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Cancer Therapy: Clinical

Phase I Study of Oral Rigosertib (ON 01910.Na), a Dual Inhibitor of the PI3K and Plk1 Pathways, in Adult Patients with Advanced Solid Malignancies

Daniel W. Bowles, Jennifer R. Diamond, Elaine T. Lam, Colin D. Weekes, David P. Astling, Ryan T. Anderson, Stephen Leong, Lia Gore, Marileila Varella-Garcia, Brian W. Vogler, Stephen B. Keysar, Elizabeth Freas, Dara L. Aisner, Chen Ren, Aik-Chook Tan, Francois Wilhelm, Manoj Maniar, S. Gail Eckhardt, Wells A. Messersmith and Antonio Jimeno
Daniel W. Bowles
1Department of Medicine, Division of Medical Oncology; 2Department of Pathology, University of Colorado School of Medicine, Aurora, Colorado; and 3Onconova Therapeutics Inc, Newtown, Pennsylvania
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Jennifer R. Diamond
1Department of Medicine, Division of Medical Oncology; 2Department of Pathology, University of Colorado School of Medicine, Aurora, Colorado; and 3Onconova Therapeutics Inc, Newtown, Pennsylvania
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Elaine T. Lam
1Department of Medicine, Division of Medical Oncology; 2Department of Pathology, University of Colorado School of Medicine, Aurora, Colorado; and 3Onconova Therapeutics Inc, Newtown, Pennsylvania
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Colin D. Weekes
1Department of Medicine, Division of Medical Oncology; 2Department of Pathology, University of Colorado School of Medicine, Aurora, Colorado; and 3Onconova Therapeutics Inc, Newtown, Pennsylvania
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David P. Astling
1Department of Medicine, Division of Medical Oncology; 2Department of Pathology, University of Colorado School of Medicine, Aurora, Colorado; and 3Onconova Therapeutics Inc, Newtown, Pennsylvania
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Ryan T. Anderson
1Department of Medicine, Division of Medical Oncology; 2Department of Pathology, University of Colorado School of Medicine, Aurora, Colorado; and 3Onconova Therapeutics Inc, Newtown, Pennsylvania
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Stephen Leong
1Department of Medicine, Division of Medical Oncology; 2Department of Pathology, University of Colorado School of Medicine, Aurora, Colorado; and 3Onconova Therapeutics Inc, Newtown, Pennsylvania
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Lia Gore
1Department of Medicine, Division of Medical Oncology; 2Department of Pathology, University of Colorado School of Medicine, Aurora, Colorado; and 3Onconova Therapeutics Inc, Newtown, Pennsylvania
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Marileila Varella-Garcia
1Department of Medicine, Division of Medical Oncology; 2Department of Pathology, University of Colorado School of Medicine, Aurora, Colorado; and 3Onconova Therapeutics Inc, Newtown, Pennsylvania
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Brian W. Vogler
1Department of Medicine, Division of Medical Oncology; 2Department of Pathology, University of Colorado School of Medicine, Aurora, Colorado; and 3Onconova Therapeutics Inc, Newtown, Pennsylvania
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Stephen B. Keysar
1Department of Medicine, Division of Medical Oncology; 2Department of Pathology, University of Colorado School of Medicine, Aurora, Colorado; and 3Onconova Therapeutics Inc, Newtown, Pennsylvania
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Elizabeth Freas
1Department of Medicine, Division of Medical Oncology; 2Department of Pathology, University of Colorado School of Medicine, Aurora, Colorado; and 3Onconova Therapeutics Inc, Newtown, Pennsylvania
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Dara L. Aisner
1Department of Medicine, Division of Medical Oncology; 2Department of Pathology, University of Colorado School of Medicine, Aurora, Colorado; and 3Onconova Therapeutics Inc, Newtown, Pennsylvania
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Chen Ren
1Department of Medicine, Division of Medical Oncology; 2Department of Pathology, University of Colorado School of Medicine, Aurora, Colorado; and 3Onconova Therapeutics Inc, Newtown, Pennsylvania
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Aik-Chook Tan
1Department of Medicine, Division of Medical Oncology; 2Department of Pathology, University of Colorado School of Medicine, Aurora, Colorado; and 3Onconova Therapeutics Inc, Newtown, Pennsylvania
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Francois Wilhelm
1Department of Medicine, Division of Medical Oncology; 2Department of Pathology, University of Colorado School of Medicine, Aurora, Colorado; and 3Onconova Therapeutics Inc, Newtown, Pennsylvania
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Manoj Maniar
1Department of Medicine, Division of Medical Oncology; 2Department of Pathology, University of Colorado School of Medicine, Aurora, Colorado; and 3Onconova Therapeutics Inc, Newtown, Pennsylvania
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S. Gail Eckhardt
1Department of Medicine, Division of Medical Oncology; 2Department of Pathology, University of Colorado School of Medicine, Aurora, Colorado; and 3Onconova Therapeutics Inc, Newtown, Pennsylvania
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Wells A. Messersmith
1Department of Medicine, Division of Medical Oncology; 2Department of Pathology, University of Colorado School of Medicine, Aurora, Colorado; and 3Onconova Therapeutics Inc, Newtown, Pennsylvania
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Antonio Jimeno
1Department of Medicine, Division of Medical Oncology; 2Department of Pathology, University of Colorado School of Medicine, Aurora, Colorado; and 3Onconova Therapeutics Inc, Newtown, Pennsylvania
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DOI: 10.1158/1078-0432.CCR-13-2506 Published March 2014
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Abstract

