Phase Ia study of the indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor navoximod (GDC-0919) in patients with recurrent advanced solid tumors

Asha Nayak-Kapoor, Zhonglin Hao, Ramses Sadek, Robin Dobbins, Lisa Marshall, Nicholas N. Vahanian, W. Jay Ramsey, Eugene Kennedy, Mario R. Mautino, Charles J. Link, Ray S. Lin, Stephanie Royer-Joo, Xiaorong Liang, Laurent Salphati, Kari M. Morrissey, Sami Mahrus, Bruce McCall, Andrea Pirzkall, David H. Munn, John E. JanikSamir N. Khleif

Research output: Contribution to journalArticle

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Abstract

Background: Indoleamine-2,3-dioxygenase 1 (IDO1) catalyzes the oxidation of tryptophan into kynurenine and is partially responsible for acquired immune tolerance associated with cancer. The IDO1 small molecule inhibitor navoximod (GDC-0919, NLG-919) is active as a combination therapy in multiple tumor models. Methods: This open-label Phase Ia study assessed safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary anti-tumor activity of navoximod in patients with recurrent/advanced solid tumors, administered as 50-800 mg BID on a 21/28 day and at 600 mg on a 28/28 day schedule. Plasma kynurenine and tryptophan were longitudinally evaluated and tumor assessments were performed. Results: Patients (n = 22) received a median of 3 cycles of navoximod. No maximum tolerated dose was reached. One dose-limiting toxicity of Grade 4 lower gastrointestinal hemorrhage was reported. Adverse events (AEs) regardless of causality in ≥20% of patients included fatigue (59%), cough, decreased appetite, and pruritus (41% each), nausea (36%), and vomiting (27%). Grade ≥ 3 AEs occurred in 14/22 patients (64%), and were related to navoximod in two patients (9%). Navoximod was rapidly absorbed (Tmax ~ 1 h) and exhibited dose-proportional increases in exposure, with a half-life (t1/2 ~ 11 h) supportive of BID dosing. Navoximod transiently decreased plasma kynurenine from baseline levels with kinetics consistent with its half-life. Of efficacy-evaluable patients, 8 (36%) had stable disease and 10 (46%) had progressive disease. Conclusions: Navoximod was well-tolerated at doses up to 800 mg BID decreasing plasma kynurenine levels consistent with its half-life. Stable disease responses were observed. Trial registration: ClinicalTrials.gov identifier: NCT02048709.

Original languageEnglish (US)
Article number61
JournalJournal for ImmunoTherapy of Cancer
Volume6
Issue number1
DOIs
StatePublished - Jun 20 2018

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Indoleamine-Pyrrole 2,3,-Dioxygenase
Kynurenine
Half-Life
Neoplasms
Tryptophan
Immune Tolerance
Gastrointestinal Hemorrhage
Maximum Tolerated Dose
Appetite
Pruritus
Cough
Causality
Nausea
Vomiting
Fatigue
Appointments and Schedules
Pharmacokinetics
Safety

Keywords

  • IDO1
  • Kynurenine
  • Navoximod
  • Phase I
  • Tryptophan

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

Cite this

Phase Ia study of the indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor navoximod (GDC-0919) in patients with recurrent advanced solid tumors. / Nayak-Kapoor, Asha; Hao, Zhonglin; Sadek, Ramses; Dobbins, Robin; Marshall, Lisa; Vahanian, Nicholas N.; Jay Ramsey, W.; Kennedy, Eugene; Mautino, Mario R.; Link, Charles J.; Lin, Ray S.; Royer-Joo, Stephanie; Liang, Xiaorong; Salphati, Laurent; Morrissey, Kari M.; Mahrus, Sami; McCall, Bruce; Pirzkall, Andrea; Munn, David H.; Janik, John E.; Khleif, Samir N.

In: Journal for ImmunoTherapy of Cancer, Vol. 6, No. 1, 61, 20.06.2018.

