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Cancer Therapy: Clinical

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

Drew W. Rasco, Kyriakos P. Papadopoulos, Michael Pourdehnad, Anita K. Gandhi, Patrick R. Hagner, Yan Li, Xin Wei, Rajesh Chopra, Kristen Hege, Jorge DiMartino and Kent Shih
Drew W. Rasco
South Texas Accelerated Research Therapeutics, San Antonio, Texas.
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  • For correspondence: drew.rasco@startsa.com
Kyriakos P. Papadopoulos
South Texas Accelerated Research Therapeutics, San Antonio, Texas.
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  • ORCID record for Kyriakos P. Papadopoulos
Michael Pourdehnad
Celgene Corporation, San Francisco, California.
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Anita K. Gandhi
Celgene Corporation, Summit, New Jersey.
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Patrick R. Hagner
Celgene Corporation, Summit, New Jersey.
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Yan Li
Celgene Corporation, Summit, New Jersey.
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Xin Wei
Celgene Corporation, Berkeley Heights, New Jersey.
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Rajesh Chopra
Division of Cancer Therapeutics, Institute of Cancer Research, London, United Kingdom.
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Kristen Hege
Celgene Corporation, San Francisco, California.
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Jorge DiMartino
Celgene Corporation, San Francisco, California.
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Kent Shih
Sarah Cannon Research Institute, Tennessee Oncology, Nashville, Tennessee.
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DOI: 10.1158/1078-0432.CCR-18-1203
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Abstract

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.

Experimental Design: 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. Clin Cancer Res; 1–9. ©2018 AACR.

Footnotes

  • Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).

  • Received April 23, 2018.
  • Revision received July 6, 2018.
  • Accepted September 5, 2018.
  • Published first September 10, 2018.
  • ©2018 American Association for Cancer Research.
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Published OnlineFirst November 14, 2018
doi: 10.1158/1078-0432.CCR-18-1203

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A First-in-Human Study of Novel Cereblon Modulator Avadomide (CC-122) in Advanced Malignancies
Drew W. Rasco, Kyriakos P. Papadopoulos, Michael Pourdehnad, Anita K. Gandhi, Patrick R. Hagner, Yan Li, Xin Wei, Rajesh Chopra, Kristen Hege, Jorge DiMartino and Kent Shih
Clin Cancer Res November 14 2018 DOI: 10.1158/1078-0432.CCR-18-1203

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A First-in-Human Study of Novel Cereblon Modulator Avadomide (CC-122) in Advanced Malignancies
Drew W. Rasco, Kyriakos P. Papadopoulos, Michael Pourdehnad, Anita K. Gandhi, Patrick R. Hagner, Yan Li, Xin Wei, Rajesh Chopra, Kristen Hege, Jorge DiMartino and Kent Shih
Clin Cancer Res November 14 2018 DOI: 10.1158/1078-0432.CCR-18-1203
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Clinical Cancer Research
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