First-in-human phase I/II study of NEOD001 in patients with light chain amyloidosis and persistent organ dysfunction

Morie Gertz, Heather Landau, Raymond L. Comenzo, David Seldin, Brendan Weiss, Jeffrey Zonder, Giampaolo Merlini, Stefan Schönland, Jackie Walling, Gene G. Kinney, Martin Koller, Dale B. Schenk, Spencer D. Guthrie, Michaela Liedtke

Research output: Contribution to journalArticle

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Abstract

Purpose: Light chain (AL) amyloidosis is caused by the accumulation of misfolded proteins, which induces the dysfunction of vital organs. NEOD001 is a monoclonal antibody targeting these misfolded proteins. We report interim data from a phase I/II dose-escalation/expansion study of NEOD001 in patients with AL amyloidosis and persistent organ dysfunction (NCT01707264). Patients and Methods: Patients who had completed at least one previous anti-plasma cell-directed therapy, had partial hematologic response or better, and had persistent organ dysfunction received NEOD001 intravenously every 28 days. Dose levels of 0.5, 1, 2, 4, 8, 16, and 24 μg/kg were evaluated (3 + 3 study design). Primary objectives were to determine the maximum tolerated dose and the recommended dose for future studies and to evaluate safety/tolerability. Secondary and exploratory objectives included pharmacokinetics, immunogenicity, and organ responses on the basis of published consensus criteria. Results: Twenty-seven patients were enrolled in seven cohorts (dose-escalation component). No drugrelated serious adverse events (AEs), discontinuations because of drug-related AEs, dose-limiting toxicities, or antidrug antibodies were reported. The most frequent AEs were fatigue, upper respiratory tract infection, cough, and dyspnea. Recommended dosing was 24 μg/kg. Pharmacokinetics support intravenous dosing every 28 days. Of 14 cardiac-evaluable patients, eight (57%) met the criteria for cardiac response and six (43%) had stable disease. Of 15 renal-evaluable patients, nine (60%) met the criteria for renal response and six (40%) had stable disease. Conclusion: Monthly infusions of NEOD001 were safe and well tolerated. Recommended future dosing was 24 μg/kg. Organ response rates compared favorably with those reported previously for chemotherapy. A phase II expansion is ongoing. A global phase III study (NCT02312206) has been initiated. Antibody therapy targeting misfolded proteins is a potential new therapy for the management of AL amyloidosis.

Original languageEnglish (US)
Pages (from-to)1097-1103
Number of pages7
JournalJournal of Clinical Oncology
Volume34
Issue number10
DOIs
StatePublished - Apr 1 2016

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Amyloidosis
Light
Protein Transport
Pharmacokinetics
Kidney
Maximum Tolerated Dose
Antibodies
Cell- and Tissue-Based Therapy
Plasma Cells
Drug-Related Side Effects and Adverse Reactions
Cough
Respiratory Tract Infections
Dyspnea
Fatigue
NEOD001
Monoclonal Antibodies
Safety
Drug Therapy
Therapeutics
Proteins

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

First-in-human phase I/II study of NEOD001 in patients with light chain amyloidosis and persistent organ dysfunction. / Gertz, Morie; Landau, Heather; Comenzo, Raymond L.; Seldin, David; Weiss, Brendan; Zonder, Jeffrey; Merlini, Giampaolo; Schönland, Stefan; Walling, Jackie; Kinney, Gene G.; Koller, Martin; Schenk, Dale B.; Guthrie, Spencer D.; Liedtke, Michaela.

In: Journal of Clinical Oncology, Vol. 34, No. 10, 01.04.2016, p. 1097-1103.

