Phase 1 study of narnatumab, an anti-RON receptor monoclonal antibody, in patients with advanced solid tumors

Patricia M. LoRusso, Mrinal Gounder, Shadia Jalal, Valérie André, Siva Rama Prasad Kambhampati, Nick Loizos, Jennifer Hall, Timothy R. Holzer, Aejaz Nasir, Jan Cosaert, John Kauh, E. Gabriela Chiorean

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Summary: Purpose Macrophage-stimulating 1-receptor (RON) is expressed on macrophages, epithelial cells, and a variety of tumors. Narnatumab (IMC-RON8; LY3012219) is a neutralizing monoclonal antibody that blocks RON binding to its ligand, macrophage-stimulating protein (MSP). This study assessed safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and efficacy of narnatumab in patients with advanced solid tumors. Methods Narnatumab was administered intravenously weekly at 5, 10, 15, or 20 mg/kg or every 2 weeks at 15, 20, 30, or 40 mg/kg in 4-week cycles. Results Thirty-nine patients were treated, and 1 dose-limiting toxicity (DLT) (grade 3 hyponatremia, 5 mg/kg) was reported. The most common narnatumab-related adverse events (AEs) were fatigue (20.5%) and decreased appetite, diarrhea, nausea, and vomiting (10.3% each). Except for 2 treatment-related grade 3 AEs (hyponatremia, hypokalemia), all treatment-related AEs were grade 1 or 2. Narnatumab had a short half-life (<7 days). After Cycle 2, no patients had concentrations above 140 μg/mL (concentration that demonstrated antitumor activity in animal models), except for 1 patient receiving 30 mg/kg biweekly. Eleven patients had a best response of stable disease, ranging from 6 weeks to 11 months. Despite only 1 DLT, due to suboptimal drug exposure, the dose was not escalated beyond 40 mg/kg biweekly. This decision was based on published data reporting that mRNA splice variants of RON are highly prevalent in tumors, accumulate in cytoplasm, and are not accessible by large-molecule monoclonal antibodies. Conclusions Narnatumab was well tolerated and showed limited antitumor activity with this dosing regimen.

Original languageEnglish (US)
Pages (from-to)1-9
Number of pages9
JournalInvestigational New Drugs
DOIs
StateAccepted/In press - Feb 4 2017

Fingerprint

Monoclonal Antibodies
Hyponatremia
Neoplasms
Macrophages
Maximum Tolerated Dose
Hypokalemia
Appetite
Neutralizing Antibodies
Nausea
Vomiting
Fatigue
Half-Life
Diarrhea
Cytoplasm
Research Design
Animal Models
Pharmacokinetics
Epithelial Cells
rice bran saccharide
Ligands

Keywords

  • IMC-RON8
  • Macrophage-stimulating protein receptor
  • Narnatumab
  • Phase 1
  • RON
  • Solid tumors

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)

Cite this

LoRusso, P. M., Gounder, M., Jalal, S., André, V., Kambhampati, S. R. P., Loizos, N., ... Chiorean, E. G. (Accepted/In press). Phase 1 study of narnatumab, an anti-RON receptor monoclonal antibody, in patients with advanced solid tumors. Investigational New Drugs, 1-9. https://doi.org/10.1007/s10637-016-0413-0

Phase 1 study of narnatumab, an anti-RON receptor monoclonal antibody, in patients with advanced solid tumors. / LoRusso, Patricia M.; Gounder, Mrinal; Jalal, Shadia; André, Valérie; Kambhampati, Siva Rama Prasad; Loizos, Nick; Hall, Jennifer; Holzer, Timothy R.; Nasir, Aejaz; Cosaert, Jan; Kauh, John; Chiorean, E. Gabriela.

In: Investigational New Drugs, 04.02.2017, p. 1-9.

Research output: Contribution to journalArticle

LoRusso, PM, Gounder, M, Jalal, S, André, V, Kambhampati, SRP, Loizos, N, Hall, J, Holzer, TR, Nasir, A, Cosaert, J, Kauh, J & Chiorean, EG 2017, 'Phase 1 study of narnatumab, an anti-RON receptor monoclonal antibody, in patients with advanced solid tumors', Investigational New Drugs, pp. 1-9. https://doi.org/10.1007/s10637-016-0413-0
LoRusso, Patricia M. ; Gounder, Mrinal ; Jalal, Shadia ; André, Valérie ; Kambhampati, Siva Rama Prasad ; Loizos, Nick ; Hall, Jennifer ; Holzer, Timothy R. ; Nasir, Aejaz ; Cosaert, Jan ; Kauh, John ; Chiorean, E. Gabriela. / Phase 1 study of narnatumab, an anti-RON receptor monoclonal antibody, in patients with advanced solid tumors. In: Investigational New Drugs. 2017 ; pp. 1-9.
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abstract = "Summary: Purpose Macrophage-stimulating 1-receptor (RON) is expressed on macrophages, epithelial cells, and a variety of tumors. Narnatumab (IMC-RON8; LY3012219) is a neutralizing monoclonal antibody that blocks RON binding to its ligand, macrophage-stimulating protein (MSP). This study assessed safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and efficacy of narnatumab in patients with advanced solid tumors. Methods Narnatumab was administered intravenously weekly at 5, 10, 15, or 20 mg/kg or every 2 weeks at 15, 20, 30, or 40 mg/kg in 4-week cycles. Results Thirty-nine patients were treated, and 1 dose-limiting toxicity (DLT) (grade 3 hyponatremia, 5 mg/kg) was reported. The most common narnatumab-related adverse events (AEs) were fatigue (20.5{\%}) and decreased appetite, diarrhea, nausea, and vomiting (10.3{\%} each). Except for 2 treatment-related grade 3 AEs (hyponatremia, hypokalemia), all treatment-related AEs were grade 1 or 2. Narnatumab had a short half-life (<7 days). After Cycle 2, no patients had concentrations above 140 μg/mL (concentration that demonstrated antitumor activity in animal models), except for 1 patient receiving 30 mg/kg biweekly. Eleven patients had a best response of stable disease, ranging from 6 weeks to 11 months. Despite only 1 DLT, due to suboptimal drug exposure, the dose was not escalated beyond 40 mg/kg biweekly. This decision was based on published data reporting that mRNA splice variants of RON are highly prevalent in tumors, accumulate in cytoplasm, and are not accessible by large-molecule monoclonal antibodies. Conclusions Narnatumab was well tolerated and showed limited antitumor activity with this dosing regimen.",
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T1 - Phase 1 study of narnatumab, an anti-RON receptor monoclonal antibody, in patients with advanced solid tumors

