RT Journal Article
SR Electronic
T1 A First-in-Human Study of Novel Cereblon Modulator Avadomide (CC-122) in Advanced Malignancies
JF Clinical Cancer Research
JO Clin Cancer Res
FD American Association for Cancer Research
SP 90
OP 98
DO 10.1158/1078-0432.CCR-18-1203
VO 25
IS 1
A1 Rasco, Drew W.
A1 Papadopoulos, Kyriakos P.
A1 Pourdehnad, Michael
A1 Gandhi, Anita K.
A1 Hagner, Patrick R.
A1 Li, Yan
A1 Wei, Xin
A1 Chopra, Rajesh
A1 Hege, Kristen
A1 DiMartino, Jorge
A1 Shih, Kent
YR 2019
UL http://clincancerres.aacrjournals.org/content/25/1/90.abstract
AB Purpose: Avadomide is a novel, small-molecule therapeutic agent that modulates cereblon E3 ligase activity and exhibits potent antitumor and immunomodulatory activities. This first-in-human phase I study (NCT01421524) evaluated the safety and clinical activity of avadomide in patients with advanced solid tumors, non-Hodgkin lymphoma (NHL), and multiple myeloma.Patients and Methods: Thirty-four patients were treated with avadomide in 7 dose-escalation cohorts using a 3 + 3 design (0.5–3.5 mg, 28-day continuous dosing cycles). The primary objectives were to determine the dose-limiting toxicity (DLT), nontolerated dose (NTD), maximum tolerated dose (MTD), recommended phase II dose, and pharmacokinetics of avadomide. The secondary objective was to determine preliminary avadomide efficacy. Exploratory objectives included evaluation of pharmacodynamic effects of avadomide.Results: DLTs were reported in 2 patients, and grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 14 patients (41%). The most common TEAEs (≥15%) were fatigue, neutropenia, and diarrhea. The NTD and MTD were 3.5 and 3.0 mg, respectively. Of 5 patients with NHL, 1 achieved a complete response, and 2 had partial responses. Although no objective responses were observed in patients with solid tumors, 5 of 6 patients with brain cancer experienced nonprogression of ≥6 months. A dose-dependent relationship between Aiolos degradation in peripheral B and T cells occurred within 5 hours of the first dose of avadomide administered, starting at 0.5 mg.Conclusions: Avadomide monotherapy demonstrated acceptable safety and favorable pharmacokinetics in patients with solid tumors, NHL, and multiple myeloma. In addition, 3 objective responses were observed in NHL.