Research output: Contribution to journalArticle

Gertz, M, Landau, H, Comenzo, RL, Seldin, D, Weiss, B, Zonder, J, Merlini, G, Schönland, S, Walling, J, Kinney, GG, Koller, M, Schenk, DB, Guthrie, SD & Liedtke, M 2016, 'First-in-human phase I/II study of NEOD001 in patients with light chain amyloidosis and persistent organ dysfunction', Journal of Clinical Oncology, vol. 34, no. 10, pp. 1097-1103. https://doi.org/10.1200/JCO.2015.63.6530
Gertz, Morie ; Landau, Heather ; Comenzo, Raymond L. ; Seldin, David ; Weiss, Brendan ; Zonder, Jeffrey ; Merlini, Giampaolo ; Schönland, Stefan ; Walling, Jackie ; Kinney, Gene G. ; Koller, Martin ; Schenk, Dale B. ; Guthrie, Spencer D. ; Liedtke, Michaela. / First-in-human phase I/II study of NEOD001 in patients with light chain amyloidosis and persistent organ dysfunction. In: Journal of Clinical Oncology. 2016 ; Vol. 34, No. 10. pp. 1097-1103.
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abstract = "Purpose: Light chain (AL) amyloidosis is caused by the accumulation of misfolded proteins, which induces the dysfunction of vital organs. NEOD001 is a monoclonal antibody targeting these misfolded proteins. We report interim data from a phase I/II dose-escalation/expansion study of NEOD001 in patients with AL amyloidosis and persistent organ dysfunction (NCT01707264). Patients and Methods: Patients who had completed at least one previous anti-plasma cell-directed therapy, had partial hematologic response or better, and had persistent organ dysfunction received NEOD001 intravenously every 28 days. Dose levels of 0.5, 1, 2, 4, 8, 16, and 24 μg/kg were evaluated (3 + 3 study design). Primary objectives were to determine the maximum tolerated dose and the recommended dose for future studies and to evaluate safety/tolerability. Secondary and exploratory objectives included pharmacokinetics, immunogenicity, and organ responses on the basis of published consensus criteria. Results: Twenty-seven patients were enrolled in seven cohorts (dose-escalation component). No drugrelated serious adverse events (AEs), discontinuations because of drug-related AEs, dose-limiting toxicities, or antidrug antibodies were reported. The most frequent AEs were fatigue, upper respiratory tract infection, cough, and dyspnea. Recommended dosing was 24 μg/kg. Pharmacokinetics support intravenous dosing every 28 days. Of 14 cardiac-evaluable patients, eight (57{\%}) met the criteria for cardiac response and six (43{\%}) had stable disease. Of 15 renal-evaluable patients, nine (60{\%}) met the criteria for renal response and six (40{\%}) had stable disease. Conclusion: Monthly infusions of NEOD001 were safe and well tolerated. Recommended future dosing was 24 μg/kg. Organ response rates compared favorably with those reported previously for chemotherapy. A phase II expansion is ongoing. A global phase III study (NCT02312206) has been initiated. Antibody therapy targeting misfolded proteins is a potential new therapy for the management of AL amyloidosis.",
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AU - Landau, Heather

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AU - Seldin, David

AU - Weiss, Brendan

AU - Zonder, Jeffrey

AU - Merlini, Giampaolo

AU - Schönland, Stefan

AU - Walling, Jackie

AU - Kinney, Gene G.

AU - Koller, Martin

AU - Schenk, Dale B.

AU - Guthrie, Spencer D.

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N2 - Purpose: Light chain (AL) amyloidosis is caused by the accumulation of misfolded proteins, which induces the dysfunction of vital organs. NEOD001 is a monoclonal antibody targeting these misfolded proteins. We report interim data from a phase I/II dose-escalation/expansion study of NEOD001 in patients with AL amyloidosis and persistent organ dysfunction (NCT01707264). Patients and Methods: Patients who had completed at least one previous anti-plasma cell-directed therapy, had partial hematologic response or better, and had persistent organ dysfunction received NEOD001 intravenously every 28 days. Dose levels of 0.5, 1, 2, 4, 8, 16, and 24 μg/kg were evaluated (3 + 3 study design). Primary objectives were to determine the maximum tolerated dose and the recommended dose for future studies and to evaluate safety/tolerability. Secondary and exploratory objectives included pharmacokinetics, immunogenicity, and organ responses on the basis of published consensus criteria. Results: Twenty-seven patients were enrolled in seven cohorts (dose-escalation component). No drugrelated serious adverse events (AEs), discontinuations because of drug-related AEs, dose-limiting toxicities, or antidrug antibodies were reported. The most frequent AEs were fatigue, upper respiratory tract infection, cough, and dyspnea. Recommended dosing was 24 μg/kg. Pharmacokinetics support intravenous dosing every 28 days. Of 14 cardiac-evaluable patients, eight (57%) met the criteria for cardiac response and six (43%) had stable disease. Of 15 renal-evaluable patients, nine (60%) met the criteria for renal response and six (40%) had stable disease. Conclusion: Monthly infusions of NEOD001 were safe and well tolerated. Recommended future dosing was 24 μg/kg. Organ response rates compared favorably with those reported previously for chemotherapy. A phase II expansion is ongoing. A global phase III study (NCT02312206) has been initiated. Antibody therapy targeting misfolded proteins is a potential new therapy for the management of AL amyloidosis.

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