A phase I study of the investigational NEDD8-activating enzyme inhibitor pevonedistat (TAK-924/MLN4924) in patients with metastatic melanoma

Investigational New Drugs

Volumn 34, Issue 4, 2016, Pages 439-449

  Bhatia, Shailender ^a   Pavlick, Anna C ^b   Boasberg, Peter ^c   Thompson, John A ^a   Mulligan, George ^d   Pickard, Michael D ^d   Faessel, Hélène ^d   Dezube, Bruce J ^d   Hamid, Omid ^c  

^a UNIVERSITY OF WASHINGTON MEDICAL CENTER   (United States)

^b NEW YORK UNIVERSITY MEDICAL CENTER   (United States)

^c Translational Oncology Research International   (United States)

^d MILLENNIUM PHARMACEUTICALS INC   (United States)

Author keywords

Melanoma; NAE inhibition; Nrf 2; Pevonedistat; Phase I

Indexed keywords

ALANINE AMINOTRANSFERASE; ALKALINE PHOSPHATASE; FENRETINIDE; GAMMA GLUTAMYLTRANSFERASE; NEDD8 PROTEIN; CYCLOPENTANE DERIVATIVE; PEVONEDISTAT; PYRIMIDINE DERIVATIVE; UBA3 PROTEIN, HUMAN; UBIQUITIN PROTEIN LIGASE;

ACUTE KIDNEY FAILURE; ADULT; AGED; ANEMIA; ANTINEOPLASTIC ACTIVITY; AREA UNDER THE CURVE; ARTHRALGIA; ARTICLE; CHILL; CLINICAL ARTICLE; DECREASED APPETITE; DIARRHEA; DOSE RESPONSE; DRUG CLEARANCE; DRUG DISTRIBUTION; DRUG DOSE ESCALATION; DRUG EFFICACY; DRUG HALF LIFE; DRUG SAFETY; DRUG TOLERABILITY; DRUG WITHDRAWAL; ENZYME INHIBITION; FATIGUE; FEMALE; FEVER; HUMAN; HUMAN TISSUE; HYPERBILIRUBINEMIA; HYPOPHOSPHATEMIA; MALE; MAXIMUM PLASMA CONCENTRATION; MAXIMUM TOLERATED DOSE; METASTATIC MELANOMA; MULTICENTER STUDY; MULTIPLE CYCLE TREATMENT; MULTIPLE ORGAN FAILURE; MYALGIA; MYOCARDITIS; NIGHT SWEAT; PERIPHERAL NEUROPATHY; PRIORITY JOURNAL; TIME TO MAXIMUM PLASMA CONCENTRATION; TREATMENT OUTCOME; VOMITING; ANTAGONISTS AND INHIBITORS; CLINICAL TRIAL; MELANOMA; METABOLISM; MIDDLE AGED; PATHOLOGY; PHASE 1 CLINICAL TRIAL;

ADULT; AGED; CYCLOPENTANES; FEMALE; HUMANS; MALE; MAXIMUM TOLERATED DOSE; MELANOMA; MIDDLE AGED; PYRIMIDINES; TREATMENT OUTCOME; UBIQUITIN-ACTIVATING ENZYMES;

EID: 84964033552     PISSN: 01676997     EISSN: 15730646     Source Type: Journal    
DOI: 10.1007/s10637-016-0348-5     Document Type: Article

References (45)

