ASCT2-Targeting Antibody-Drug Conjugate MEDI7247 in Adult Patients with Relapsed/Refractory Hematological Malignancies: A First-in-Human, Phase 1 Study.
Journal
Targeted oncology
ISSN: 1776-260X
Titre abrégé: Target Oncol
Pays: France
ID NLM: 101270595
Informations de publication
Date de publication:
29 Apr 2024
29 Apr 2024
Historique:
accepted:
10
03
2024
medline:
29
4
2024
pubmed:
29
4
2024
entrez:
29
4
2024
Statut:
aheadofprint
Résumé
MEDI7247 is a first-in-class antibody-drug conjugate (ADC) consisting of an anti-sodium-dependent alanine-serine-cysteine transporter 2 antibody-conjugated to a pyrrolobenzodiazepine dimer. This first-in-human phase 1 trial evaluated MEDI7247 in patients with hematological malignancies. Adults with acute myeloid leukemia (AML), multiple myeloma (MM), or diffuse large B-cell lymphoma (DLBCL) relapsed or refractory (R/R) to standard therapies, or for whom no standard therapy exists, were eligible. Primary endpoints were safety and determination of the maximum tolerated dose (MTD). Secondary endpoints included assessments of antitumor activity, pharmacokinetics (PK), and immunogenicity. As of 26 March 2020, 67 patients were treated (AML: n = 27; MM: n = 18; DLBCL: n = 22). The most common MEDI7247-related adverse events (AEs) were thrombocytopenia (41.8%), neutropenia (35.8%), and anemia (28.4%). The most common treatment-related grade 3/4 AEs were thrombocytopenia (38.8%), neutropenia (34.3%), and anemia (22.4%). Anticancer activity (number of responders/total patients evaluated) was observed in 11/67 (16.4%) patients. No correlation was observed between ASCT2 expression and clinical response. Between-patient variability of systemic exposure of MEDI7247 ADC and total antibody were high (AUC Thrombocytopenia and neutropenia limited repeat dosing. Although limited clinical activity was detected, the dose-escalation phase was stopped early without establishing an MTD. The study was registered with ClinicalTrials.gov (NCT03106428).
Sections du résumé
BACKGROUND
BACKGROUND
MEDI7247 is a first-in-class antibody-drug conjugate (ADC) consisting of an anti-sodium-dependent alanine-serine-cysteine transporter 2 antibody-conjugated to a pyrrolobenzodiazepine dimer.
OBJECTIVE
OBJECTIVE
This first-in-human phase 1 trial evaluated MEDI7247 in patients with hematological malignancies.
PATIENTS AND METHODS
METHODS
Adults with acute myeloid leukemia (AML), multiple myeloma (MM), or diffuse large B-cell lymphoma (DLBCL) relapsed or refractory (R/R) to standard therapies, or for whom no standard therapy exists, were eligible. Primary endpoints were safety and determination of the maximum tolerated dose (MTD). Secondary endpoints included assessments of antitumor activity, pharmacokinetics (PK), and immunogenicity.
RESULTS
RESULTS
As of 26 March 2020, 67 patients were treated (AML: n = 27; MM: n = 18; DLBCL: n = 22). The most common MEDI7247-related adverse events (AEs) were thrombocytopenia (41.8%), neutropenia (35.8%), and anemia (28.4%). The most common treatment-related grade 3/4 AEs were thrombocytopenia (38.8%), neutropenia (34.3%), and anemia (22.4%). Anticancer activity (number of responders/total patients evaluated) was observed in 11/67 (16.4%) patients. No correlation was observed between ASCT2 expression and clinical response. Between-patient variability of systemic exposure of MEDI7247 ADC and total antibody were high (AUC
CONCLUSIONS
CONCLUSIONS
Thrombocytopenia and neutropenia limited repeat dosing. Although limited clinical activity was detected, the dose-escalation phase was stopped early without establishing an MTD. The study was registered with ClinicalTrials.gov (NCT03106428).
Identifiants
pubmed: 38683495
doi: 10.1007/s11523-024-01054-z
pii: 10.1007/s11523-024-01054-z
doi:
Banques de données
ClinicalTrials.gov
['NCT03106428']
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2024. The Author(s).
