CC-122 Dosing on a Novel Intermittent Schedule Mitigates Neutropenia and Maintains Clinical Activity in Subjects with Relapsed or Refractory Diffuse Large B Cell Lymphoma

Background:  CC-122, a first in class PPM™ pleiotropic pathway modifier, has anti-tumor activity against B cell lymphomas. The molecular target of CC-122 is cereblon (CRBN) and CC-122 promotes ubiquitination of lymphoid transcription factor Aiolos in a CRBN-dependent manner, leading to its degradation in Diffuse Large B Cell Lymphoma (DLBCL) tumor tissue and immune cells. CC-122 also depletes Ikaros, which is expressed in immature stages of myeloid differentiation and regulates early neutrophil differentiation (Blood 101:2219 2003).

Following establishment of CC-122 3mg daily (QD) as the maximum tolerated dose (MTD) on a continuous schedule (Blood 122:2905 2013), subjects with advanced lymphoma, myeloma, and select solid tumors were enrolled in parallel expansion. In DLBCL subjects, CC-122 treatment demonstrated promising clinical efficacy, however, dose reductions due to neutropenia were frequent with the QD schedule (Blood 124:3500 2014). Therefore, a second cohort of DLBCL subjects was enrolled to evaluate the tolerability and clinical activity of intermittent schedules.

Methods: Subjects with relapsed/refractory DLBCL were enrolled in parallel dose escalation of CC-122 given orally at 4mg or 5mg on two intermittent schedules. CC-122 given 21/28 days was tested based on lenalidomide experience. In order to model a second schedule, human bone marrow CD34+ cells were cultured for two weeks in SCF, Flt3L and G-CSF for expansion towards granulocytic lineage followed by 6 days with media plus G-CSF for neutrophil maturation. CC-122 0.5 uM was added continuously or on a 5 out of 7 day (5/7d) schedule. Myeloid maturation stages were measured 14 days later by CD34, CD33 and CD11b flow cytometry.  Continuous exposure to CC-122 led to reversible myeloid maturation arrest and 90% decreased mature neutrophils compared to vehicle, whereas, CC-122 exposure for 5/7d resulted in only 50% decreased mature neutrophils. Based on this rationale, CC-122 given 5/7d was selected as the second intermittent schedule tested in DLBCL.

Results:   As of June 25, 2015, 22 subjects with relapsed/refractory DLBCL were enrolled in the 2^nd cohort; all were evaluable for safety, 16 were efficacy evaluable (EE) as of the cutoff date.  The median age was 60 years and 54% were male. The median time since diagnosis was 14 months and all subjects were ECOG 0-1. For subjects treated with CC-122 4mg 21/28 days (N=3), there were no dose limiting toxicities (DLTs) in cycle 1, however, all subjects required dose reduction due to neutropenia and therefore this dose level was considered a non-tolerated dose (NTD). For subjects treated with CC-122 on a 5/7 days schedule, the NTD was at 5mg due to 2 DLTs in 2 of 5 subjects (grade 3 febrile neutropenia and grade 3 pneumonitis). CC-122 4mg was the MTD on 5/7d and was selected for ongoing expansion in up to 50 subjects (N=14 as of cutoff date). There were no DLTs in 12 DLT-evaluable subjects. Median relative dose intensity achieved for 4mg 5/7d vs 3mg QD was 99% vs 79%.  The most common (≥ 10%) related adverse events (AEs) were neutropenia (36%), constipation (29%), asthenia (21%) and grade 3/4 related AEs were neutropenia (36%) and lipase elevation (14%).  In addition, drug-related serious AEs included pneumonia, neck pain, and respiratory failure. AEs were an uncommon cause of discontinuation (7%, n=14). Response rates for the EE DLBCL subjects treated at 5mg 5/7d (N=3), 4mg 5/7d (N=10), and 3mg QD (N=22) was 67% (2 PR), 30% (1CR, 2 PR) and 23% (1CR, 4PR), respectively. Aiolos protein levels in peripheral T cells was measured by flow cytometry pre (baseline) and 5 hours post dosing on C1D1, C1D10 and C1D22.  The median % change Aiolos levels at each of these visits were -47, -28 and -52%, respectively, indicating that Aiolos degradation occurs throughout the cycle.  In addition, the median increase from baseline in cytotoxic memory T cells and helper memory T cells at cycle 1 day 22 in peripheral blood samples was 580% and 76%, respectively.

Conclusion: In an in vitro myeloid differentiation assay, myeloid maturation arrest by CC-122, possibly due to Ikaros degradation, can be partially bypassed with a 2 day drug holiday. From a clinical standpoint, exploration of intermittent dosing confirmed that 5/7d schedule mitigates neutropenia-related dose reductions and improves CC-122 clinical activity in relapse/refractory DLBCL patients. Of note, the immunomodulatory effects of CC-122 are maintained on the 5/7d schedule.