TY - JOUR
T1 - Phase I study of the anti-FcRH5 antibody-drug conjugate DFRF4539A in relapsed or refractory multiple myeloma
AU - Stewart, A. Keith
AU - Krishnan, Amrita Y.
AU - Singhal, Seema
AU - Boccia, Ralph V.
AU - Patel, Manish R.
AU - Niesvizky, Ruben
AU - Chanan-Khan, Asher A.
AU - Ailawadhi, Sikander
AU - Brumm, Jochen
AU - Mundt, Kirsten E.
AU - Hong, Kyu
AU - McBride, Jacqueline
AU - Shon-Nguyen, Quyen
AU - Xiao, Yuanyuan
AU - Ramakrishnan, Vanitha
AU - Polson, Andrew G.
AU - Samineni, Divya
AU - Leipold, Douglas
AU - Humke, Eric W.
AU - McClellan, James Scott
AU - Berdeja, Jesus G.
N1 - Publisher Copyright:
© 2019, The Author(s).
PY - 2019/2/1
Y1 - 2019/2/1
N2 - FcRH5 is a cell surface marker enriched on malignant plasma cells when compared to other hematologic malignancies and normal tissues. DFRF4539A is an anti-FcRH5 antibody-drug conjugated to monomethyl auristatin E (MMAE), a potent anti-mitotic agent. This phase I study assessed safety, tolerability, maximum tolerated dose (MTD), anti-tumor activity, and pharmacokinetics of DFRF4539A in patients with relapsed/refractory multiple myeloma. DFRF4539A was administered at 0.3–2.4 mg/kg every 3 weeks or 0.8–1.1 mg/kg weekly as a single-agent by intravenous infusion to 39 patients. Exposure of total antibody and antibody-conjugate-MMAE analytes was linear across the doses tested. There were 37 (95%) adverse events (AEs), 8 (21%) serious AEs, and 15 (39%) AEs ≥ grade 3. Anemia (n = 10, 26%) was the most common AE considered related to DFRF4539A. Two cases of grade 3 acute renal failure were attributed to DFRF4539A. There were no deaths; the MTD was not reached. DFRF4539A demonstrated limited activity in patients at the doses tested with 2 (5%) partial response, 1 (3%) minimal response, 18 (46%) stable disease, and 16 (41%) progressive disease. FcRH5 was confirmed to be expressed and occupied by antibody post-treatment and thus remains a valid myeloma target. Nevertheless, this MMAE-based antibody-drug-conjugate targeting FcRH5 was unsuccessful for myeloma.
AB - FcRH5 is a cell surface marker enriched on malignant plasma cells when compared to other hematologic malignancies and normal tissues. DFRF4539A is an anti-FcRH5 antibody-drug conjugated to monomethyl auristatin E (MMAE), a potent anti-mitotic agent. This phase I study assessed safety, tolerability, maximum tolerated dose (MTD), anti-tumor activity, and pharmacokinetics of DFRF4539A in patients with relapsed/refractory multiple myeloma. DFRF4539A was administered at 0.3–2.4 mg/kg every 3 weeks or 0.8–1.1 mg/kg weekly as a single-agent by intravenous infusion to 39 patients. Exposure of total antibody and antibody-conjugate-MMAE analytes was linear across the doses tested. There were 37 (95%) adverse events (AEs), 8 (21%) serious AEs, and 15 (39%) AEs ≥ grade 3. Anemia (n = 10, 26%) was the most common AE considered related to DFRF4539A. Two cases of grade 3 acute renal failure were attributed to DFRF4539A. There were no deaths; the MTD was not reached. DFRF4539A demonstrated limited activity in patients at the doses tested with 2 (5%) partial response, 1 (3%) minimal response, 18 (46%) stable disease, and 16 (41%) progressive disease. FcRH5 was confirmed to be expressed and occupied by antibody post-treatment and thus remains a valid myeloma target. Nevertheless, this MMAE-based antibody-drug-conjugate targeting FcRH5 was unsuccessful for myeloma.
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U2 - 10.1038/s41408-019-0178-8
DO - 10.1038/s41408-019-0178-8
M3 - Article
C2 - 30718503
AN - SCOPUS:85061037366
SN - 2044-5385
VL - 9
JO - Blood cancer journal
JF - Blood cancer journal
IS - 2
M1 - 17
ER -