Cancer Chemotherapy and Pharmacology

, Volume 75, Issue 4, pp 869–874 | Cite as

Phase I trial of valproic acid and lenalidomide in patients with advanced cancer

  • Mehmet Asim Bilen
  • Siqing Fu
  • Gerald S. Falchook
  • Chaan S. Ng
  • Jennifer J. Wheler
  • Maen Abdelrahim
  • Basak Erguvan-Dogan
  • David S. Hong
  • Apostolia M. Tsimberidou
  • Razelle Kurzrock
  • Aung Naing
Clinical Trial Report



The objectives of this study were to evaluate the tolerability and efficacy of valproic acid (VPA) and lenalidomide.


In this 3+3 design study, VPA was administered daily on a 7-day-on, 7-day-off schedule, and lenalidomide was administered daily for 28 days. Because of the response noted during the dose-escalation phase, 12 additional patients with adenoid cystic carcinoma (ACC) received the maximum tolerated dose (MTD) in a dose-expansion phase.


Twenty-six patients with advanced cancer (14 men/12 women), median age of 56 years (range 38–70 years), and a median number of two prior therapies (range 0–12) were enrolled. The most common toxicities were fatigue, rash, neutropenia, thrombocytopenia, and change in mental status. Dose-limiting toxic (DLT) effects were grade III confusion (n = 3), somnolence (n = 1), and gait disturbance (n = 1). The MTD was reached at VPA 30 mg/kg and lenalidomide 25 mg. Although only two of the 12 patients from the dose-expansion phase had DLT during the first cycle at the MTD, during subsequent cycles the majority of patients required dose reduction of VPA to 5–20 mg/kg because of fatigue and drowsiness. No significant tumor reductions were noticed in patients with ACC, but seven of these patients had stable disease over four cycles. Of non-ACC patients, one patient with melanoma and one patient with parathyroid carcinoma had stable disease for six cycles and eight cycles, respectively.


Lenalidomide combined with VPA was well tolerated. We recommend starting VPA at 5 mg/kg and titrating upward to 20 mg/kg. No significant tumor reductions were noticed in patients with ACC.


Valproic acid Lenalidomide Phase I Advanced cancer Toxicity 


Conflict of interest

G.Falchook and A.M. Tsimberidou have received research funding from Celgene. No other author has any disclosures.