Références
Scalise M, Pochini L, Console L, Losso MA, Indiveri C. The Human SLC1A5 (ASCT2) amino acid transporter: from function to structure and role in cell biology. Front Cell Dev Biol. 2018;6:96. https://doi.org/10.3389/fcell.2018.00096 .
doi: 10.3389/fcell.2018.00096
pubmed: 30234109
pmcid: 6131531
Liu Y, Zhao T, Li Z, Wang L, Yuan S, Sun L. The role of ASCT2 in cancer: a review. Eur J Pharmacol. 2018;837:81–7. https://doi.org/10.1016/j.ejphar.2018.07.007 .
doi: 10.1016/j.ejphar.2018.07.007
pubmed: 30025811
Hassanein M, Hoeksema MD, Shiota M, Qian J, Harris BK, Chen H, et al. SLC1A5 mediates glutamine transport required for lung cancer cell growth and survival. Clin Cancer Res. 2013;19(3):560–70. https://doi.org/10.1158/1078-0432.CCR-12-2334 .
doi: 10.1158/1078-0432.CCR-12-2334
pubmed: 23213057
Nikkuni O, Kaira K, Toyoda M, Shino M, Sakakura K, Takahashi K, et al. Expression of amino acid transporters (LAT1 and ASCT2) in patients with stage III/IV laryngeal squamous cell carcinoma. Pathol Oncol Res. 2015;21(4):1175–81. https://doi.org/10.1007/s12253-015-9954-3 .
doi: 10.1007/s12253-015-9954-3
pubmed: 26024742
Kaira K, Sunose Y, Arakawa K, Sunaga N, Shimizu K, Tominaga H, et al. Clinicopathological significance of ASC amino acid transporter-2 expression in pancreatic ductal carcinoma. Histopathology. 2015;66(2):234–43. https://doi.org/10.1111/his.12464 .
doi: 10.1111/his.12464
pubmed: 24845232
Wang Q, Hardie RA, Hoy AJ, van Geldermalsen M, Gao D, Fazli L, et al. Targeting ASCT2-mediated glutamine uptake blocks prostate cancer growth and tumour development. J Pathol. 2015;236(3):278–89. https://doi.org/10.1002/path.4518 .
doi: 10.1002/path.4518
pubmed: 25693838
pmcid: 4973854
van Geldermalsen M, Wang Q, Nagarajah R, Marshall AD, Thoeng A, Gao D, et al. ASCT2/SLC1A5 controls glutamine uptake and tumour growth in triple-negative basal-like breast cancer. Oncogene. 2016;35(24):3201–8. https://doi.org/10.1038/onc.2015.381 .
doi: 10.1038/onc.2015.381
pubmed: 26455325
Shimizu K, Kaira K, Tomizawa Y, Sunaga N, Kawashima O, Oriuchi N, et al. ASC amino-acid transporter 2 (ASCT2) as a novel prognostic marker in non-small cell lung cancer. Br J Cancer. 2014;110(8):2030–9. https://doi.org/10.1038/bjc.2014.88 .
doi: 10.1038/bjc.2014.88
pubmed: 24603303
pmcid: 3992511
Monks NR, Schifferli KP, Tammali R, Borrok MJ, Coats SR, Herbst R, et al. MEDI7247, a novel pyrrolobenzodiazepine ADC targeting ASCT2 with potent in vivo activity across a spectrum of hematological malignancies. Cancer Res. 2018;78(13_Supplement):LB-295. https://doi.org/10.1158/1538-7445.AM2018-LB-295 .
doi: 10.1158/1538-7445.AM2018-LB-295
Pore N, Schifferli KP, Monks NR, Tammali R, Borrok M, Hurt E, et al. Discovery and development of MEDI7247, a novel pyrrolobenzodiazepine (PBD)-based antibody drug conjugate targeting ASCT2, for treating hematological cancers. Blood. 2018;132(Supplement 1):4071. https://doi.org/10.1182/blood-2018-99-119836 .