1. Ciechanover A (2012) Intracellular protein degradation: from a vague idea through the lysosome and the ubiquitin-proteasome system and onto human diseases and drug targeting. Neurodegener Dis 10(1–4):7–22
2. Shen M, Schmitt S, Buac D, Dou QP (2013) Targeting the ubiquitin-proteasome system for cancer therapy. Expert Opin Ther Targets 17(9):1091–1108
3. Esseltine DL, Mulligan G (2012) An historic perspective of proteasome inhibition. Semin Hematol 49(3):196–206
4. Bedford L, Lowe J, Dick LR, Mayer RJ, Brownell JE (2011) Ubiquitin-like protein conjugation and the ubiquitin-proteasome system as drug targets. Nat Rev Drug Discov 10(1):29–46
5. Soucy TA, Dick LR, Smith PG, Milhollen MA, Brownell JE (2010) The NEDD8 conjugation pathway and its relevance in cancer biology and therapy. Genes Cancer 1(7):708–716
6. Petroski MD, Deshaies RJ (2005) Function and regulation of cullin-RING ubiquitin ligases. Nat Rev Mol Cell Biol 6(1):9–20
7. Soucy TA, Smith PG, Milhollen MA, Berger AJ, Gavin JM, Adhikari S, Brownell JE, Burke KE, Cardin DP, Critchley S, Cullis CA, Doucette A, Garnsey JJ, Gaulin JL, Gershman RE, Lublinsky AR, McDonald A, Mizutani H, Narayanan U, Olhava EJ, Peluso S, Rezaei M, Sintchak MD, Talreja T, Thomas MP, Traore T, Vyskocil S, Weatherhead GS, Yu J, Zhang J, Dick LR, Claiborne CF, Rolfe M, Bolen JB, Langston SP (2009) An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer. Nature 458(7239):732–736
8. Brownell JE, Sintchak MD, Gavin JM, Liao H, Bruzzese FJ, Bump NJ, Soucy TA, Milhollen MA, Yang X, Burkhardt AL, Ma J, Loke HK, Lingaraj T, Wu D, Hamman KB, Spelman JJ, Cullis CA, Langston SP, Vyskocil S, Sells TB, Mallender WD, Visiers I, Li P, Claiborne CF, Rolfe M, Bolen JB, Dick LR (2010) Substrate-assisted inhibition of ubiquitin-like protein-activating enzymes: the NEDD8 E1 inhibitor MLN4924 forms a NEDD8-AMP mimetic in situ. Mol Cell 37(1):102–111
9. Li L, Liu B, Dong T, Lee HW, Yu J, Zheng Y, Gao H, Zhang Y, Chu Y, Liu G, Niu W, Zheng S, Jeong LS, Jia L (2013) Neddylation pathway regulates the proliferation and survival of macrophages. Biochem Biophys Res Commun 432(3):494–498
10. Li L, Wang M, Yu G, Chen P, Li H, Wei D, Zhu J, Xie L, Jia H, Shi J, Li C, Yao W, Wang Y, Gao Q, Jeong LS, Lee HW, Yu J, Hu F, Mei J, Wang P, Chu Y, Qi H, Yang M, Dong Z, Sun Y, Hoffman RM, Jia L (2014) Overactivated neddylation pathway as a therapeutic target in lung cancer. J Natl Cancer Inst 106(6):dju083
11. Healey M, Crow MS, Molina CA (2013) Ras-induced melanoma transformation is associated with the proteasomal degradation of the transcriptional repressor ICER. Mol Carcinog 52(9):692–704
12. Chen G, Wang Y, Garate M, Zhou J, Li G (2010) The tumor suppressor ING3 is degraded by SCF(Skp2)-mediated ubiquitin-proteasome system. Oncogene 29(10):1498–1508
13. Lin JJ, Milhollen MA, Smith PG, Narayanan U, Dutta A (2010) NEDD8-targeting drug MLN4924 elicits DNA rereplication by stabilizing Cdt1 in S phase, triggering checkpoint activation, apoptosis, and senescence in cancer cells. Cancer Res 70(24):10310–10320
14. Luo Z, Yu G, Lee HW, Li L, Wang L, Yang D, Pan Y, Ding C, Qian J, Wu L, Chu Y, Yi J, Wang X, Sun Y, Jeong LS, Liu J, Jia L (2012) The Nedd8-activating enzyme inhibitor MLN4924 induces autophagy and apoptosis to suppress liver cancer cell growth. Cancer Res 72(13):3360–3371
15. Nawrocki ST, Kelly KR, Smith PG, Espitia CM, Possemato A, Beausoleil SA, Milhollen M, Blakemore S, Thomas M, Berger A, Carew JS (2013) Disrupting protein NEDDylation with MLN4924 is a novel strategy to target cisplatin resistance in ovarian cancer. Clin Cancer Res 19(13):3577–3590
16. Swords RT, Kelly KR, Smith PG, Garnsey JJ, Mahalingam D, Medina E, Oberheu K, Padmanabhan S, O’Dwyer M, Nawrocki ST, Giles FJ, Carew JS (2010) Inhibition of NEDD8-activating enzyme: a novel approach for the treatment of acute myeloid leukemia. Blood 115(18):3796–3800
