18 years of age, irrespective of number of prior treatments, received VPA 40 mg/kg orally for 5 days prior to day 1, bevacizumab at 15 mg/kg IV on day 1, gemcitabine 900 mg/m² (day 1, day 8), and docetaxel 75 mg/m² (day 8). Cycles were of 28 day duration. Bevacizumab and VPA were continued as maintenance after 6 cycles, until disease progression. A standard 3 + 3 phase I dose de-escalation design was utilized to evaluate safety. Gain of function p53 gene mutation testing was performed on available archival tissue specimens. A total of 46 patients (30 female, 16 male) with median age of 60 (range 24-81) years were enrolled; 34 (73.9%) patients received prior chemotherapy, 14 (30%) of which received prior gemcitabine and docetaxel. Patients received a median of 5.5 cycles (range 0-24 of treatment (min 0, one patient died prior to completing the first cycle; max: 24, one patient received 6 cycles and 18 maintenance cycles before progressing). Seventeen patients underwent dose reduction, of which VPA was reduced in 6 patients. Forty-one patients were evaluable for response. There was a confirmed complete response in 1 (epithelioid sarcoma), and a partial response (PR) in 6 (1 carcinosarcoma, 2 extrauterine leiomyosarcoma (LMS), 2 undifferentiated pleomorphic sarcoma, and 1 uterine LMS) patients. Stable disease (SD) was seen in 21 patients for at least 2 months. One subject with prior gemcitabine and docetaxel had PR, and 7 had SD. Median progression-free survival (PFS) was 5.7 months (95% CI: 2.1-8.0), and overall survival (OS) was 12.9 months (95% CI: 8.3-14.5). Three patients died due to tumor progression while on the study. The combination of VPA, bevacizumab, gemcitabine, and docetaxel appears to be moderately safe and well tolerated. Given that there are very limited options for patients with relapsed refractory STS, this drug combination may be an important therapy to consider. This combination treatment deserves further investigation in epithelioid and carcinosarcoma subtypes." />
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Monga V, Swami U, Tanas M, et al. A Phase I/II Study Targeting Angiogenesis Using Bevacizumab Combined with Chemotherapy and a Histone Deacetylase Inhibitor (Valproic Acid) in Advanced Sarcomas. Cancers (Basel). 2018;10(2)doi: 10.3390/cancers10020053.
Monga, V., Swami, U., Tanas, M., Bossler, A., Mott, S. L., Smith, B. J., & Milhem, M. (2018). A Phase I/II Study Targeting Angiogenesis Using Bevacizumab Combined with Chemotherapy and a Histone Deacetylase Inhibitor (Valproic Acid) in Advanced Sarcomas. Cancers, 10(2), . https://doi.org/10.3390/cancers10020053
Monga, Varun, et al. "A Phase I/II Study Targeting Angiogenesis Using Bevacizumab Combined with Chemotherapy and a Histone Deacetylase Inhibitor (Valproic Acid) in Advanced Sarcomas." Cancers vol. 10,2 (2018). doi: https://doi.org/10.3390/cancers10020053
Monga V, Swami U, Tanas M, Bossler A, Mott SL, Smith BJ, Milhem M. A Phase I/II Study Targeting Angiogenesis Using Bevacizumab Combined with Chemotherapy and a Histone Deacetylase Inhibitor (Valproic Acid) in Advanced Sarcomas. Cancers (Basel). 2018 Feb 17;10(2). doi: 10.3390/cancers10020053. PMID: 29462961; PMCID: PMC5836085.
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Cancers (Basel). 2018 Feb 17;10(2). doi: 10.3390/cancers10020053.

A Phase I/II Study Targeting Angiogenesis Using Bevacizumab Combined with Chemotherapy and a Histone Deacetylase Inhibitor (Valproic Acid) in Advanced Sarcomas.

Cancers

Varun Monga, Umang Swami, Munir Tanas, Aaron Bossler, Sarah L Mott, Brian J Smith, Mohammed Milhem

Affiliations

  1. Division of Hematology, Oncology, and Blood and Marrow Transplantation, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA. [email protected].
  2. Division of Hematology, Oncology, and Blood and Marrow Transplantation, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA. [email protected].
  3. Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA. [email protected].
  4. Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA. [email protected].
  5. Holden Comprehensive Cancer Center, Iowa City, IA 52242, USA. [email protected].
  6. Department of Biostatistics, University of Iowa College of Public Health & Holden Comprehensive Cancer Center, Iowa City, IA 52242, USA. [email protected].
  7. Division of Hematology, Oncology, and Blood and Marrow Transplantation, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA. [email protected].

