A phase 1, first-in-human study of AMG 900, an orally administered pan-Aurora kinase inhibitor, in adult patients with advanced solid tumors

Michael A Carducci, Montaser Shaheen, Ben Markman, Sara Hurvitz, Daruka Mahadevan, Dusan Kotasek, Oscar B. Goodman, Erik Rasmussen, Vincent Chow, Gloria Juan, Gregory R. Friberg, Erick Gamelin, Florian D. Vogl, Jayesh Desai

Research output: Contribution to journalArticle

Abstract

Summary: Background Aurora kinase overexpression or amplifications are associated with high proliferation, poor prognosis, and therapeutic resistance in human tumors. AMG 900 is an investigational, oral, selective pan-Aurora kinase inhibitor. Methods This first-in-human trial included dose-escalation and dose-expansion phases (ClinicalTrials.gov: NCT00858377). Dose escalation evaluated the safety, tolerability, and pharmacokinetics of AMG 900 in advanced solid tumors and determined the maximum tolerated dose (MTD) with/without granulocyte colony-stimulating factor (G-CSF) prophylaxis. Dose expansion evaluated clinical activity in three tumor types: taxane- and platinum-resistant ovarian cancer, taxane-resistant triple-negative breast cancer (TNBC), and castration-resistant and taxane- or cisplatin/etoposide–resistant prostate cancer (CRPC). AMG 900 was administered 4 days on/10 days off at 1–50 mg/day during escalation and at the MTD with G-CSF during expansion. Results AMG 900 showed rapid absorption with fast clearance, supporting once-daily dosing. The MTD was 25 mg/day, increasing to 40 mg/day with G-CSF. Grade ≥ 3 treatment-related adverse events included neutropenia (37%), anemia (23%), leukopenia (14%), and thrombocytopenia (12%). During dose expansion, 3/29 (10.3%, 95% CI: 2.0%–28.0%) evaluable patients with ovarian cancer experienced partial response by central imaging per RECIST 1.1; median duration of response was 24.1 weeks (95% CI: 16.1–34.1). Seven patients (24.1%, 95% CI: 10.3%–43.5%) experienced partial response per Gynecologic Cancer InterGroup criteria; 5/9 patients positive for p53 expression responded to treatment. No objective responses were observed in patients with TNBC or CRPC per RECIST 1.1. Conclusions AMG 900 40 mg/day with G-CSF had manageable toxicity and demonstrated single-agent activity in patients with heavily pretreated, chemotherapy-resistant ovarian cancer.

Original languageEnglish (US)
Pages (from-to)1-12
Number of pages12
JournalInvestigational New Drugs
DOIs
StateAccepted/In press - Jul 7 2018

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Aurora Kinases
Granulocyte Colony-Stimulating Factor
Maximum Tolerated Dose
Ovarian Neoplasms
Triple Negative Breast Neoplasms
Neoplasms
Cisplatin
Prostatic Neoplasms
Castration
Leukopenia
Neutropenia
Platinum
Thrombocytopenia
Anemia
Therapeutics
Pharmacokinetics
N-(4-((3-(2-amino-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-4-(4-methyl-2-thienyl)-1-phthalazinamine
Safety
Drug Therapy
taxane

Keywords

  • AMG 900
  • Antimitotic
  • Aurora kinase
  • pan-Aurora kinase inhibitor

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)

Cite this

A phase 1, first-in-human study of AMG 900, an orally administered pan-Aurora kinase inhibitor, in adult patients with advanced solid tumors. / Carducci, Michael A; Shaheen, Montaser; Markman, Ben; Hurvitz, Sara; Mahadevan, Daruka; Kotasek, Dusan; Goodman, Oscar B.; Rasmussen, Erik; Chow, Vincent; Juan, Gloria; Friberg, Gregory R.; Gamelin, Erick; Vogl, Florian D.; Desai, Jayesh.

In: Investigational New Drugs, 07.07.2018, p. 1-12.

