Camidanlumab tesirine, an antibody-drug conjugate, in relapsed/refractory CD25-positive acute myeloid leukemia or acute lymphoblastic leukemia: A phase I study. (August 2020)

• Record Type: Journal Article
• Authors: Goldberg, Aaron D.; Atallah, Ehab; Rizzieri, David; Walter, Roland B.; Chung, Ki-Young; Spira, Alexander; Stock, Wendy; Tallman, Martin S.; Cruz, Hans G.; Boni, Joseph; Havenith, Karin E.G.; Chao, Grace; Feingold, Jay M.; Wuerthner, Jens; Solh, Melhem
• Is Part Of: Leukemia research. Volume 95(2020)
• Publication Date: 2020-08
• Subjects: ADA anti-drug antibody -- ADC antibody-drug conjugate -- AE adverse event -- ALL acute lymphoblastic leukemia -- AML acute myeloid leukemia -- BiTE bispecific T-cell engager -- CR complete response -- CRi complete response with incomplete hematologic recovery -- DESC Dose Escalation Steering Committee -- DLT dose-limiting toxicity -- ECOG Eastern Cooperative Oncology Group -- GGT gamma-glutamyltransferase -- HL Hodgkin lymphoma -- MTD maximum tolerated dose -- ORR overall response rate -- PBD pyrrolobenzodiazepine -- PK pharmacokinetic -- PR partial response -- QW every week -- Q3W every 3 weeks -- R/R relapsed/refractory -- SAE serious AE -- TEAE treatment-emergent AE -- Treg regulatory T-cell; ADCT-301 -- Acute myeloid leukemia -- Acute lymphoblastic leukemia -- Antibody-drug conjugate -- Camidanlumab tesirine -- CD25 -- Relapsed/refractory; Leukemia -- Periodicals; Leukemia -- Periodicals; Leucémie -- Périodiques; Leukemia; Periodicals; Electronic journals; Electronic journals; 616.9941905
• DOI: 10.1016/j.leukres.2020.106385
• Languages: English
• ISSNs: 0145-2126

Abstract

Graphical abstract: The mechanism of action of camidanlumab tesirine . Camidanlumab tesirine binds to the CD25 antigen on AML/ALL tumor cells. Upon binding, the ADC is internalized and releases PBD dimers after the protease-sensitive linker is cleaved in lysosomes. The released PBD molecules migrate into the nucleus and sequence-selectively bind to the DNA minor groove, forming inter-strand cross-links that block tumor cell division and, hence, directly kill the cell. ADC, antibody-drug conjugate; ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; PBD, pyrrolobenzodiazepine. Highlights: Camidanlumab tesirine demonstrated an acceptable safety and tolerability profile in adults with R/R CD25+ ALL or AML. The maximum tolerated dose was not reached at the investigated doses, with only one dose-limiting toxicity observed. Camidanlumab tesirine demonstrated modest efficacy, with two complete remissions in patients with R/R CD25+ AML with a weekly dosing schedule These results warrant possible further investigation of camidanlumab tesirine and/or combination treatments in patients with R/R CD25+ acute leukemia. Abstract: There is a significant need for improved therapeutics in older patients with acute leukemia. Camidanlumab tesirine is an antibody-drug conjugate against CD25, an antigen expressed in several malignancies, including acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). This open-label, dose-escalation and -expansion study (NCT02588092 ) assessed the safety, activity, pharmacokinetics (PK), and immunogenicity of camidanlumab tesirine in patients with relapsed/refractory ALL/AML. A total of 35 patients (34 AML and 1 ALL) were enrolled and received camidanlumab tesirine intravenously at 3–92 μg/kg once every three weeks (Q3W, n = 26) or 30 or 37.5 μg/kg every week (QW, n = 9). One dose-limiting toxicity of maculopapular rash occurred in the 30 μg/kg QW group; the maximum tolerated dose was not reached. No additional safety concerns or adverse events (AEs) of interest were identified. The most common (>10 % of patients) Grade ≥3 treatment-emergent AEs were febrile neutropenia (25.7 %), lymphopenia, neutropenia, thrombocytopenia or fatigue (all 14.3 %), pneumonia, increased gamma-glutamyltransferase, and hypophosphatemia (each 11.4 %). No signal for serious immune-related AEs such as Guillain-Barré syndrome/polyradiculopathy was observed and there was no evidence of immunogenicity. PK showed rapid clearance with apparent half-life <2 days for conjugated and total antibody, suggesting that Q3W dosing may be insufficient for therapeutic efficacy, and prompting exploration of a QW schedule. Two patients achieved complete responses with incomplete hematologic recovery; one each at 30 and 37.5 μg/kg QW. The trial was terminated during dose escalation due to programmatic reasons other than safety. Hence, recommended dose was not determined.