ASCT2-targeting antibody-drug conjugate medi7247 in adult patients with relapsed/refractory hematological malignancies: A first-in-human, phase 1 study Journal Article
| Authors: | Maris, M.; Salles, G.; Kim, W. S.; Kim, T. M.; Lyons, R. M.; Arellano, M.; Karmali, R.; Schiller, G.; Cull, E.; Abboud, C. N.; Batlevi, C.; Kagiampakis, I.; Rebelatto, M. C.; Lee, Y.; Kirby, L. C.; Wang, F.; Bothos, J.; Townsley, D. M.; Fathi, A. T.; Ribrag, V. |
| Article Title: | ASCT2-targeting antibody-drug conjugate medi7247 in adult patients with relapsed/refractory hematological malignancies: A first-in-human, phase 1 study |
| Abstract: | 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: This first-in-human phase 1 trial evaluated MEDI7247 in patients with hematological malignancies. Patients and 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: 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 (AUCinf geometric CV%: 62.3–134.2, and 74.8–126.1, respectively). SG3199 (PBD dimer) plasma concentrations were below the limit of quantification for all patients after Study Day 8. Anti-drug antibody (ADA) prevalence was 7.7%, ADA incidence was 1.9%, and persistent-positive ADA was 5.8%. 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). © The Author(s) 2024. |
| Keywords: | adult; controlled study; treatment response; aged; aged, 80 and over; middle aged; unclassified drug; major clinical study; somatic mutation; clinical trial; fatigue; neutropenia; area under the curve; drug efficacy; drug safety; treatment duration; drug targeting; cytarabine; antineoplastic agent; cancer incidence; gene; multiple cycle treatment; multiple myeloma; neutrophil count; anemia; nausea; thrombocytopenia; prevalence; qt prolongation; creatinine; stem cell transplantation; antineoplastic activity; drug potency; retrospective study; protein p53; alanine aminotransferase blood level; aspartate aminotransferase blood level; dyspnea; febrile neutropenia; gamma glutamyl transferase blood level; alanine aminotransferase; aspartate aminotransferase; bilirubin; drug fatality; maculopapular rash; correlation analysis; disease severity; myelodysplastic syndrome; hematologic neoplasms; multicenter study; immunogenicity; daunorubicin; drug clearance; pleura effusion; pancytopenia; time to maximum plasma concentration; drug blood level; leukocyte count; maximum tolerated dose; phase 1 clinical trial; drug half life; drug therapy; bilirubin blood level; electrocardiogram; genomic dna; hematologic disease; creatinine clearance; platelet count; papular rash; drug elimination; prostatitis; transcription factor runx1; minor histocompatibility antigens; asxl1 gene; blister; antibody conjugate; immunoconjugates; minor histocompatibility antigen; international normalized ratio; acute myeloid leukemia; diffuse large b cell lymphoma; liver vein obstruction; tp53 gene; high throughput sequencing; very elderly; limit of quantitation; dna sequencing; humans; human; male; female; article; amino acid transporter; runx1 gene; amino acid transport system asc; volume of distribution; ecog performance status; maximum concentration; antibody drug conjugate; protein expression level; excitatory amino acid transporter; medi 7247; sodium dependent alanine serine cysteine transporter 2; uzoptirine; slc1a5 protein, human |
| Journal Title: | Targeted Oncology |
| Volume: | 19 |
| Issue: | 3 |
| ISSN: | 1776-2596 |
| Publisher: | Springer |
| Date Published: | 2024-05-01 |
| Start Page: | 321 |
| End Page: | 332 |
| Language: | English |
| DOI: | 10.1007/s11523-024-01054-z |
| PUBMED: | 38683495 |
| PROVIDER: | scopus |
| PMCID: | PMC11111564 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