Research output: Contribution to journalArticle

Carducci, MA, Shaheen, M, Markman, B, Hurvitz, S, Mahadevan, D, Kotasek, D, Goodman, OB, Rasmussen, E, Chow, V, Juan, G, Friberg, GR, Gamelin, E, Vogl, FD & Desai, J 2018, 'A phase 1, first-in-human study of AMG 900, an orally administered pan-Aurora kinase inhibitor, in adult patients with advanced solid tumors', Investigational New Drugs, pp. 1-12. https://doi.org/10.1007/s10637-018-0625-6
Carducci, Michael A ; Shaheen, Montaser ; Markman, Ben ; Hurvitz, Sara ; Mahadevan, Daruka ; Kotasek, Dusan ; Goodman, Oscar B. ; Rasmussen, Erik ; Chow, Vincent ; Juan, Gloria ; Friberg, Gregory R. ; Gamelin, Erick ; Vogl, Florian D. ; Desai, Jayesh. / A phase 1, first-in-human study of AMG 900, an orally administered pan-Aurora kinase inhibitor, in adult patients with advanced solid tumors. In: Investigational New Drugs. 2018 ; pp. 1-12.
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abstract = "Summary: Background Aurora kinase overexpression or amplifications are associated with high proliferation, poor prognosis, and therapeutic resistance in human tumors. AMG 900 is an investigational, oral, selective pan-Aurora kinase inhibitor. Methods This first-in-human trial included dose-escalation and dose-expansion phases (ClinicalTrials.gov: NCT00858377). Dose escalation evaluated the safety, tolerability, and pharmacokinetics of AMG 900 in advanced solid tumors and determined the maximum tolerated dose (MTD) with/without granulocyte colony-stimulating factor (G-CSF) prophylaxis. Dose expansion evaluated clinical activity in three tumor types: taxane- and platinum-resistant ovarian cancer, taxane-resistant triple-negative breast cancer (TNBC), and castration-resistant and taxane- or cisplatin/etoposide–resistant prostate cancer (CRPC). AMG 900 was administered 4 days on/10 days off at 1–50 mg/day during escalation and at the MTD with G-CSF during expansion. Results AMG 900 showed rapid absorption with fast clearance, supporting once-daily dosing. The MTD was 25 mg/day, increasing to 40 mg/day with G-CSF. Grade ≥ 3 treatment-related adverse events included neutropenia (37{\%}), anemia (23{\%}), leukopenia (14{\%}), and thrombocytopenia (12{\%}). During dose expansion, 3/29 (10.3{\%}, 95{\%} CI: 2.0{\%}–28.0{\%}) evaluable patients with ovarian cancer experienced partial response by central imaging per RECIST 1.1; median duration of response was 24.1 weeks (95{\%} CI: 16.1–34.1). Seven patients (24.1{\%}, 95{\%} CI: 10.3{\%}–43.5{\%}) experienced partial response per Gynecologic Cancer InterGroup criteria; 5/9 patients positive for p53 expression responded to treatment. No objective responses were observed in patients with TNBC or CRPC per RECIST 1.1. Conclusions AMG 900 40 mg/day with G-CSF had manageable toxicity and demonstrated single-agent activity in patients with heavily pretreated, chemotherapy-resistant ovarian cancer.",
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T1 - A phase 1, first-in-human study of AMG 900, an orally administered pan-Aurora kinase inhibitor, in adult patients with advanced solid tumors

AU - Carducci, Michael A

AU - Shaheen, Montaser

AU - Markman, Ben

AU - Hurvitz, Sara

AU - Mahadevan, Daruka

AU - Kotasek, Dusan

AU - Goodman, Oscar B.

AU - Rasmussen, Erik

AU - Chow, Vincent

AU - Juan, Gloria

AU - Friberg, Gregory R.

AU - Gamelin, Erick

AU - Vogl, Florian D.