Purpose: To determine the pharmacokinetics (PK), maximum tolerated dose (MTD), safety, and antitumor activity of an oral formulation of rigosertib, a dual phosphoinositide 3-kinase (PI3K) and polo-like kinase 1 (Plk1) pathway inhibitor, in patients with advanced solid malignancies.

Experimental Design: Patients with advanced solid malignancies received rigosertib twice daily continuously in 21-day cycles. Doses were escalated until intolerable grade ≥2 toxicities, at which point the previous dose level was expanded to define the MTD. All patients were assessed for safety, PK, and response. Urinary PK were performed at the MTD. Archival tumors were assessed for potential molecular biomarkers with multiplex mutation testing. A subset of squamous cell carcinomas (SCC) underwent exome sequencing.

Results: Forty-eight patients received a median of 2 cycles of therapy at 5 dose levels. Rigosertib exposure increased with escalating doses. Dose-limiting toxicities were hematuria and dysuria. The most common grade ≥2 drug-related toxicities involved urothelial irritation. The MTD is 560 mg twice daily. Activity was seen in head and neck SCCs (1 complete response, 1 partial response) and stable disease for ≥12 weeks was observed in 8 additional patients. Tumors experiencing ≥partial response had PI3K pathway activation, inactivated p53, and unique variants in ROBO3 and FAT1, two genes interacting with the Wnt/β-catenin pathway.

Conclusions: The recommended phase II dose of oral rigosertib is 560 mg twice daily given continuously. Urinary toxicity is the dose-limiting and most common toxicity. Alterations in PI3K, p53, and Wnt/β-catenin pathway signaling should be investigated as potential biomarkers of response in future trials. Clin Cancer Res; 20(6); 1656–65. ©2014 AACR.

Footnotes

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

  • Prior presentations: American Society of Clinical Oncology Annual Meeting, 2012, Chicago, IL, abstract 3017; American Association for Cancer Research Annual Meeting, 2013, Washington, DC, abstract LB-198.

  • Received September 14, 2013.
  • Revision received December 5, 2013.
  • Accepted December 21, 2013.
  • ©2014 American Association for Cancer Research.
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Clinical Cancer Research: 20 (6)
March 2014
Volume 20, Issue 6
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Phase I Study of Oral Rigosertib (ON 01910.Na), a Dual Inhibitor of the PI3K and Plk1 Pathways, in Adult Patients with Advanced Solid Malignancies
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Phase I Study of Oral Rigosertib (ON 01910.Na), a Dual Inhibitor of the PI3K and Plk1 Pathways, in Adult Patients with Advanced Solid Malignancies
Daniel W. Bowles, Jennifer R. Diamond, Elaine T. Lam, Colin D. Weekes, David P. Astling, Ryan T. Anderson, Stephen Leong, Lia Gore, Marileila Varella-Garcia, Brian W. Vogler, Stephen B. Keysar, Elizabeth Freas, Dara L. Aisner, Chen Ren, Aik-Chook Tan, Francois Wilhelm, Manoj Maniar, S. Gail Eckhardt, Wells A. Messersmith and Antonio Jimeno
Clin Cancer Res March 15 2014 (20) (6) 1656-1665; DOI: 10.1158/1078-0432.CCR-13-2506

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Phase I Study of Oral Rigosertib (ON 01910.Na), a Dual Inhibitor of the PI3K and Plk1 Pathways, in Adult Patients with Advanced Solid Malignancies
Daniel W. Bowles, Jennifer R. Diamond, Elaine T. Lam, Colin D. Weekes, David P. Astling, Ryan T. Anderson, Stephen Leong, Lia Gore, Marileila Varella-Garcia, Brian W. Vogler, Stephen B. Keysar, Elizabeth Freas, Dara L. Aisner, Chen Ren, Aik-Chook Tan, Francois Wilhelm, Manoj Maniar, S. Gail Eckhardt, Wells A. Messersmith and Antonio Jimeno
Clin Cancer Res March 15 2014 (20) (6) 1656-1665; DOI: 10.1158/1078-0432.CCR-13-2506
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