PMID: 29462961 PMCID: PMC5836085 DOI: 10.3390/cancers10020053

Abstract

Epigenetic events and genetic alterations under the control of the tumor microenvironment potentially mediate tumor induced angiogenesis involved in soft tissue sarcoma (STS) metastasis. Addition of antiangiogenic agent, such as bevacizumab, to standard chemotherapy in treatment of sarcoma has been studied in clinical trials, but most of the findings have not supported its use. We hypothesized the existence of an epigenetically mediated "angiogenic switch", and the tumor microenvironment, prevents bevacizumab from truly blocking angiogenesis. The addition of valproic acid (VPA), a weak histone deacetylase inhibitor, and bevacizumab, a monoclonal antibody against vascular endothelial growth factor, together with the cytotoxic effects of gemcitabine and docetaxel, may enhance responses and alter chemoresistance. This was designed as a phase I/II trial with primary endpoints including safety of the treatment combination and tumor response. Unresectable or metastatic sarcoma patients >18 years of age, irrespective of number of prior treatments, received VPA 40 mg/kg orally for 5 days prior to day 1, bevacizumab at 15 mg/kg IV on day 1, gemcitabine 900 mg/m² (day 1, day 8), and docetaxel 75 mg/m² (day 8). Cycles were of 28 day duration. Bevacizumab and VPA were continued as maintenance after 6 cycles, until disease progression. A standard 3 + 3 phase I dose de-escalation design was utilized to evaluate safety. Gain of function p53 gene mutation testing was performed on available archival tissue specimens. A total of 46 patients (30 female, 16 male) with median age of 60 (range 24-81) years were enrolled; 34 (73.9%) patients received prior chemotherapy, 14 (30%) of which received prior gemcitabine and docetaxel. Patients received a median of 5.5 cycles (range 0-24 of treatment (min 0, one patient died prior to completing the first cycle; max: 24, one patient received 6 cycles and 18 maintenance cycles before progressing). Seventeen patients underwent dose reduction, of which VPA was reduced in 6 patients. Forty-one patients were evaluable for response. There was a confirmed complete response in 1 (epithelioid sarcoma), and a partial response (PR) in 6 (1 carcinosarcoma, 2 extrauterine leiomyosarcoma (LMS), 2 undifferentiated pleomorphic sarcoma, and 1 uterine LMS) patients. Stable disease (SD) was seen in 21 patients for at least 2 months. One subject with prior gemcitabine and docetaxel had PR, and 7 had SD. Median progression-free survival (PFS) was 5.7 months (95% CI: 2.1-8.0), and overall survival (OS) was 12.9 months (95% CI: 8.3-14.5). Three patients died due to tumor progression while on the study. The combination of VPA, bevacizumab, gemcitabine, and docetaxel appears to be moderately safe and well tolerated. Given that there are very limited options for patients with relapsed refractory STS, this drug combination may be an important therapy to consider. This combination treatment deserves further investigation in epithelioid and carcinosarcoma subtypes.

Keywords: angiogenesis; bevacizumab; epigenetics; rheostat; sarcoma; valproic acid

Conflict of interest statement

The authors declare no conflict of interest. M.M. is a consultant for Genentech and Amgen. The funding sponsors had no role in the design of the study; in the collection, analyses, or interpretation o

References

  1. Circ Res. 2002 Nov 1;91(9):837-44 - PubMed
  2. N Engl J Med. 1996 Jan 18;334(3):168-75 - PubMed
  3. Br J Cancer. 2006 Apr 24;94(8):1087-92 - PubMed
  4. N Engl J Med. 2004 Jun 3;350(23 ):2335-42 - PubMed
  5. Oncogene. 2002 Jan 17;21(3):427-36 - PubMed
  6. J Clin Oncol. 2005 Oct 1;23(28):7135-42 - PubMed
  7. Int J Mol Sci. 2013 Sep 23;14(9):19257-75 - PubMed
  8. J Clin Oncol. 2007 Jul 1;25(19):2755-63 - PubMed
  9. CA Cancer J Clin. 2017 Jan;67(1):7-30 - PubMed
  10. Ann Oncol. 2016 Mar;27(3):539-43 - PubMed
  11. N Engl J Med. 1971 Nov 18;285(21):1182-6 - PubMed
  12. Arch Pathol Lab Med. 1997 Apr;121(4):395-9 - PubMed
  13. Mol Pharmacol. 2004 Mar;65(3):520-7 - PubMed
  14. J Cancer Res Clin Oncol. 2000 Apr;126(4):219-25 - PubMed
  15. J Cancer Res Clin Oncol. 1997;123(4):211-8 - PubMed
  16. Mol Med. 1998 Jun;4(6):365-72 - PubMed
  17. J Clin Oncol. 2009 Oct 1;27(28):4733-40 - PubMed
  18. Mol Cancer. 2005 Jul 07;4(1):22 - PubMed
  19. J Clin Oncol. 2015 Apr 1;33(10):1180-5 - PubMed
  20. Cancer Res. 2005 Oct 1;65(19):8961-7 - PubMed
  21. Cancer Res. 2003 Nov 1;63(21):7291-300 - PubMed
  22. Cancer Res. 2000 Jul 1;60(13):3655-61 - PubMed
  23. Ann Oncol. 2012 Mar;23(3):785-90 - PubMed
  24. Ann Oncol. 2013 Jan;24(1):257-63 - PubMed
  25. N Engl J Med. 2003 Jul 31;349(5):427-34 - PubMed
  26. Clin Cancer Res. 2006 Jan 15;12(2):634-42 - PubMed
  27. J Cell Physiol. 2000 Jul;184(1):1-16 - PubMed
  28. Prostate. 2002 Apr 1;51(1):59-72 - PubMed
  29. Cell Mol Life Sci. 2001 May;58(5-6):728-36 - PubMed
  30. Ann Oncol. 2007 Sep;18(9):1529-38 - PubMed
  31. Gastroenterology. 2013 Nov;145(5):1098-1109.e1 - PubMed
  32. N Engl J Med. 2006 Dec 14;355(24):2542-50 - PubMed
  33. Cancer Cell. 2014 Mar 17;25(3):304-17 - PubMed
  34. Mol Med. 2000 Aug;6(8):623-44 - PubMed
  35. J Cancer Res Clin Oncol. 2004 Jan;130(1):52-6 - PubMed

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