AU - Desai, Jayesh

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N2 - Summary: Background Aurora kinase overexpression or amplifications are associated with high proliferation, poor prognosis, and therapeutic resistance in human tumors. AMG 900 is an investigational, oral, selective pan-Aurora kinase inhibitor. Methods This first-in-human trial included dose-escalation and dose-expansion phases (ClinicalTrials.gov: NCT00858377). Dose escalation evaluated the safety, tolerability, and pharmacokinetics of AMG 900 in advanced solid tumors and determined the maximum tolerated dose (MTD) with/without granulocyte colony-stimulating factor (G-CSF) prophylaxis. Dose expansion evaluated clinical activity in three tumor types: taxane- and platinum-resistant ovarian cancer, taxane-resistant triple-negative breast cancer (TNBC), and castration-resistant and taxane- or cisplatin/etoposide–resistant prostate cancer (CRPC). AMG 900 was administered 4 days on/10 days off at 1–50 mg/day during escalation and at the MTD with G-CSF during expansion. Results AMG 900 showed rapid absorption with fast clearance, supporting once-daily dosing. The MTD was 25 mg/day, increasing to 40 mg/day with G-CSF. Grade ≥ 3 treatment-related adverse events included neutropenia (37%), anemia (23%), leukopenia (14%), and thrombocytopenia (12%). During dose expansion, 3/29 (10.3%, 95% CI: 2.0%–28.0%) evaluable patients with ovarian cancer experienced partial response by central imaging per RECIST 1.1; median duration of response was 24.1 weeks (95% CI: 16.1–34.1). Seven patients (24.1%, 95% CI: 10.3%–43.5%) experienced partial response per Gynecologic Cancer InterGroup criteria; 5/9 patients positive for p53 expression responded to treatment. No objective responses were observed in patients with TNBC or CRPC per RECIST 1.1. Conclusions AMG 900 40 mg/day with G-CSF had manageable toxicity and demonstrated single-agent activity in patients with heavily pretreated, chemotherapy-resistant ovarian cancer.

AB - Summary: Background Aurora kinase overexpression or amplifications are associated with high proliferation, poor prognosis, and therapeutic resistance in human tumors. AMG 900 is an investigational, oral, selective pan-Aurora kinase inhibitor. Methods This first-in-human trial included dose-escalation and dose-expansion phases (ClinicalTrials.gov: NCT00858377). Dose escalation evaluated the safety, tolerability, and pharmacokinetics of AMG 900 in advanced solid tumors and determined the maximum tolerated dose (MTD) with/without granulocyte colony-stimulating factor (G-CSF) prophylaxis. Dose expansion evaluated clinical activity in three tumor types: taxane- and platinum-resistant ovarian cancer, taxane-resistant triple-negative breast cancer (TNBC), and castration-resistant and taxane- or cisplatin/etoposide–resistant prostate cancer (CRPC). AMG 900 was administered 4 days on/10 days off at 1–50 mg/day during escalation and at the MTD with G-CSF during expansion. Results AMG 900 showed rapid absorption with fast clearance, supporting once-daily dosing. The MTD was 25 mg/day, increasing to 40 mg/day with G-CSF. Grade ≥ 3 treatment-related adverse events included neutropenia (37%), anemia (23%), leukopenia (14%), and thrombocytopenia (12%). During dose expansion, 3/29 (10.3%, 95% CI: 2.0%–28.0%) evaluable patients with ovarian cancer experienced partial response by central imaging per RECIST 1.1; median duration of response was 24.1 weeks (95% CI: 16.1–34.1). Seven patients (24.1%, 95% CI: 10.3%–43.5%) experienced partial response per Gynecologic Cancer InterGroup criteria; 5/9 patients positive for p53 expression responded to treatment. No objective responses were observed in patients with TNBC or CRPC per RECIST 1.1. Conclusions AMG 900 40 mg/day with G-CSF had manageable toxicity and demonstrated single-agent activity in patients with heavily pretreated, chemotherapy-resistant ovarian cancer.

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