17. Wang X, Li L, Liang Y, Li C, Zhao H, Ye D, Sun M, Jeong LS, Feng Y, Fu S, Jia L, Guo X (2014) Targeting the neddylation pathway to suppress the growth of prostate cancer cells: therapeutic implication for the men’s cancer. Biomed Res Int 2014:974309
18. Yang D, Tan M, Wang G, Sun Y (2012) The p21-dependent radiosensitization of human breast cancer cells by MLN4924, an investigational inhibitor of NEDD8 activating enzyme. PLoS One 7(3):e34079
19. Milhollen MA, Traore T, Adams-Duffy J, Thomas MP, Berger AJ, Dang L, Dick LR, Garnsey JJ, Koenig E, Langston SP, Manfredi M, Narayanan U, Rolfe M, Staudt LM, Soucy TA, Yu J, Zhang J, Bolen JB, Smith PG (2010) MLN4924, a NEDD8-activating enzyme inhibitor, is active in diffuse large B-cell lymphoma models: rationale for treatment of NF-kappaB-dependent lymphoma. Blood 116(9):1515–1523
20. Smith MA, Maris JM, Gorlick R, Kolb EA, Lock R, Carol H, Keir ST, Reynolds CP, Kang MH, Morton CL, Wu J, Smith PG, Yu J, Houghton PJ (2012) Initial testing of the investigational NEDD8-activating enzyme inhibitor MLN4924 by the pediatric preclinical testing program. Pediatr Blood Cancer 59(2):246–253
21. Jia L, Li H, Sun Y (2011) Induction of p21-dependent senescence by an NAE inhibitor, MLN4924, as a mechanism of growth suppression. Neoplasia 13(6):561–569
22. Milhollen MA, Narayanan U, Soucy TA, Veiby PO, Smith PG, Amidon B (2011) Inhibition of NEDD8-activating enzyme induces rereplication and apoptosis in human tumor cells consistent with deregulating CDT1 turnover. Cancer Res 71(8):3042–3051
23. Luo Z, Pan Y, Jeong LS, Liu J, Jia L (2012) Inactivation of the Cullin (CUL)-RING E3 ligase by the NEDD8-activating enzyme inhibitor MLN4924 triggers protective autophagy in cancer cells. Autophagy 8(11):1677–1679
24. Blank JL, Liu XJ, Cosmopoulos K, Bouck DC, Garcia K, Bernard H, Tayber O, Hather G, Liu R, Narayanan U, Milhollen MA, Lightcap ES (2013) Novel DNA damage checkpoints mediating cell death induced by the NEDD8-activating enzyme inhibitor MLN4924. Cancer Res 73(1):225–234
25. Liao H, Liu XJ, Blank JL, Bouck DC, Bernard H, Garcia K, Lightcap ES (2011) Quantitative proteomic analysis of cellular protein modulation upon inhibition of the NEDD8-activating enzyme by MLN4924. Mol Cell Proteomics 10(11):M111
26. Tan M, Li H, Sun Y (2014) Endothelial deletion of Sag/Rbx2/Roc2 E3 ubiquitin ligase causes embryonic lethality and blocks tumor angiogenesis. Oncogene 33(44):5211–5220
27. Tentler JJ, Micel LN, Selby HM, Tan AC, Brunkow KL, Pitts TM, Blakemore S, Smith PG, Eckhardt SG (2011) Molecular determinants of response to the investigational small molecule inhibitor of Nedd8-activating enzyme (NAE) MLN4924 in melanoma cell lines and patient-derived tumor explant models (Abstract). Mol Cancer Ther 10:B178
28. Traore T, Milhollen M, Garnsey JJ, Berger A, Manfredi M, Cosmopoulos K, Donelan J, Smith PG (2011) Antitumor activity of MLN4924, an investigational inhibitor of NEDD8-activating enzyme (NAE), in preclinical models of melanoma (Abstract). J Clin Oncol 29:8594
29. Sarantopoulos J, Shapiro GI, Cohen RB, Clark JW, Kauh JS, Weiss GJ, Cleary JM, Mahalingam D, Pickard MD, Faessel HM, Berger AJ, Burke K, Mulligan G, Dezube BJ, Harvey RD (2016) Phase I study of the investigational NEDD8-activating enzyme inhibitor pevonedistat (TAK-924/MLN4924) in patients with advanced solid tumors. Clin Cancer Res 22(4):847–857
30. Richardson PG, Sonneveld P, Schuster MW, Irwin D, Stadtmauer EA, Facon T, Harousseau JL, Ben-Yehuda D, Lonial S, Goldschmidt H, Reece D, San-Miguel JF, Blade J, Boccadoro M, Cavenagh J, Dalton WS, Boral AL, Esseltine DL, Porter JB, Schenkein D, Anderson KC (2005) Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 352(24):2487–2498
