A First-in-Human Study of Novel Cereblon Modulator Avadomide (CC-122) in Advanced Malignancies.
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Date
2019-01-01ICR Author
Author
Rasco, DW
Papadopoulos, KP
Pourdehnad, M
Gandhi, AK
Hagner, PR
Li, Y
Wei, X
Chopra, R
Hege, K
DiMartino, J
Shih, K
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
Humans
Lymphoma, Non-Hodgkin
Multiple Myeloma
Piperidones
Adaptor Proteins, Signal Transducing
Antineoplastic Agents
Drug Administration Schedule
Maximum Tolerated Dose
Dose-Response Relationship, Drug
Adult
Aged
Middle Aged
Female
Male
Quinazolinones
Drug-Related Side Effects and Adverse Reactions
Language
eng
Date accepted
2018-09-05
License start date
2019-01
Citation
Clinical cancer research : an official journal of the American Association for Cancer Research, 2019, 25 (1), pp. 90 - 98
Publisher
AMER ASSOC CANCER RESEARCH