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

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

Abstract

Purpose The therapeutic index of proteasome inhibitors may be improved through selective inhibition of a sub-component of the ubiquitin-proteasome system, such as the NEDD8-conjugation pathway. This multicenter, phase I, dose-escalation study assessed safety and the maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and antitumor activity of pevonedistat, an investigational NEDD8-activating enzyme (NAE) inhibitor, in patients with metastatic melanoma. Methods Patients received intravenous pevonedistat on Days 1, 4, 8, 11 (schedule A) or 1, 8, 15 (schedule B) of 21-day cycles. Results 26 patients received pevonedistat 50-278 mg/m(2) on schedule A; 11 patients received pevonedistat 157 mg/m(2) on schedule B. The schedule A MTD was 209 mg/m(2): dose-limiting toxicities (DLTs) included grade 3 hypophosphatemia and grade 3 increased blood creatinine (associated with grade 3 hyperbilirubinemia). Two schedule A patients experienced acute organ failure toxicities, one of whom experienced grade 5 acute renal failure. Dose escalation did not occur in schedule B: DLTs included grade 3 myocarditis, grade 2 acute renal failure, and grade 2 hyperbilirubinemia in a single patient. Pevonedistat pharmacokinetics were approximately dose-proportional across the dose range studied, with a biphasic disposition profile characterized by a short elimination half-life (~10 h). Pharmacodynamic studies showed increases in NAE-regulated transcripts post-treatment; all post-dose biopsy samples were positive for pevonedistat-NEDD8 adduct. One schedule A patient achieved a partial response; 15 patients had stable disease (4 lasting ≥6.5 months). Conclusions Pevonedistat was generally well tolerated at the MTD. Anticipated pharmacodynamic effects of NAE inhibition were observed with single-agent pevonedistat in peripheral blood and tumor tissue.

Keywords: Melanoma; NAE inhibition; Nrf-2; Pevonedistat; Phase I.

Figures

Fig. 1
Fig. 1
Mean pevonedistat plasma concentration–time profiles on Cycle 1, Day 1 following 1-h intravenous infusion of pevonedistat in patients receiving different dose levels on schedule A (Days 1, 4, 8, and 11) and patients receiving the one dose level on schedule B (Days 1, 8, and 15)
Fig. 2
Fig. 2
Representative immunohistochemistry images of tumor formalin-fixed paraffin-embedded serial sections stained for pevonedistat–NEDD8 adduct, Cdt1, and Nrf-2, at screening/baseline and at 3–6 h after the Day 4, Cycle 1 dose, indicating increases in post-dose staining for all three markers (patient received pevonedistat 209 mg/m2 on schedule A)
Fig. 3
Fig. 3
Duration of pevonedistat exposure among all 37 patients on schedules A and B, including the 15 patients achieving stable disease and the 1 patient achieving a partial response

