Phase I study of the anti-FcRH5 antibody-drug conjugate DFRF4539A in relapsed or refractory multiple myeloma

Alexander Keith Stewart, Amrita Y. Krishnan, Seema Singhal, Ralph V. Boccia, Manish R. Patel, Ruben Niesvizky, Asher A Chanan Khan, Sikander Ailawadhi, Jochen Brumm, Kirsten E. Mundt, Kyu Hong, Jacqueline McBride, Quyen Shon-Nguyen, Yuanyuan Xiao, Vanitha Ramakrishnan, Andrew G. Polson, Divya Samineni, Douglas Leipold, Eric W. Humke, James Scott McClellan & 1 others Jesus G. Berdeja

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

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.

Original languageEnglish (US)
Article number17
JournalBlood cancer journal
Volume9
Issue number2
DOIs
StatePublished - Feb 1 2019

Fingerprint

Multiple Myeloma
Anti-Idiotypic Antibodies
Maximum Tolerated Dose
Antibodies
Pharmaceutical Preparations
Hematologic Neoplasms
Drug Delivery Systems
Plasma Cells
Acute Kidney Injury
Intravenous Infusions
Anemia
Pharmacokinetics
Safety
monomethyl auristatin E
Neoplasms
Therapeutics

ASJC Scopus subject areas

  • Hematology
  • Oncology

Cite this

Phase I study of the anti-FcRH5 antibody-drug conjugate DFRF4539A in relapsed or refractory multiple myeloma. / Stewart, Alexander Keith; Krishnan, Amrita Y.; Singhal, Seema; Boccia, Ralph V.; Patel, Manish R.; Niesvizky, Ruben; Chanan Khan, Asher A; Ailawadhi, Sikander; Brumm, Jochen; Mundt, Kirsten E.; Hong, Kyu; McBride, Jacqueline; Shon-Nguyen, Quyen; Xiao, Yuanyuan; Ramakrishnan, Vanitha; Polson, Andrew G.; Samineni, Divya; Leipold, Douglas; Humke, Eric W.; McClellan, James Scott; Berdeja, Jesus G.

In: Blood cancer journal, Vol. 9, No. 2, 17, 01.02.2019.

Research output: Contribution to journalArticle

Stewart, AK, Krishnan, AY, Singhal, S, Boccia, RV, Patel, MR, Niesvizky, R, Chanan Khan, AA, Ailawadhi, S, Brumm, J, Mundt, KE, Hong, K, McBride, J, Shon-Nguyen, Q, Xiao, Y, Ramakrishnan, V, Polson, AG, Samineni, D, Leipold, D, Humke, EW, McClellan, JS & Berdeja, JG 2019, 'Phase I study of the anti-FcRH5 antibody-drug conjugate DFRF4539A in relapsed or refractory multiple myeloma', Blood cancer journal, vol. 9, no. 2, 17. https://doi.org/10.1038/s41408-019-0178-8
Stewart, Alexander Keith ; Krishnan, Amrita Y. ; Singhal, Seema ; Boccia, Ralph V. ; Patel, Manish R. ; Niesvizky, Ruben ; Chanan Khan, Asher A ; Ailawadhi, Sikander ; Brumm, Jochen ; Mundt, Kirsten E. ; Hong, Kyu ; McBride, Jacqueline ; Shon-Nguyen, Quyen ; Xiao, Yuanyuan ; Ramakrishnan, Vanitha ; Polson, Andrew G. ; Samineni, Divya ; Leipold, Douglas ; Humke, Eric W. ; McClellan, James Scott ; Berdeja, Jesus G. / Phase I study of the anti-FcRH5 antibody-drug conjugate DFRF4539A in relapsed or refractory multiple myeloma. In: Blood cancer journal. 2019 ; Vol. 9, No. 2.
@article{fb1b49042cd441738f96ff0c4ffec887,
title = "Phase I study of the anti-FcRH5 antibody-drug conjugate DFRF4539A in relapsed or refractory multiple myeloma",
abstract = "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.",
author = "Stewart, {Alexander Keith} and Krishnan, {Amrita Y.} and Seema Singhal and Boccia, {Ralph V.} and Patel, {Manish R.} and Ruben Niesvizky and {Chanan Khan}, {Asher A} and Sikander Ailawadhi and Jochen Brumm and Mundt, {Kirsten E.} and Kyu Hong and Jacqueline McBride and Quyen Shon-Nguyen and Yuanyuan Xiao and Vanitha Ramakrishnan and Polson, {Andrew G.} and Divya Samineni and Douglas Leipold and Humke, {Eric W.} and McClellan, {James Scott} and Berdeja, {Jesus G.}",
year = "2019",
month = "2",
day = "1",
doi = "10.1038/s41408-019-0178-8",
language = "English (US)",
volume = "9",
journal = "Blood Cancer Journal",
issn = "2044-5385",
publisher = "Nature Publishing Group",
number = "2",

}

TY - JOUR

T1 - Phase I study of the anti-FcRH5 antibody-drug conjugate DFRF4539A in relapsed or refractory multiple myeloma

AU - Stewart, Alexander 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.

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.

UR - http://www.scopus.com/inward/record.url?scp=85061037366&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85061037366&partnerID=8YFLogxK

U2 - 10.1038/s41408-019-0178-8

DO - 10.1038/s41408-019-0178-8

M3 - Article

VL - 9

JO - Blood Cancer Journal

JF - Blood Cancer Journal

SN - 2044-5385

IS - 2

M1 - 17

ER -