doi: 10.1182/blood-2018-99-119836
Crump M, Neelapu SS, Farooq U, Van Den Neste E, Kuruvilla J, Westin J, et al. Outcomes in refractory diffuse large B-cell lymphoma: results from the international SCHOLAR-1 study. Blood. 2017;130(16):1800–8. https://doi.org/10.1182/blood-2017-03-769620 .
doi: 10.1182/blood-2017-03-769620
pubmed: 28774879
pmcid: 5649550
Luppi M, Fabbiano F, Visani G, Martinelli G, Venditti A. Novel agents for acute myeloid leukemia. Cancers (Basel). 2018. https://doi.org/10.3390/cancers10110429 .
doi: 10.3390/cancers10110429
pubmed: 30423907
Ndaru E, Garibsingh RA, Shi Y, Wallace E, Zakrepine P, Wang J, et al. Novel alanine serine cysteine transporter 2 (ASCT2) inhibitors based on sulfonamide and sulfonic acid ester scaffolds. J Gen Physiol. 2019;151(3):357–68. https://doi.org/10.1085/jgp.201812276 .
doi: 10.1085/jgp.201812276
pubmed: 30718375
pmcid: 6400523
Mecklenburg L. A brief introduction to antibody-drug conjugates for toxicologic pathologists. Toxicol Pathol. 2018;46(7):746–52. https://doi.org/10.1177/0192623318803059 .
doi: 10.1177/0192623318803059
pubmed: 30295169
Hartley JA, Flynn MJ, Bingham JP, Corbett S, Reinert H, Tiberghien A, et al. Pre-clinical pharmacology and mechanism of action of SG3199, the pyrrolobenzodiazepine (PBD) dimer warhead component of antibody-drug conjugate (ADC) payload tesirine. Sci Rep. 2018;8(1):10479. https://doi.org/10.1038/s41598-018-28533-4 .
doi: 10.1038/s41598-018-28533-4
pubmed: 29992976
pmcid: 6041317
Nejadmoghaddam MR, Minai-Tehrani A, Ghahremanzadeh R, Mahmoudi M, Dinarvand R, Zarnani AH. Antibody-drug conjugates: possibilities and challenges. Avicenna J Med Biotechnol. 2019;11(1):3–23.
pubmed: 30800238
pmcid: 6359697
Ji Y, Liu P, Li Y, Bekele BN. A modified toxicity probability interval method for dose-finding trials. Clin Trials. 2010;7(6):653–63. https://doi.org/10.1177/1740774510382799 .
doi: 10.1177/1740774510382799
pubmed: 20935021
pmcid: 5038924
Dohner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Buchner T, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129(4):424–47. https://doi.org/10.1182/blood-2016-08-733196 .
doi: 10.1182/blood-2016-08-733196
pubmed: 27895058
pmcid: 5291965
Kumar S, Paiva B, Anderson KC, Durie B, Landgren O, Moreau P, et al. International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol. 2016;17(8):e328–46. https://doi.org/10.1016/S1470-2045(16)30206-6 .
doi: 10.1016/S1470-2045(16)30206-6
pubmed: 27511158
Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014;32(27):3059–68. https://doi.org/10.1200/JCO.2013.54.8800 .
doi: 10.1200/JCO.2013.54.8800
pubmed: 25113753
pmcid: 4979083
Papaemmanuil E, Dohner H, Campbell PJ. Genomic classification in acute myeloid leukemia. N Engl J Med. 2016;375(9):900–1. https://doi.org/10.1056/NEJMc1608739 .
doi: 10.1056/NEJMc1608739
pubmed: 27579651
Rothenberg-Thurley M, Amler S, Goerlich D, Kohnke T, Konstandin NP, Schneider S, et al. Persistence of pre-leukemic clones during first remission and risk of relapse in acute myeloid leukemia. Leukemia. 2018;32(7):1598–608. https://doi.org/10.1038/s41375-018-0034-z .
doi: 10.1038/s41375-018-0034-z
pubmed: 29472724
pmcid: 6035153
Yilmaz M, Richard S, Jabbour E. The clinical potential of inotuzumab ozogamicin in relapsed and refractory acute lymphocytic leukemia. Ther Adv Hematol. 2015;6(5):253–61. https://doi.org/10.1177/2040620715596715 .
