TY - JOUR
T1 - Safety, tolerability, and preliminary activity of IMGN529, a CD37-targeted antibody-drug conjugate, in patients with relapsed or refractory B-cell non-Hodgkin lymphoma
T2 - a dose-escalation, phase I study
AU - Stathis, Anastasios
AU - Flinn, Ian W.
AU - Madan, Sumit
AU - Maddocks, Kami
AU - Freedman, Arnold
AU - Weitman, Steven
AU - Zucca, Emanuele
AU - Munteanu, Mihaela C.
AU - Lia Palomba, M.
N1 - Funding Information:
We wish to thank all the patients and their families, as well as the support staff at the clinical sites, who participated in the trial. We also thank Richard Bates, Sr. Manager of Publications at ImmunoGen, who provided drafts and editorial assistance during the production of this manuscript. MCM is a former employee of ImmunoGen, Inc. AS, IWF, SW and EZ report grant/funding support from ImmunoGen to conduct the trial.
Publisher Copyright:
© 2018, The Author(s).
PY - 2018/10/1
Y1 - 2018/10/1
N2 - Background CD37 is expressed on B-cell lymphoid malignancies, thus making it an attractive candidate for targeted therapy in non-Hodgkin lymphoma (NHL). IMGN529 is an antibody-drug conjugate comprising a CD37-binding antibody linked to the maytansinoid DM1, a potent anti-mitotic agent. Methods This first-in-human, phase 1 trial recruited adult patients with relapsed or refractory B-cell NHL. The primary objective was to determine the maximum tolerated dose (MTD) and recommended phase 2 dose. Secondary objectives were to evaluate safety, pharmacokinetics, and preliminary clinical activity. IMGN529 was administered intravenously once every 3 weeks, and dosed using a conventional 3 + 3 dose-escalation design. Results Forty-nine patients were treated at doses escalating from 0.1 to 1.8 mg/kg. Dose limiting toxicities occurred in eight patients and included peripheral neuropathy, febrile neutropenia, neutropenia, and thrombocytopenia. The most frequent treatment-emergent adverse events were fatigue (39%), neutropenia, pyrexia, and thrombocytopenia (each 37%). Adverse events led to treatment discontinuation in 10 patients (20%). Eight patients (16%) had treatment-related serious adverse events, the most common being grade 3 febrile neutropenia. The MTD (with growth factor support) was 1.4 mg/kg every 3 weeks. IMGN529 plasma exposure increased monotonically with dose and was consistent with target-mediated drug disposition. Five (13%) of 39 response-evaluable patients achieved an objective response (one complete response and four partial responses), four of which occurred in the subgroup of patients with diffuse large B-cell lymphoma. Conclusions The manageable safety profile of IMGN529 and preliminary evidence of activity, particularly in DLBCL patients, support the continued development of this novel CD37-targeting agent.
AB - Background CD37 is expressed on B-cell lymphoid malignancies, thus making it an attractive candidate for targeted therapy in non-Hodgkin lymphoma (NHL). IMGN529 is an antibody-drug conjugate comprising a CD37-binding antibody linked to the maytansinoid DM1, a potent anti-mitotic agent. Methods This first-in-human, phase 1 trial recruited adult patients with relapsed or refractory B-cell NHL. The primary objective was to determine the maximum tolerated dose (MTD) and recommended phase 2 dose. Secondary objectives were to evaluate safety, pharmacokinetics, and preliminary clinical activity. IMGN529 was administered intravenously once every 3 weeks, and dosed using a conventional 3 + 3 dose-escalation design. Results Forty-nine patients were treated at doses escalating from 0.1 to 1.8 mg/kg. Dose limiting toxicities occurred in eight patients and included peripheral neuropathy, febrile neutropenia, neutropenia, and thrombocytopenia. The most frequent treatment-emergent adverse events were fatigue (39%), neutropenia, pyrexia, and thrombocytopenia (each 37%). Adverse events led to treatment discontinuation in 10 patients (20%). Eight patients (16%) had treatment-related serious adverse events, the most common being grade 3 febrile neutropenia. The MTD (with growth factor support) was 1.4 mg/kg every 3 weeks. IMGN529 plasma exposure increased monotonically with dose and was consistent with target-mediated drug disposition. Five (13%) of 39 response-evaluable patients achieved an objective response (one complete response and four partial responses), four of which occurred in the subgroup of patients with diffuse large B-cell lymphoma. Conclusions The manageable safety profile of IMGN529 and preliminary evidence of activity, particularly in DLBCL patients, support the continued development of this novel CD37-targeting agent.
KW - Antibody-drug conjugate
KW - CD37
KW - IMGN529
KW - Non-Hodgkin lymphoma
KW - Phase I
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U2 - 10.1007/s10637-018-0570-4
DO - 10.1007/s10637-018-0570-4
M3 - Article
C2 - 29453628
AN - SCOPUS:85042075085
SN - 0167-6997
VL - 36
SP - 869
EP - 876
JO - Investigational New Drugs
JF - Investigational New Drugs
IS - 5
ER -