References

    1. Ciechanover A. Intracellular protein degradation: from a vague idea through the lysosome and the ubiquitin-proteasome system and onto human diseases and drug targeting. Neurodegener Dis. 2012;10(1–4):7–22. doi: 10.1159/000334283.
    1. Shen M, Schmitt S, Buac D, Dou QP. Targeting the ubiquitin-proteasome system for cancer therapy. Expert Opin Ther Targets. 2013;17(9):1091–1108. doi: 10.1517/14728222.2013.815728.
    1. Esseltine DL, Mulligan G. An historic perspective of proteasome inhibition. Semin Hematol. 2012;49(3):196–206. doi: 10.1053/j.seminhematol.2012.04.009.
    1. Bedford L, Lowe J, Dick LR, Mayer RJ, Brownell JE. Ubiquitin-like protein conjugation and the ubiquitin-proteasome system as drug targets. Nat Rev Drug Discov. 2011;10(1):29–46. doi: 10.1038/nrd3321.
    1. Soucy TA, Dick LR, Smith PG, Milhollen MA, Brownell JE. The NEDD8 conjugation pathway and its relevance in cancer biology and therapy. Genes Cancer. 2010;1(7):708–716. doi: 10.1177/1947601910382898.
    1. Petroski MD, Deshaies RJ. Function and regulation of cullin-RING ubiquitin ligases. Nat Rev Mol Cell Biol. 2005;6(1):9–20. doi: 10.1038/nrm1547.
    1. 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. An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer. Nature. 2009;458(7239):732–736. doi: 10.1038/nature07884.
    1. 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. Substrate-assisted inhibition of ubiquitin-like protein-activating enzymes: the NEDD8 E1 inhibitor MLN4924 forms a NEDD8-AMP mimetic in situ. Mol Cell. 2010;37(1):102–111. doi: 10.1016/j.molcel.2009.12.024.
    1. 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. Neddylation pathway regulates the proliferation and survival of macrophages. Biochem Biophys Res Commun. 2013;432(3):494–498. doi: 10.1016/j.bbrc.2013.02.028.
    1. 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
    1. Healey M, Crow MS, Molina CA. Ras-induced melanoma transformation is associated with the proteasomal degradation of the transcriptional repressor ICER. Mol Carcinog. 2013;52(9):692–704. doi: 10.1002/mc.21908.
    1. Chen G, Wang Y, Garate M, Zhou J, Li G. The tumor suppressor ING3 is degraded by SCF(Skp2)-mediated ubiquitin-proteasome system. Oncogene. 2010;29(10):1498–1508. doi: 10.1038/onc.2009.424.
    1. Lin JJ, Milhollen MA, Smith PG, Narayanan U, Dutta A. NEDD8-targeting drug MLN4924 elicits DNA rereplication by stabilizing Cdt1 in S phase, triggering checkpoint activation, apoptosis, and senescence in cancer cells. Cancer Res. 2010;70(24):10310–10320. doi: 10.1158/0008-5472.CAN-10-2062.
    1. 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. The Nedd8-activating enzyme inhibitor MLN4924 induces autophagy and apoptosis to suppress liver cancer cell growth. Cancer Res. 2012;72(13):3360–3371. doi: 10.1158/0008-5472.CAN-12-0388.
    1. Nawrocki ST, Kelly KR, Smith PG, Espitia CM, Possemato A, Beausoleil SA, Milhollen M, Blakemore S, Thomas M, Berger A, Carew JS. Disrupting protein NEDDylation with MLN4924 is a novel strategy to target cisplatin resistance in ovarian cancer. Clin Cancer Res. 2013;19(13):3577–3590. doi: 10.1158/1078-0432.CCR-12-3212.
    1. 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. Inhibition of NEDD8-activating enzyme: a novel approach for the treatment of acute myeloid leukemia. Blood. 2010;115(18):3796–3800. doi: 10.1182/blood-2009-11-254862.
    1. Wang X, Li L, Liang Y, Li C, Zhao H, Ye D, Sun M, Jeong LS, Feng Y, Fu S, Jia L, Guo X. Targeting the neddylation pathway to suppress the growth of prostate cancer cells: therapeutic implication for the men’s cancer. Biomed Res Int. 2014;2014:974309.
    1. 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
    1. 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. MLN4924, a NEDD8-activating enzyme inhibitor, is active in diffuse large B-cell lymphoma models: rationale for treatment of NF-kappaB-dependent lymphoma. Blood. 2010;116(9):1515–1523. doi: 10.1182/blood-2010-03-272567.
    1. 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. Initial testing of the investigational NEDD8-activating enzyme inhibitor MLN4924 by the pediatric preclinical testing program. Pediatr Blood Cancer. 2012;59(2):246–253. doi: 10.1002/pbc.23357.
    1. Jia L, Li H, Sun Y. Induction of p21-dependent senescence by an NAE inhibitor, MLN4924, as a mechanism of growth suppression. Neoplasia. 2011;13(6):561–569. doi: 10.1593/neo.11420.