AU - LoRusso, Patricia M.

AU - Gounder, Mrinal

AU - Jalal, Shadia

AU - André, Valérie

AU - Kambhampati, Siva Rama Prasad

AU - Loizos, Nick

AU - Hall, Jennifer

AU - Holzer, Timothy R.

AU - Nasir, Aejaz

AU - Cosaert, Jan

AU - Kauh, John

AU - Chiorean, E. Gabriela

PY - 2017/2/4

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N2 - Summary: Purpose Macrophage-stimulating 1-receptor (RON) is expressed on macrophages, epithelial cells, and a variety of tumors. Narnatumab (IMC-RON8; LY3012219) is a neutralizing monoclonal antibody that blocks RON binding to its ligand, macrophage-stimulating protein (MSP). This study assessed safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and efficacy of narnatumab in patients with advanced solid tumors. Methods Narnatumab was administered intravenously weekly at 5, 10, 15, or 20 mg/kg or every 2 weeks at 15, 20, 30, or 40 mg/kg in 4-week cycles. Results Thirty-nine patients were treated, and 1 dose-limiting toxicity (DLT) (grade 3 hyponatremia, 5 mg/kg) was reported. The most common narnatumab-related adverse events (AEs) were fatigue (20.5%) and decreased appetite, diarrhea, nausea, and vomiting (10.3% each). Except for 2 treatment-related grade 3 AEs (hyponatremia, hypokalemia), all treatment-related AEs were grade 1 or 2. Narnatumab had a short half-life (<7 days). After Cycle 2, no patients had concentrations above 140 μg/mL (concentration that demonstrated antitumor activity in animal models), except for 1 patient receiving 30 mg/kg biweekly. Eleven patients had a best response of stable disease, ranging from 6 weeks to 11 months. Despite only 1 DLT, due to suboptimal drug exposure, the dose was not escalated beyond 40 mg/kg biweekly. This decision was based on published data reporting that mRNA splice variants of RON are highly prevalent in tumors, accumulate in cytoplasm, and are not accessible by large-molecule monoclonal antibodies. Conclusions Narnatumab was well tolerated and showed limited antitumor activity with this dosing regimen.

AB - Summary: Purpose Macrophage-stimulating 1-receptor (RON) is expressed on macrophages, epithelial cells, and a variety of tumors. Narnatumab (IMC-RON8; LY3012219) is a neutralizing monoclonal antibody that blocks RON binding to its ligand, macrophage-stimulating protein (MSP). This study assessed safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and efficacy of narnatumab in patients with advanced solid tumors. Methods Narnatumab was administered intravenously weekly at 5, 10, 15, or 20 mg/kg or every 2 weeks at 15, 20, 30, or 40 mg/kg in 4-week cycles. Results Thirty-nine patients were treated, and 1 dose-limiting toxicity (DLT) (grade 3 hyponatremia, 5 mg/kg) was reported. The most common narnatumab-related adverse events (AEs) were fatigue (20.5%) and decreased appetite, diarrhea, nausea, and vomiting (10.3% each). Except for 2 treatment-related grade 3 AEs (hyponatremia, hypokalemia), all treatment-related AEs were grade 1 or 2. Narnatumab had a short half-life (<7 days). After Cycle 2, no patients had concentrations above 140 μg/mL (concentration that demonstrated antitumor activity in animal models), except for 1 patient receiving 30 mg/kg biweekly. Eleven patients had a best response of stable disease, ranging from 6 weeks to 11 months. Despite only 1 DLT, due to suboptimal drug exposure, the dose was not escalated beyond 40 mg/kg biweekly. This decision was based on published data reporting that mRNA splice variants of RON are highly prevalent in tumors, accumulate in cytoplasm, and are not accessible by large-molecule monoclonal antibodies. Conclusions Narnatumab was well tolerated and showed limited antitumor activity with this dosing regimen.

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