Phase 1 dose escalation study of the MDM2 inhibitor milademetan as monotherapy and in combination with azacitidine in patients with myeloid malignancies.
Humans
Male
Azacitidine
/ administration & dosage
Female
Aged
Middle Aged
Proto-Oncogene Proteins c-mdm2
/ antagonists & inhibitors
Antineoplastic Combined Chemotherapy Protocols
/ therapeutic use
Leukemia, Myeloid, Acute
/ drug therapy
Maximum Tolerated Dose
Aged, 80 and over
Myelodysplastic Syndromes
/ drug therapy
Adult
Treatment Outcome
Carbolines
Heterocyclic Compounds, 4 or More Rings
acute myeloid leukemia
milademetan
mouse double minute‐2 homolog
myelodysplastic syndromes
Journal
Cancer medicine
ISSN: 2045-7634
Titre abrégé: Cancer Med
Pays: United States
ID NLM: 101595310
Informations de publication
Date de publication:
Jul 2024
Jul 2024
Historique:
revised:
29
05
2024
received:
29
02
2024
accepted:
07
07
2024
medline:
20
7
2024
pubmed:
20
7
2024
entrez:
20
7
2024
Statut:
ppublish
Résumé
Mouse double minute-2 homolog (MDM2) plays a key role in downregulating p53 activity in hematologic malignancies, and its overexpression is associated with poor outcomes. This phase 1 study assessed the safety and efficacy of different dosing regimens of the MDM2 inhibitor milademetan as monotherapy and in combination with azacitidine (AZA) in patients with relapsed or refractory acute myeloid leukemia or high-risk myelodysplastic syndromes. Seventy-four patients (monotherapy, n = 57; milademetan-AZA combination, n = 17) were treated. The maximum tolerated dose of milademetan was 160 mg once daily given for the first 14-21 days of 28-day cycles as monotherapy and on Days 5-14 in combination with AZA. Dose-limiting toxicities were gastrointestinal, fatigue, or renal/electrolyte abnormalities. Treatment-emergent adverse events related to milademetan occurred in 82.5% and 64.7% of participants in the monotherapy and AZA combination arms, respectively. Two participants (4.2%) in the monotherapy arm achieved complete remission (CR), and 1 (2.1%) achieved CR with incomplete blood count recovery (CRi). Two participants (13.3%) achieved CRi in the combination arm. New TP53 mutations, detected only during milademetan monotherapy, were found pre-existing below standard detection frequency by droplet digital polymerase chain reaction. Milademetan was relatively well tolerated in this population; however, despite signals of activity, clinical efficacy was minimal.
Sections du résumé
BACKGROUND
BACKGROUND
Mouse double minute-2 homolog (MDM2) plays a key role in downregulating p53 activity in hematologic malignancies, and its overexpression is associated with poor outcomes.
METHODS
METHODS
This phase 1 study assessed the safety and efficacy of different dosing regimens of the MDM2 inhibitor milademetan as monotherapy and in combination with azacitidine (AZA) in patients with relapsed or refractory acute myeloid leukemia or high-risk myelodysplastic syndromes.
RESULTS
RESULTS
Seventy-four patients (monotherapy, n = 57; milademetan-AZA combination, n = 17) were treated. The maximum tolerated dose of milademetan was 160 mg once daily given for the first 14-21 days of 28-day cycles as monotherapy and on Days 5-14 in combination with AZA. Dose-limiting toxicities were gastrointestinal, fatigue, or renal/electrolyte abnormalities. Treatment-emergent adverse events related to milademetan occurred in 82.5% and 64.7% of participants in the monotherapy and AZA combination arms, respectively. Two participants (4.2%) in the monotherapy arm achieved complete remission (CR), and 1 (2.1%) achieved CR with incomplete blood count recovery (CRi). Two participants (13.3%) achieved CRi in the combination arm. New TP53 mutations, detected only during milademetan monotherapy, were found pre-existing below standard detection frequency by droplet digital polymerase chain reaction.
INTERPRETATION
CONCLUSIONS
Milademetan was relatively well tolerated in this population; however, despite signals of activity, clinical efficacy was minimal.