Research output: Contribution to journalArticle

Nayak-Kapoor, A, Hao, Z, Sadek, R, Dobbins, R, Marshall, L, Vahanian, NN, Jay Ramsey, W, Kennedy, E, Mautino, MR, Link, CJ, Lin, RS, Royer-Joo, S, Liang, X, Salphati, L, Morrissey, KM, Mahrus, S, McCall, B, Pirzkall, A, Munn, DH, Janik, JE & Khleif, SN 2018, 'Phase Ia study of the indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor navoximod (GDC-0919) in patients with recurrent advanced solid tumors', Journal for ImmunoTherapy of Cancer, vol. 6, no. 1, 61. https://doi.org/10.1186/s40425-018-0351-9
Nayak-Kapoor, Asha ; Hao, Zhonglin ; Sadek, Ramses ; Dobbins, Robin ; Marshall, Lisa ; Vahanian, Nicholas N. ; Jay Ramsey, W. ; Kennedy, Eugene ; Mautino, Mario R. ; Link, Charles J. ; Lin, Ray S. ; Royer-Joo, Stephanie ; Liang, Xiaorong ; Salphati, Laurent ; Morrissey, Kari M. ; Mahrus, Sami ; McCall, Bruce ; Pirzkall, Andrea ; Munn, David H. ; Janik, John E. ; Khleif, Samir N. / Phase Ia study of the indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor navoximod (GDC-0919) in patients with recurrent advanced solid tumors. In: Journal for ImmunoTherapy of Cancer. 2018 ; Vol. 6, No. 1.
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abstract = "Background: Indoleamine-2,3-dioxygenase 1 (IDO1) catalyzes the oxidation of tryptophan into kynurenine and is partially responsible for acquired immune tolerance associated with cancer. The IDO1 small molecule inhibitor navoximod (GDC-0919, NLG-919) is active as a combination therapy in multiple tumor models. Methods: This open-label Phase Ia study assessed safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary anti-tumor activity of navoximod in patients with recurrent/advanced solid tumors, administered as 50-800 mg BID on a 21/28 day and at 600 mg on a 28/28 day schedule. Plasma kynurenine and tryptophan were longitudinally evaluated and tumor assessments were performed. Results: Patients (n = 22) received a median of 3 cycles of navoximod. No maximum tolerated dose was reached. One dose-limiting toxicity of Grade 4 lower gastrointestinal hemorrhage was reported. Adverse events (AEs) regardless of causality in ≥20{\%} of patients included fatigue (59{\%}), cough, decreased appetite, and pruritus (41{\%} each), nausea (36{\%}), and vomiting (27{\%}). Grade ≥ 3 AEs occurred in 14/22 patients (64{\%}), and were related to navoximod in two patients (9{\%}). Navoximod was rapidly absorbed (Tmax ~ 1 h) and exhibited dose-proportional increases in exposure, with a half-life (t1/2 ~ 11 h) supportive of BID dosing. Navoximod transiently decreased plasma kynurenine from baseline levels with kinetics consistent with its half-life. Of efficacy-evaluable patients, 8 (36{\%}) had stable disease and 10 (46{\%}) had progressive disease. Conclusions: Navoximod was well-tolerated at doses up to 800 mg BID decreasing plasma kynurenine levels consistent with its half-life. Stable disease responses were observed. Trial registration: ClinicalTrials.gov identifier: NCT02048709.",
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T1 - Phase Ia study of the indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor navoximod (GDC-0919) in patients with recurrent advanced solid tumors

AU - Nayak-Kapoor, Asha

AU - Hao, Zhonglin

AU - Sadek, Ramses

AU - Dobbins, Robin

AU - Marshall, Lisa

AU - Vahanian, Nicholas N.

AU - Jay Ramsey, W.

AU - Kennedy, Eugene

AU - Mautino, Mario R.

AU - Link, Charles J.

AU - Lin, Ray S.

AU - Royer-Joo, Stephanie

AU - Liang, Xiaorong

AU - Salphati, Laurent

AU - Morrissey, Kari M.