31. de Vos S, Goy A, Dakhil SR, Saleh MN, McLaughlin P, Belt R, Flowers CR, Knapp M, Hart L, Patel-Donnelly D, Glenn M, Gregory SA, Holladay C, Zhang T, Boral AL (2009) Multicenter randomized phase II study of weekly or twice-weekly bortezomib plus rituximab in patients with relapsed or refractory follicular or marginal-zone B-cell lymphoma. J Clin Oncol 27(30):5023–5030
32. Reece DE, Hegenbart U, Sanchorawala V, Merlini G, Palladini G, Blade J, Fermand JP, Hassoun H, Heffner L, Vescio RA, Liu K, Enny C, Esseltine DL, van d, V, Cakana A, Comenzo RL (2011) Efficacy and safety of once-weekly and twice-weekly bortezomib in patients with relapsed systemic AL amyloidosis: results of a phase 1/2 study. Blood 118(4):865-873
33. Shah JJ, Jakubowiak AJ, O’Connor OA, Orlowski RZ, Harvey RD, Smith MR, Lebovic D, Diefenbach C, Kelly K, Hua Z, Berger AJ, Mulligan G, Faessel HM, Tirrell S, Dezube BJ, Lonial S (2016) Phase I study of the novel investigational NEDD8-activating enzyme inhibitor pevonedistat (MLN4924) in patients with relapsed/refractory multiple myeloma or lymphoma. Clin Cancer Res 22(1):34–43
34. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45(2):228–247
35. Swords RT, Erba HP, DeAngelo DJ, Bixby DL, Altman JK, Maris M, Hua Z, Blakemore SJ, Faessel H, Sedarati F, Dezube BJ, Giles FJ, Medeiros BC (2015) Pevonedistat (MLN4924), a first-in-class NEDD8-activating enzyme inhibitor, in patients with acute myeloid leukaemia and myelodysplastic syndromes: a phase 1 study. Br J Haematol 169(4):534–543
36. Swords RT, Savona MR, Maris MB, Erba HP, Hua Z, Faessel H, Blakemore S, Sederati F, Dezube BJ, Medeiros BC (2014) First-in-class NAE inhibitor MLN4924 in combination with azacitidine for acute myeloid leukemia (AML) patients considered unfit for conventional chemotherapy: results from the C15009 trial (Abstract). Haematologica 99:223–224
37. DeAngelo DJ, Erba HP, Maris MB, Swords RT, Anwer F, Altman JK, Hua Z, Blakemore S, Faessel H, Dezube BJ, Medeiros BC (2013) MLN4924, a novel investigational inhibitor of NEDD8-activating enzyme (NAE), in adult patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS): results from multiple dosing schedules in a phase 1 study (Abstract). Blood 122:1443
38. Wolenski FS, Fisher CD, Sano T, Wyllie SD, Cicia LA, Gallacher MJ, Baker RA, Kirby PJ, Senn JJ (2015) The NAE inhibitor pevonedistat (MLN4924) synergizes with TNF-α to activate apoptosis. Cell Death Discov. doi:10.1038/cddiscovery.2015.34
39. Azijli K, Stelloo E, Peters GJ, VAN DEN Eertwegh AJ (2014) New developments in the treatment of metastatic melanoma: immune checkpoint inhibitors and targeted therapies. Anticancer Res 34(4):1493–1505
40. Wolchok JD, Hodi FS, Weber JS, Allison JP, Urba WJ, Robert C, O’Day SJ, Hoos A, Humphrey R, Berman DM, Lonberg N, Korman AJ (2013) Development of ipilimumab: a novel immunotherapeutic approach for the treatment of advanced melanoma. Ann N Y Acad Sci 1291:1–13
41. Robert C, Ribas A, Wolchok JD, Hodi FS, Hamid O, Kefford R, Weber JS, Joshua AM, Hwu WJ, Gangadhar TC, Patnaik A, Dronca R, Zarour H, Joseph RW, Boasberg P, Chmielowski B, Mateus C, Postow MA, Gergich K, Elassaiss-Schaap J, Li XN, Iannone R, Ebbinghaus SW, Kang SP, Daud A (2014) Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet 384(9948):1109–1117
42. Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, Wolchok JD, Hersey P, Joseph RW, Weber JS, Dronca R, Gangadhar TC, Patnaik A, Zarour H, Joshua AM, Gergich K, Elassaiss-Schaap J, Algazi A, Mateus C, Boasberg P, Tumeh PC, Chmielowski B, Ebbinghaus SW, Li XN, Kang SP, Ribas A (2013) Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med 369(2):134–144
43. Shaw HM, Nathan PD (2013) Vemurafenib in melanoma. Expert Rev Anticancer Ther 13(5):513–522
44. Kainthla R, Kim KB, Falchook GS (2014) Dabrafenib. Recent Results Cancer Res 201:227–240
45. Salama AK, Kim KB (2013) Trametinib (GSK1120212) in the treatment of melanoma. Expert Opin Pharmacother 14(5):619–627