Substances chimiques
Azacitidine
M801H13NRU
Proto-Oncogene Proteins c-mdm2
EC 2.3.2.27
MDM2 protein, human
EC 2.3.2.27
PM 01183
0
Carbolines
0
Heterocyclic Compounds, 4 or More Rings
0
Types de publication
Journal Article
Clinical Trial, Phase I
Langues
eng
Sous-ensembles de citation
IM
Pagination
e70028Informations de copyright
© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.
Références
Duffy MJ, Synnott NC, O'Grady S, et al. Targeting p53 for the treatment of cancer. Semin Cancer Biol. 2022;79:58‐67.
Boettcher S, Miller PG, Sharma R, et al. A dominant‐negative effect drives selection of TP53 missense mutations in myeloid malignancies. Science. 2019;365:599‐604.
Prochazka KT, Pregartner G, Rucker FG, et al. Clinical implications of subclonal TP53 mutations in acute myeloid leukemia. Haematologica. 2019;104:516‐523.
Stengel A, Kern W, Haferlach T, Meggendorfer M, Fasan A, Haferlach C. The impact of TP53 mutations and TP53 deletions on survival varies between AML, ALL, MDS and CLL: an analysis of 3307 cases. Leukemia. 2017;31:705‐711.
Papaemmanuil E, Gerstung M, Bullinger L, et al. Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med. 2016;374:2209‐2221.
Hou HA, Chou WC, Kuo YY, et al. TP53 mutations in de novo acute myeloid leukemia patients: longitudinal follow‐ups show the mutation is stable during disease evolution. Blood Cancer J. 2015;5:e331.
Kadia TM, Jain P, Ravandi F, et al. TP53 mutations in newly diagnosed acute myeloid leukemia: clinicomolecular characteristics, response to therapy, and outcomes. Cancer. 2016;122:3484‐3491.
Rucker FG, Schlenk RF, Bullinger L, et al. TP53 alterations in acute myeloid leukemia with complex karyotype correlate with specific copy number alterations, monosomal karyotype, and dismal outcome. Blood. 2012;119:2114‐2121.
Quintas‐Cardama A, Hu C, Qutub A, et al. p53 pathway dysfunction is highly prevalent in acute myeloid leukemia independent of TP53 mutational status. Leukemia. 2017;31:1296‐1305.
Levine AJ. The many faces of p53: something for everyone. J Mol Cell Biol. 2019;11:524‐530.
Haupt Y, Maya R, Kazaz A, Oren M. Mdm2 promotes the rapid degradation of p53. Nature. 1997;387:296‐299.
Kojima K, Ishizawa J, Andreeff M. Pharmacological activation of wild‐type p53 in the therapy of leukemia. Exp Hematol. 2016;44:791‐798.
Bueso‐Ramos CE, Yang Y, deLeon E, McCown P, Stass SA, Albitar M. The human MDM‐2 oncogene is overexpressed in leukemias. Blood. 1993;82:2617‐2623.
Faderl S, Kantarjian HM, Estey E, et al. The prognostic significance of p16(INK4a)/p14(ARF) locus deletion and MDM‐2 protein expression in adult acute myelogenous leukemia. Cancer. 2000;89:1976‐1982.
Andreeff M, Zhao S, Drach D, et al. Expression of multidrug resistance (mdr‐1) and p53 genes in hematologic cell systems: implications for biology and gene therapy. Cancer Bull. 1993;45:131‐138.
Kojima K, Konopleva M, Samudio IJ, et al. MDM2 antagonists induce p53‐dependent apoptosis in AML: implications for leukemia therapy. Blood. 2005;106:3150‐3159.
Kojima K, Konopleva M, McQueen T, O'Brien S, Plunkett W, Andreeff M. Mdm2 inhibitor nutlin‐3a induces p53‐mediated apoptosis by transcription‐dependent and transcription‐independent mechanisms and may overcome atm‐mediated resistance to fludarabine in chronic lymphocytic leukemia. Blood. 2006;108:993‐1000.
Andreeff M, Kelly KR, Yee K, et al. Results of the phase I trial of RG7112, a small‐molecule MDM2 antagonist in leukemia. Clin Cancer Res. 2016;22:868‐876.
Ishizawa J, Nakamaru K, Seki T, et al. Predictive gene signatures determine tumor sensitivity to MDM2 inhibition. Cancer Res. 2018;78:2721‐2731.