  1. 1.
    Linde M, Mulleners WM, Chronicle EP, McCrory DC (2013) Valproate (valproic acid or sodium valproate or a combination of the two) for the prophylaxis of episodic migraine in adults. The Cochrane database of systematic reviews 6:CD010611. doi: 10.1002/14651858.CD010611
  2. 2.
    Chiu CT, Wang Z, Hunsberger JG, Chuang DM (2013) Therapeutic potential of mood stabilizers lithium and valproic acid: beyond bipolar disorder. Pharmacol Rev 65(1):105–142. doi: 10.1124/pr.111.005512 CrossRefPubMedCentralPubMedGoogle Scholar
  3. 3.
    Schwarz C, Volz A, Li C, Leucht S (2008) Valproate for schizophrenia. The Cochrane database of systematic reviews 3:CD004028. doi: 10.1002/14651858.CD004028.pub3
  4. 4.
    Haddad PM, Das A, Ashfaq M, Wieck A (2009) A review of valproate in psychiatric practice. Expert opin drug metabg toxicol 5(5):539–551. doi: 10.1517/17425250902911455 CrossRefGoogle Scholar
  5. 5.
    Phiel CJ, Zhang F, Huang EY, Guenther MG, Lazar MA, Klein PS (2001) Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen. J Biol Chem 276(39):36734–36741. doi: 10.1074/jbc.M101287200 CrossRefPubMedGoogle Scholar
  6. 6.
    Blaheta RA, Cinatl J Jr (2002) Anti-tumor mechanisms of valproate: a novel role for an old drug. Med Res Rev 22(5):492–511. doi: 10.1002/med.10017 CrossRefPubMedGoogle Scholar
  7. 7.
    Berendsen S, Broekman M, Seute T, Snijders T, van Es C, de Vos F, Regli L, Robe P (2012) Valproic acid for the treatment of malignant gliomas: review of the preclinical rationale and published clinical results. Expert Opin Investig Drugs 21(9):1391–1415. doi: 10.1517/13543784.2012.694425 CrossRefPubMedGoogle Scholar
  8. 8.
    Blaheta RA, Michaelis M, Driever PH, Cinatl J Jr (2005) Evolving anticancer drug valproic acid: insights into the mechanism and clinical studies. Med Res Rev 25(4):383–397. doi: 10.1002/med.20027 CrossRefPubMedGoogle Scholar
  9. 9.
    Tan J, Cang S, Ma Y, Petrillo RL, Liu D (2010) Novel histone deacetylase inhibitors in clinical trials as anti-cancer agents. J Hematol oncol 3:5. doi: 10.1186/1756-8722-3-5 CrossRefPubMedCentralPubMedGoogle Scholar
  10. 10.
    Catalano MG, Fortunati N, Pugliese M, Costantino L, Poli R, Bosco O, Boccuzzi G (2005) Valproic acid induces apoptosis and cell cycle arrest in poorly differentiated thyroid cancer cells. J Clin Endocrinol Metab 90(3):1383–1389. doi: 10.1210/jc.2004-1355 CrossRefPubMedGoogle Scholar
  11. 11.
    Takai N, Desmond JC, Kumagai T, Gui D, Said JW, Whittaker S, Miyakawa I, Koeffler HP (2004) Histone deacetylase inhibitors have a profound antigrowth activity in endometrial cancer cells. Clin Cancer Res 10(3):1141–1149CrossRefPubMedGoogle Scholar
  12. 12.
    Takai N, Kawamata N, Gui D, Said JW, Miyakawa I, Koeffler HP (2004) Human ovarian carcinoma cells: histone deacetylase inhibitors exhibit antiproliferative activity and potently induce apoptosis. Cancer 101(12):2760–2770. doi: 10.1002/cncr.20709 CrossRefPubMedGoogle Scholar
  13. 13.
    Sato T, Suzuki M, Sato Y, Echigo S, Rikiishi H (2006) Sequence-dependent interaction between cisplatin and histone deacetylase inhibitors in human oral squamous cell carcinoma cells. Int J Oncol 28(5):1233–1241PubMedGoogle Scholar
  14. 14.
    Chavez-Blanco A, Perez-Plasencia C, Perez-Cardenas E, Carrasco-Legleu C, Rangel-Lopez E, Segura-Pacheco B, Taja-Chayeb L, Trejo-Becerril C, Gonzalez-Fierro A, Candelaria M, Cabrera G, Duenas-Gonzalez A (2006) Antineoplastic effects of the DNA methylation inhibitor hydralazine and the histone deacetylase inhibitor valproic acid in cancer cell lines. Cancer Cell Int 6:2. doi: 10.1186/1475-2867-6-2 CrossRefPubMedCentralPubMedGoogle Scholar
  15. 15.
    Dredge K, Horsfall R, Robinson SP, Zhang LH, Lu L, Tang Y, Shirley MA, Muller G, Schafer P, Stirling D, Dalgleish AG, Bartlett JB (2005) Orally administered lenalidomide (CC-5013) is anti-angiogenic in vivo and inhibits endothelial cell migration and Akt phosphorylation in vitro. Microvasc Res 69(1–2):56–63. doi: 10.1016/j.mvr.2005.01.002 CrossRefPubMedGoogle Scholar
  16. 16.
    Verhelle D, Corral LG, Wong K, Mueller JH, Moutouh-de Parseval L, Jensen-Pergakes K, Schafer PH, Chen R, Glezer E, Ferguson GD, Lopez-Girona A, Muller GW, Brady HA, Chan KW (2007) Lenalidomide and CC-4047 inhibit the proliferation of malignant B cells while expanding normal CD34+progenitor cells. Cancer Res 67(2):746–755. doi: 10.1158/0008-5472.CAN-06-2317 CrossRefPubMedGoogle Scholar