doi: 10.1177/2040620715596715
pubmed: 26425338
pmcid: 4556970
Wynne J, Wright D, Stock W. Inotuzumab: from preclinical development to success in B-cell acute lymphoblastic leukemia. Blood Adv. 2019;3(1):96–104. https://doi.org/10.1182/bloodadvances.2018026211 .
doi: 10.1182/bloodadvances.2018026211
pubmed: 30622147
pmcid: 6325303
Yu B, Liu D. Gemtuzumab ozogamicin and novel antibody-drug conjugates in clinical trials for acute myeloid leukemia. Biomark Res. 2019;7:24. https://doi.org/10.1186/s40364-019-0175-x .
doi: 10.1186/s40364-019-0175-x
pubmed: 31695916
pmcid: 6824118
Phillips T, Barr PM, Park SI, Kolibaba K, Caimi PF, Chhabra S, et al. A phase 1 trial of SGN-CD70A in patients with CD70-positive diffuse large B cell lymphoma and mantle cell lymphoma. Invest New Drugs. 2019;37(2):297–306. https://doi.org/10.1007/s10637-018-0655-0 .
doi: 10.1007/s10637-018-0655-0
pubmed: 30132271
Janjigian YY, Lee W, Kris MG, Miller VA, Krug LM, Azzoli CG, et al. A phase I trial of SJG-136 (NSC#694501) in advanced solid tumors. Cancer Chemother Pharmacol. 2010;65(5):833–8. https://doi.org/10.1007/s00280-009-1088-4 .
doi: 10.1007/s00280-009-1088-4
pubmed: 19672598
Morgensztern D, Besse B, Greillier L, Santana-Davila R, Ready N, Hann CL, et al. Efficacy and safety of rovalpituzumab tesirine in third-line and beyond patients with DLL3-expressing, relapsed/refractory small-cell lung cancer: results from the phase II TRINITY study. Clin Cancer Res. 2019;25(23):6958–66. https://doi.org/10.1158/1078-0432.CCR-19-1133 .
doi: 10.1158/1078-0432.CCR-19-1133
pubmed: 31506387
pmcid: 7105795
McDonald GB, Freston JW, Boyer JL, DeLeve LD. Liver complications following treatment of hematologic malignancy with anti-CD22-calicheamicin (inotuzumab ozogamicin). Hepatology. 2019;69(2):831–44. https://doi.org/10.1002/hep.30222 .
doi: 10.1002/hep.30222
pubmed: 30120894
Chau CH, Steeg PS, Figg WD. Antibody-drug conjugates for cancer. Lancet. 2019;394(10200):793–804. https://doi.org/10.1016/S0140-6736(19)31774-X .
doi: 10.1016/S0140-6736(19)31774-X
pubmed: 31478503
Zhao H, Gulesserian S, Ganesan SK, Ou J, Morrison K, Zeng Z, et al. Inhibition of megakaryocyte differentiation by antibody-drug conjugates (ADCs) is mediated by macropinocytosis: implications for ADC-induced thrombocytopenia. Mol Cancer Ther. 2017;16(9):1877–86. https://doi.org/10.1158/1535-7163.MCT-16-0710 .
doi: 10.1158/1535-7163.MCT-16-0710
pubmed: 28655784
Ramesh R, Marrogi AJ, Munshi A, Abboud CN, Freeman SM. In vivo analysis of the “bystander effect”: a cytokine cascade. Exp Hematol. 1996;24(7):829–38.
pubmed: 8647234
Freeman SM, Abboud CN, Whartenby KA, Packman CH, Koeplin DS, Moolten FL, et al. The “bystander effect”: tumor regression when a fraction of the tumor mass is genetically modified. Cancer Res. 1993;53(21):5274–83.
pubmed: 8221662
Cancer Cell Line Encyclopedia. 2021. https://portals.broadinstitute.org/ccle .
Lagunas-Rangel FA, Chavez-Valencia V. FLT3-ITD and its current role in acute myeloid leukaemia. Med Oncol. 2017;34(6):114. https://doi.org/10.1007/s12032-017-0970-x .
doi: 10.1007/s12032-017-0970-x
pubmed: 28470536