Gounder MM, Bauer TM, Schwartz GK, et al. A first‐in‐human phase I study of milademetan, an MDM2 inhibitor, in patients with advanced liposarcoma, solid tumors, or lymphomas. J Clin Oncol. 2023;41:1714‐1724.
Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127:2391‐2405.
Greenberg PL, Tuechler H, Schanz J, et al. Revised international prognostic scoring system for myelodysplastic syndromes. Blood. 2012;120:2454‐2465.
Dohner H, Estey E, Grimwade D, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129:424‐447.
Cheson BD, Greenberg PL, Bennett JM, et al. Clinical application and proposal for modification of the international working group (IWG) response criteria in myelodysplasia. Blood. 2006;108:419‐425.
Yang H, Filipovic Z, Brown D, Breit SN, Vassilev LT. Macrophage inhibitory cytokine‐1: a novel biomarker for p53 pathway activation. Mol Cancer Ther. 2003;2:1023‐1029.
Takahashi S, Fujiwara Y, Nakano K, et al. Safety and pharmacokinetics of milademetan, a MDM2 inhibitor, in Japanese patients with solid tumors: a phase I study. Cancer Sci. 2021;112:2361‐2370.
Konopleva MY, Rollig C, Cavenagh J, et al. Idasanutlin plus cytarabine in relapsed or refractory acute myeloid leukemia: results of the MIRROS trial. Blood Adv. 2022;6:4147‐4156.
Pan R, Ruvolo V, Mu H, et al. Synthetic lethality of combined Bcl‐2 inhibition and p53 activation in AML: mechanisms and superior antileukemic efficacy. Cancer Cell. 2017;32:748.
Daver NG, Dail M, Garcia JS, et al. Venetoclax and idasanutlin in relapsed/refractory AML: a non‐randomized, open‐label phase 1b trial. Blood. 2023;141:1265‐1276.
Han X, Medeiros LJ, Zhang YH, et al. High expression of human homologue of murine double minute 4 and the short splicing variant, HDM4‐S, in bone marrow in patients with acute myeloid leukemia or myelodysplastic syndrome. Clin Lymphoma Myeloma Leuk. 2016;16(Suppl):S30‐S38.
Grieselhuber NR, Mims AS. Novel targeted therapeutics in acute myeloid leukemia: an embarrassment of riches. Curr Hematol Malig Rep. 2021;16:192‐206.
Carvajal LA, Neriah DB, Senecal A, et al. Dual inhibition of MDMX and MDM2 as a therapeutic strategy in leukemia. Sci Transl Med. 2018;10:eaao3003.
Maslah N, Verger E, Giraudier S, et al. Single‐cell analysis reveals selection of TP53‐mutated clones after MDM2 inhibition. Blood Adv. 2022;6:2813‐2823.
Long J, Parkin B, Ouillette P, et al. Multiple distinct molecular mechanisms influence sensitivity and resistance to MDM2 inhibitors in adult acute myelogenous leukemia. Blood. 2010;116:171‐180.
Marcellino BK, Farnoud N, Cassinat B, et al. Transient expansion of TP53 mutated clones in polycythemia vera patients treated with idasanutlin. Blood Adv. 2020;4:5735‐5744.
Chakraborty J, Banerjee S, Ray P, et al. Gain of cellular adaptation due to prolonged p53 impairment leads to functional switchover from p53 to p73 during DNA damage in acute myeloid leukemia cells. J Biol Chem. 2010;285:33104‐33112.
Costantini B, Kordasti SY, Kulasekararaj AG, et al. The effects of 5‐azacytidine on the function and number of regulatory T cells and T‐effectors in myelodysplastic syndrome. Haematologica. 2013;98:1196‐1205.
Tabe Y, Sebasigari D, Jin L, et al. MDM2 antagonist nutlin‐3 displays antiproliferative and proapoptotic activity in mantle cell lymphoma. Clin Cancer Res. 2009;15:933‐942.
Endo S, Yamato K, Hirai S, et al. Potent in vitro and in vivo antitumor effects of MDM2 inhibitor nutlin‐3 in gastric cancer cells. Cancer Sci. 2011;102:605‐613.