AU - Mahrus, Sami

AU - McCall, Bruce

AU - Pirzkall, Andrea

AU - Munn, David H.

AU - Janik, John E.

AU - Khleif, Samir N.

PY - 2018/6/20

Y1 - 2018/6/20

N2 - Background: Indoleamine-2,3-dioxygenase 1 (IDO1) catalyzes the oxidation of tryptophan into kynurenine and is partially responsible for acquired immune tolerance associated with cancer. The IDO1 small molecule inhibitor navoximod (GDC-0919, NLG-919) is active as a combination therapy in multiple tumor models. Methods: This open-label Phase Ia study assessed safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary anti-tumor activity of navoximod in patients with recurrent/advanced solid tumors, administered as 50-800 mg BID on a 21/28 day and at 600 mg on a 28/28 day schedule. Plasma kynurenine and tryptophan were longitudinally evaluated and tumor assessments were performed. Results: Patients (n = 22) received a median of 3 cycles of navoximod. No maximum tolerated dose was reached. One dose-limiting toxicity of Grade 4 lower gastrointestinal hemorrhage was reported. Adverse events (AEs) regardless of causality in ≥20% of patients included fatigue (59%), cough, decreased appetite, and pruritus (41% each), nausea (36%), and vomiting (27%). Grade ≥ 3 AEs occurred in 14/22 patients (64%), and were related to navoximod in two patients (9%). Navoximod was rapidly absorbed (Tmax ~ 1 h) and exhibited dose-proportional increases in exposure, with a half-life (t1/2 ~ 11 h) supportive of BID dosing. Navoximod transiently decreased plasma kynurenine from baseline levels with kinetics consistent with its half-life. Of efficacy-evaluable patients, 8 (36%) had stable disease and 10 (46%) had progressive disease. Conclusions: Navoximod was well-tolerated at doses up to 800 mg BID decreasing plasma kynurenine levels consistent with its half-life. Stable disease responses were observed. Trial registration: ClinicalTrials.gov identifier: NCT02048709.

AB - Background: Indoleamine-2,3-dioxygenase 1 (IDO1) catalyzes the oxidation of tryptophan into kynurenine and is partially responsible for acquired immune tolerance associated with cancer. The IDO1 small molecule inhibitor navoximod (GDC-0919, NLG-919) is active as a combination therapy in multiple tumor models. Methods: This open-label Phase Ia study assessed safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary anti-tumor activity of navoximod in patients with recurrent/advanced solid tumors, administered as 50-800 mg BID on a 21/28 day and at 600 mg on a 28/28 day schedule. Plasma kynurenine and tryptophan were longitudinally evaluated and tumor assessments were performed. Results: Patients (n = 22) received a median of 3 cycles of navoximod. No maximum tolerated dose was reached. One dose-limiting toxicity of Grade 4 lower gastrointestinal hemorrhage was reported. Adverse events (AEs) regardless of causality in ≥20% of patients included fatigue (59%), cough, decreased appetite, and pruritus (41% each), nausea (36%), and vomiting (27%). Grade ≥ 3 AEs occurred in 14/22 patients (64%), and were related to navoximod in two patients (9%). Navoximod was rapidly absorbed (Tmax ~ 1 h) and exhibited dose-proportional increases in exposure, with a half-life (t1/2 ~ 11 h) supportive of BID dosing. Navoximod transiently decreased plasma kynurenine from baseline levels with kinetics consistent with its half-life. Of efficacy-evaluable patients, 8 (36%) had stable disease and 10 (46%) had progressive disease. Conclusions: Navoximod was well-tolerated at doses up to 800 mg BID decreasing plasma kynurenine levels consistent with its half-life. Stable disease responses were observed. Trial registration: ClinicalTrials.gov identifier: NCT02048709.

KW - IDO1

KW - Kynurenine

KW - Navoximod

KW - Phase I

KW - Tryptophan

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