A Phase II Study of the Fc Engineered CD19 Antibody MOR208 in Combination with Lenalidomide for Patients with Chronic Lymphocytic Leukemia (CLL)

MOR208 is an Fc engineered CD19 monoclonal antibody which has been shown in a Phase I trial in patients with relapsed and refractory CLL to be generally well tolerated and have preliminary efficacy, with an overall response rate (ORR) of 30% by IWCLL 2008 guidelines (Woyach et al, Blood 2014). Compared to non-engineered CD19 monoclonal antibodies, MOR208 has significantly enhanced antibody dependent cellular cytotoxicity (ADCC), which can be further augmented in vitro with the addition of lenalidomide. Given the in vitro synergy of these agents, acceptable individual safety profiles, and efficacy of each as a single agent, we chose to combine MOR208 and lenalidomide in patients with both previously treated and previously untreated CLL.

This study is a single institution phase II trial of MOR208 in combination with lenalidomide with an initial safety run-in as part of each cohort. MOR208 was given at a dose of 1 mg/kg on cycle 1 day 1, then 9 mg/kg on days 2, 8, 15, and 22 of cycle 1, and then on day 1 of cycles 2-12. Lenalidomide was started at a dose of 2.5 mg daily on cycle 1 day 8 and given continuously. The dose of lenalidomide could be escalated up to 10 mg daily in patients without toxicity. After 12 cycles, lenalidomide could be continued indefinitely in responding patients. Toxicity was assessed using the National Cancer Institute's Common Criteria for Adverse Events v4.0 for non-hematologic toxicity, and IWCLL 2008 guidelines for hematologic toxicity. Disease response by IWCLL 2008 guidelines was assessed at cycle 7 day 1 and at the end of cycle 12.

This study will enroll 20 patients with treatment-naïve CLL and 20 patients with relapsed/refractory CLL. At this time, 7 patients with relapsed/refractory disease and 5 patients with treatment-naïve disease have been enrolled and evaluated. The most common toxicities observed related to protocol therapy have been infusion related reactions, fatigue, thrombocytopenia, and neutropenia. In patients with relapsed disease, all toxicities except neutropenia have been grade 1 or 2, and 2 patients experienced grade 3 neutropenia. Of the 5 patients with treatment-naïve CLL, two experienced significant infusion reactions on cycle 1 day 1 that prevented further administration of MOR208. After a protocol amendment escalating steroid premedication, no further grade 3 infusion reactions have been observed. While the majority of patients were able to escalate lenalidomide to either 5 or 10 mg, all patients had lenalidomide eventually dose reduced to 2.5 mg daily due to cytopenias, rash, or fatigue.

This combination has shown preliminary efficacy. In the cohort of patients with relapsed disease, two experienced progressive disease during cycle 2 and cycle 5 respectively. The remaining 5 patients achieved stable disease (SD, n=3) or a partial response (PR, n=2) at cycle 7 day 1, with one patient converting to PR by cycle 12. Three patients completed 12 cycles of therapy, and the remaining two completed 12 cycles and now remain on lenalidomide alone at cycle 18 and cycle 19 respectively. In the cohort of patients with treatment-naïve disease, three patients completed more than 1 day of therapy. All of these patients achieved a PR at cycle 7 day 1, and are now in cycle 10 (n=1) or cycle 11 (n=2).

In conclusion, this Phase II trial in progress demonstrates preliminary safety and activity of the combination of MOR208 and lenalidomide in patients with CLL. This combination also has the potential to positively modulate the immune system, and detailed correlative studies are evaluating T cell and NK cell function in these patients. Trial accrual is ongoing and updated results will be presented at the meeting.