  17. 17.
    Reddy N, Hernandez-Ilizaliturri FJ, Deeb G, Roth M, Vaughn M, Knight J, Wallace P, Czuczman MS (2008) Immunomodulatory drugs stimulate natural killer-cell function, alter cytokine production by dendritic cells, and inhibit angiogenesis enhancing the anti-tumour activity of rituximab in vivo. Br J Haematol 140(1):36–45. doi: 10.1111/j.1365-2141.2007.06841.x PubMedGoogle Scholar
  18. 18.
    Dredge K, Marriott JB, Macdonald CD, Man HW, Chen R, Muller GW, Stirling D, Dalgleish AG (2002) Novel thalidomide analogues display anti-angiogenic activity independently of immunomodulatory effects. Br J Cancer 87(10):1166–1172. doi: 10.1038/sj.bjc.6600607 CrossRefPubMedCentralPubMedGoogle Scholar
  19. 19.
    Davies FE, Raje N, Hideshima T, Lentzsch S, Young G, Tai YT, Lin B, Podar K, Gupta D, Chauhan D, Treon SP, Richardson PG, Schlossman RL, Morgan GJ, Muller GW, Stirling DI, Anderson KC (2001) Thalidomide and immunomodulatory derivatives augment natural killer cell cytotoxicity in multiple myeloma. Blood 98(1):210–216CrossRefPubMedGoogle Scholar
  20. 20.
    Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92(3):205–216CrossRefPubMedGoogle Scholar
  21. 21.
    Naing A, Sokol L, List AF (2006) Developmental therapeutics for myelodysplastic syndromes. J Natl Compr Cancer Netw 4(1):78–82Google Scholar
  22. 22.
    Ganesan P, Piha-Paul S, Naing A, Falchook G, Wheler J, Fu S, Hong DS, Kurzrock R, Janku F, Laday S, Bedikian AY, Kies M, Wolff RA, Tsimberidou AM (2013) Phase I clinical trial of lenalidomide in combination with sorafenib in patients with advanced cancer. Invest New Drugs. doi: 10.1007/s10637-013-9966-3 Google Scholar
  23. 23.
    Ganesan P, Piha-Paul S, Naing A, Falchook G, Wheler J, Janku F, Zinner R, Laday S, Kies M, Tsimberidou AM (2013) Phase I clinical trial of lenalidomide in combination with temsirolimus in patients with advanced cancer. Invest New Drugs 31(6):1505–1513. doi: 10.1007/s10637-013-0013-1 CrossRefPubMedGoogle Scholar
  24. 24.
    Gaitanis JN, Drislane FW (2003) Status epilepticus: a review of different syndromes, their current evaluation, and treatment. Neurologist 9(2):61–76. doi: 10.1097/01.nrl.0000051445.03160.2e CrossRefPubMedGoogle Scholar
  25. 25.
    Richardson PG, Schlossman RL, Weller E, Hideshima T, Mitsiades C, Davies F, LeBlanc R, Catley LP, Doss D, Kelly K, McKenney M, Mechlowicz J, Freeman A, Deocampo R, Rich R, Ryoo JJ, Chauhan D, Balinski K, Zeldis J, Anderson KC (2002) Immunomodulatory drug CC-5013 overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma. Blood 100(9):3063–3067. doi: 10.1182/blood-2002-03-0996 CrossRefPubMedGoogle Scholar
  26. 26.
    Zonder JA (2006) Thrombotic complications of myeloma therapy. Hematology Am Soc Hematol Educ Prog:348–355. doi: 10.1182/asheducation-2006.1.348
  27. 27.
    Spiro RH (1997) Distant metastasis in adenoid cystic carcinoma of salivary origin. Am J Surg 174(5):495–498CrossRefPubMedGoogle Scholar
  28. 28.
    Gilbert J, Li Y, Pinto HA, Jennings T, Kies MS, Silverman P, Forastiere AA (2006) Phase II trial of taxol in salivary gland malignancies (E1394): a trial of the eastern cooperative oncology group. Head Neck 28(3):197–204. doi: 10.1002/hed.20327 CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Mehmet Asim Bilen
    • 1
  • Siqing Fu
    • 2
  • Gerald S. Falchook
    • 2
  • Chaan S. Ng
    • 3
  • Jennifer J. Wheler
    • 2
  • Maen Abdelrahim
    • 4
  • Basak Erguvan-Dogan
    • 3
  • David S. Hong
    • 2
  • Apostolia M. Tsimberidou
    • 2
  • Razelle Kurzrock
    • 5
  • Aung Naing
    • 2
  1. 1.Division of Cancer MedicineThe University of Texas MD Anderson Cancer CenterHoustonUSA
  2. 2.Department of Investigational Cancer TherapeuticsThe University of Texas MD Anderson Cancer CenterHoustonUSA
  3. 3.Department of Diagnostic RadiologyThe University of Texas MD Anderson Cancer CenterHoustonUSA
  4. 4.Department of Internal MedicineBaylor College of MedicineHoustonUSA
  5. 5.Division of Hematology-OncologyUC San Diego Moores Cancer CenterLa JollaUSA

Personalised recommendations