A First In Human Dose Escalation Study Of CC-122, A First-In-Class Pleiotropic Pathway Modulator™ (PPM) Compound In Subjects With Relapsed Or Refractory Solid Tumors, Multiple Myeloma and Non-Hodgkin’s Lymphoma
Authors: Rasco Drew W , Gandhi Anita K , James Angela , Li Shaoyi , O'Mara Edward , Chopra Rajesh , DiMartino Jorge F. , Shih Kent 
Published: October 2019

Abstract

Background
CC-122 is a novel PPMTM compound with multiple biological activities, including potent anti-proliferative, anti-angiogenic and immunomodulatory effects. The molecular target of CC-122 is the protein cereblon (CRBN), a substrate receptor of the cullin ring E3 ubiquitin ligase complex CRL4CRBN.

Methods
Subjects with advanced solid tumors, non-Hodgkin's lymphoma (NHL), multiple myeloma (MM), and other malignancies were enrolled in the dose escalation portion (Part A) of Study CC-122-ST-001. The primary objective was to determine both the non-tolerated dose (NTD) and maximally tolerated dose (MTD). Subjects were administered oral daily doses (either 0.5, 1, 1.5, 2, 2.5, 3 or 3.5 mg) during 28-day continuous dosing cycles. Pharmacokinetic (PK) and pharmacodynamic (PD) assessments were performed. Measures of general safety including hematology, clinical chemistry, and ECGs were collected and analyzed.

Results
34 subjects with solid or hematologic malignancies were treated in Part A, including NHL (5), MM (2), hepatocellular carcinoma (HCC) (2), primary central nervous system (CNS) malignancy (6), and others (19). Twenty-eight (28) of these patients were evaluable for efficacy. The most common (≥ 10%) treatment emergent adverse events (TEAEs, all grades) were fatigue, neutropenia, asthenia, constipation, nausea, dyspnea, vomiting, anemia, decreased appetite, diarrhea, dizziness, pruritis, pyrexia, alopecia, cough, headache, edema peripheral, tumor pain and urinary tract infection. In addition, drug-related serious adverse events (SAEs) included fever and fatigue in one subject (n=1, 3%), angioedema (n=1, 3%), and pneumocystis jiroveci pneumonia (n=1, 3%). An NTD of 3.5 mg was determined with 2 DLTs in 6 subjects; one with Grade 3 fever and fatigue and one with Grade 3 generalized muscle weakness. The MTD was defined as 3 mg, with no DLTs. AEs were an uncommon cause of discontinuation (n = 2, 6%). Preliminary PK results support CC-122 being rapidly absorbed, with peak CC-122 plasma levels achieved between 0.5 and 3 hours after single (Day 1) and multiple oral doses of CC-122. Across the dose range evaluated, both Cmax and AUC appear to increase in an apparent dose-proportional manner. CC-122 mean exposure ranged from approximately 200 ng/mL to 1100 ng/mL across the dose range evaluated. The mean terminal half-life of CC-122 is generally between 10 and 15 hours. Moderate (30% - 40%) accumulation of CC-122 is observed after multiple-dose administration. Dose and exposure-dependent decreases in peripheral B cell counts and enhanced T cell activation, as measured by ex vivo IL-2 production, were observed. Among 5 subjects with NHL, there was one partial and one complete response in 2 subjects with diffuse large B cell lymphoma (DLBCL) and one partial response in a patient diagnosed with mantle cell lymphoma (MCL).

Conclusions
CC-122 is a first-in-class PPM TM compound and a modulator of the CRL4CRBN E3 ubiquitin ligase complex. CC-122 was dosed to a NTD of 3.5 mg, administered once-daily continuously. An MTD of 3 mg, administered once-daily continuously, was established. The main drug-related AEs were fatigue and neutropenia. AEs were an uncommon cause of discontinuation; therefore, the general safety findings support continued development. Increases in PK parameters were noted to be approximately dose-proportional and predictable through the range of doses evaluated. Exposure-dependent pharmacodynamic effects involving immunomodulation were observed. Further tumor cohorts will be explored at the 3 mg once-daily dose. Given the encouraging signals of clinical and biomarker activity observed, CC-122 shows promising activity in hematological malignancies.

Disclosures:
Rasco: Celgene: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Gandhi:Celgene: Employment, Equity Ownership. James:Celgene: Employment, Equity Ownership. Li:Celgene: Employment, Equity Ownership. O'Mara:Celgene: Employment, Equity Ownership. Chopra:Celgene: Employment, Equity Ownership. DiMartino:Celgene: Employment, Equity Ownership.