstr 227). doi: 10.1182/blood-2018-99-113399.