CC-122 Degrades the Lymphoid Transcription Factor Aiolos (IKZF3) By Modulating Cereblon and Shows Clinical Activity in a Phase Ib Study of Subjects with Relapsed or Refractory Non-Hodgkin’s Lymphoma and Multiple Myeloma

Abstract

Background: CC-122 is a novel non-phthalimide analog of the IMiDs® immunomodulatory drugs (lenalidomide and pomalidomide) and a first in class PPMTM (Pleiotropic Pathway Modifier) compound with multiple biological activities including potent anti-proliferative activity against B-lineage cells (10-fold greater than lenalidomide), anti-angiogenic activity (100-fold greater than lenalidomide) and immunomodulatory effects (10-fold greater than lenalidomide). The molecular target of CC-122 is cereblon (CRBN), a substrate receptor of the Cullin ring E3 ubiquitin ligase complex (CRL4CRBN). CC-122 promotes ubiquitination of lymphoid transcription factors Ikaros (IKZF1) and Aiolos (IKZF3) in a CRBN-dependent manner, leading to their subsequent degradation. Following establishment of 3mg once daily (QD) as the maximum tolerated dose (Blood 122:2905 2013), patients with advanced aggressive non-Hodgkin lymphoma (NHL), multiple myeloma (MM), and select solid tumors were enrolled in parallel expansion cohorts of up to 20 evaluable patients. CC-122 was dosed at 3 mg QD in 28-day cycles until disease progression. Results: As of May 1, 2014, 93 total patients were enrolled in the expansion phase of the study. The NHL cohort included 21 patients with diffuse large B-cell lymphoma (DLBCL) and 1 patient with mantle cell lymphoma, and twenty-four patients were enrolled in the MM cohort. Results in solid tumor cohorts will be reported separately. All patients were ECOG performance status 0-2, the median number of prior systemic therapies was 4 (NHL) and 6 (MM). The most common (> 20%) adverse events (AEs) (grades 1-4) included neutropenia (69.6%), anemia (52%), asthenia (50%), pyrexia (35%), diarrhea (30%), cough (30%), thrombocytopenia (28%), and constipation (22%). Grade 3/4 AEs occurring in more than one patient were neutropenia (52%), anemia (26%), febrile neutropenia (13%), and thrombocytopenia (7%). CC-122 dose reduction was required in 36.4% of patients with NHL and 63% of patients with MM, the majority of which was due to neutropenia and occurred during cycle 1 or 2. CC-122 systemic exposure in NHL and MM patients was generally comparable after administration of single and multiple doses. Peak concentrations were observed between 30 minutes and 2 hours (median Tmax concentration = 1.5 h). Four treated patients with DLBCL had objective responses; one patient with complete response (CR) and 3 with partial responses (PR). Responses were observed in patients with germinal center B cell (GCB), non-GCB and Myc/Bcl2 over-expressing DLBCL. Four treated patients with MM had PR, and two of these responders were progression free beyond 10 cycles. A single dose of CC-122 3mg resulted in decreased Aiolos protein expression at 1.5 and 5 hours compared with baseline in peripheral B cells (median 38% and 53%) and T cells (median 31% and 54%) in the combined NHL (n = 16) and MM (n = 19) cohorts. Decrease in expression of Aiolos protein from baseline was also observed in lymph node biopsies of patients with DLBCL. Furthermore, CC-122 treatment decreased CD19+ B cells (median = 57% of baseline), expanded CD4-/CD8+/CD45RA-/CD45RO+ cytotoxic memory T cells (median = 320% of baseline), and expanded CD4+/CD8-/CD45RA-/CD45RO+ helper memory T cells (median = 154% of baseline) in peripheral blood samples from patients with MM (n = 9) and NHL (n = 3-12) subjects. Additionally, ex vivo activation of T cells after a single dose of CC-122 compared with baseline, as measured by IL-2 production, increased by a median of 776% (NHL n = 3 and MM n = 7). Conclusions: CC-122 shows promising initial clinical and pharmacodynamic activity in heavily pretreated relapse/refractory NHL and MM patients. Biomarker analysis indicates that the 3 mg QD dose of CC-122 results in rapid CRBN target engagement and Aiolos degradation in the peripheral blood lymphocytes of patients with NHL and MM patients and in NHL tumor tissue. Exploration of an intermittent dosing to mitigate neutropenia-related dose reductions and interruptions is ongoing and clinical studies exploring drug combinations with CC-122 are underway. Disclosures Ribrag: Celgene Corp: Consultancy. Rasco:Celgene Corp: Membership on an entity's Board of Directors or advisory committees. Wei:Celgene Corp: Employment, Equity Ownership. James:Celgene Corp: Employment. Hagner:Celgene Corp: Employment, Equity Ownership. Gandhi:Celgene Corp: Employment, Equity Ownership. Chopra:Celgene Corp: Employment, Equity Ownership. DiMartino:Celgene Corp: Employment, Equity Ownership. Pourdehnad:Celgene Corp: Employment, Equity Ownership. Stoppa:Celgene Jansen: Honoraria.

Phase I, multicenter, dose‐escalation study of avadomide in adult Japanese patients with advanced malignancies

“…Most of the TEAE were manageable with dose interruptions or reductions, or with the use of appropriate supportive care, and the safety profile of avadomide was considered acceptable. Overall, the safety results of this study were consistent with the known safety profile of avadomide from global studies 12,13,15,19,20 …”

“…Ex vivo studies showed that avadomide significantly activated T cells, as measured by a dramatic increase in IL‐2 secretion upon stimulation 6,11 . Avadomide also decreased CD19 + B cells and expanded cytotoxic memory T cells in patients with NHL 12,13 . Furthermore, paired biopsies from DLBCL patients showed increased infiltration of T cells and macrophages upon treatment with avadomide 11 .…”

“…6,11 Avadomide also decreased CD19 + B cells and expanded cytotoxic memory T cells in patients with NHL. 12,13 Furthermore, paired biopsies from DLBCL patients showed increased infiltration of T cells and macrophages upon treatment with avadomide. 11 Avadomide has also been shown to activate NK cells that mediate antibody-dependent, cell-mediated cytotoxicity.…”

A First-in-Human Study of Novel Cereblon Modulator Avadomide (CC-122) in Advanced Malignancies

“…Current treatment options for patients with advanced solid and hematologic malignancies relapsed or refractory to standard therapies are limited. Avadomide's cell-autonomous effects, immune modulation, and antiangiogenic activity make it a potential therapeutic agent for hematologic and solid tumors (1,2,10,11). Herein, we report results from the first-in-human phase I dose-escalation study of avadomide in patients with advanced solid tumors, non-Hodgkin lymphoma (NHL), and multiple myeloma.…”

Novel drug targets for personalized precision medicine in relapsed/refractory diffuse large B-cell lymphoma: a comprehensive review

“…Moreover, other potential immunomodulatory mechanisms for its activity in (GCB)-DLBCL likely do exist and may impact the nonimmune environment in vivo , in patients as well [301]. CC-122 has already demonstrated clinical activity as single-agent in DLBCL [ 300 – 302 , 303 ]. CC-122 is currently in phase I trials in patients with newly diagnosed DLBCL or relapsed/refractory DLBCL, either as a single-agent (NCT01421524) [ 300 – 302 , 303 ] (Additional file 1 : Table S2) or in combination with the novel dual mTORC1/mTORC2 inhibitor CC-223 [ 304 ], the novel BTK inhibitor CC-293 [ 305 ] and/or rituximab (NCT02031419) as well as in combination with obinutuzumab, (NCT02417285) [ 303 ] (Additional file 1 : Tables S5 and S14).…”