    1. Milhollen MA, Narayanan U, Soucy TA, Veiby PO, Smith PG, Amidon B. Inhibition of NEDD8-activating enzyme induces rereplication and apoptosis in human tumor cells consistent with deregulating CDT1 turnover. Cancer Res. 2011;71(8):3042–3051. doi: 10.1158/0008-5472.CAN-10-2122.
    1. Luo Z, Pan Y, Jeong LS, Liu J, Jia L. Inactivation of the Cullin (CUL)-RING E3 ligase by the NEDD8-activating enzyme inhibitor MLN4924 triggers protective autophagy in cancer cells. Autophagy. 2012;8(11):1677–1679. doi: 10.4161/auto.21484.
    1. Blank JL, Liu XJ, Cosmopoulos K, Bouck DC, Garcia K, Bernard H, Tayber O, Hather G, Liu R, Narayanan U, Milhollen MA, Lightcap ES. Novel DNA damage checkpoints mediating cell death induced by the NEDD8-activating enzyme inhibitor MLN4924. Cancer Res. 2013;73(1):225–234. doi: 10.1158/0008-5472.CAN-12-1729.
    1. Liao H, Liu XJ, Blank JL, Bouck DC, Bernard H, Garcia K, Lightcap ES. Quantitative proteomic analysis of cellular protein modulation upon inhibition of the NEDD8-activating enzyme by MLN4924. Mol Cell Proteomics. 2011;10(11):M111. doi: 10.1074/mcp.M111.009183.
    1. Tan M, Li H, Sun Y. Endothelial deletion of Sag/Rbx2/Roc2 E3 ubiquitin ligase causes embryonic lethality and blocks tumor angiogenesis. Oncogene. 2014;33(44):5211–5220. doi: 10.1038/onc.2013.473.
    1. Tentler JJ, Micel LN, Selby HM, Tan AC, Brunkow KL, Pitts TM, Blakemore S, Smith PG, Eckhardt SG. 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. 2011;10:B178. doi: 10.1158/1535-7163.TARG-11-B178.
    1. Traore T, Milhollen M, Garnsey JJ, Berger A, Manfredi M, Cosmopoulos K, Donelan J, Smith PG. Antitumor activity of MLN4924, an investigational inhibitor of NEDD8-activating enzyme (NAE), in preclinical models of melanoma (Abstract) J Clin Oncol. 2011;29:8594.
    1. 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
    1. 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. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med. 2005;352(24):2487–2498. doi: 10.1056/NEJMoa043445.
    1. 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. 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. 2009;27(30):5023–5030. doi: 10.1200/JCO.2008.17.7980.
    1. 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
    1. 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
    1. 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. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1) Eur J Cancer. 2009;45(2):228–247. doi: 10.1016/j.ejca.2008.10.026.
    1. 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
    1. Swords RT, Savona MR, Maris MB, Erba HP, Hua Z, Faessel H, Blakemore S, Sederati F, Dezube BJ, Medeiros BC. 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. 2014;99:223–224.
    1. DeAngelo DJ, Erba HP, Maris MB, Swords RT, Anwer F, Altman JK, Hua Z, Blakemore S, Faessel H, Dezube BJ, Medeiros BC. 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. 2013;122:1443.
    1. 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
    1. Azijli K, Stelloo E, Peters GJ, VAN DEN Eertwegh AJ. New developments in the treatment of metastatic melanoma: immune checkpoint inhibitors and targeted therapies. Anticancer Res. 2014;34(4):1493–1505.
    1. 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. Development of ipilimumab: a novel immunotherapeutic approach for the treatment of advanced melanoma. Ann N Y Acad Sci. 2013;1291:1–13. doi: 10.1111/nyas.12180.
    1. 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. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet. 2014;384(9948):1109–1117. doi: 10.1016/S0140-6736(14)60958-2.
    1. 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. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med. 2013;369(2):134–144. doi: 10.1056/NEJMoa1305133.
    1. Shaw HM, Nathan PD. Vemurafenib in melanoma. Expert Rev Anticancer Ther. 2013;13(5):513–522. doi: 10.1586/era.13.24.
    1. Kainthla R, Kim KB, Falchook GS. Dabrafenib. Recent Results Cancer Res. 2014;201:227–240. doi: 10.1007/978-3-642-54490-3_14.
    1. Salama AK, Kim KB. Trametinib (GSK1120212) in the treatment of melanoma. Expert Opin Pharmacother. 2013;14(5):619–627. doi: 10.1517/14656566.2013.770475.

Source: PubMed

Sponzoři a spolupracovníci

Zdravotní podmínky

Drogové intervence

3
Předplatit