Treatment with PF-04449913, an oral smoothened antagonist, in patients with myeloid malignancies: A phase 1 safety and pharmacokinetics study

Giovanni Martinelli, Vivian G. Oehler, Cristina Papayannidis, Rachel Courtney, M. Naveed Shaik, Xiaoxi Zhang, Ashleigh O'Connell, Karen R. McLachlan, Xianxian Zheng, Jerald Radich, Michele Baccarani, Hagop M. Kantarjian, Wendy J. Levin, Jorge E. Cortes, Catriona Jamieson

Research output: Contribution to journalArticle

Abstract

BACKGROUND: Activation of the Hedgehog signalling pathway contributes to cancer progression and the development of myeloid leukaemia stem cell therapeutic resistance. We aimed to identify the maximum tolerated dose (MTD) and the recommended phase 2 dose of the selective Hedgehog antagonist PF-04449913 in myeloid malignancies. METHODS: We undertook an open-label, dose-finding, standard 3+3 design phase 1 study of PF-04449913 in adult patients with acute myeloid leukaemia, chronic myeloid leukaemia, chronic myelomonocytic leukaemia, myelodysplastic syndrome, or myelofibrosis who were refractory, resistant, or intolerant to previous treatments, at three centres in the USA and one in Italy. Patients who had newly diagnosed, untreated disease were included if they were not eligible for standard treatment options or if standard treatments were not deemed appropriate. Patients received PF-04449913 once daily continuously until disease progression, unacceptable toxic effects, or patient withdrawal for up to 12 28-day cycles. Additional cycles were given if patients showed evidence of clinical benefit. The starting dose was 5 mg and was increased by 100% until the first dose-limiting toxic effect (DLT) and by 50% thereafter, in keeping with a 3+3 clinical trial statistical design. The primary endpoint was first-cycle DLTs. Secondary endpoints were safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary clinical activity. This trial is registered with ClinicalTrials.gov, number NCT00953758. FINDINGS: Between March 24, 2010, and Sept 7, 2012, 47 patients were enrolled and included in the study: 28 with acute myeloid leukaemia, six with myelodysplastic syndrome, five with chronic myeloid leukaemia (two with chronic-phase and three with blast-phase disease), one with chronic myelomonocytic leukaemia, and seven with myelofibrosis. Patients received PF-04449913 once daily at 5 mg (n=3), 10 mg (n=3), 20 mg (n=4), 40 mg (n=4), 80 mg (n=8), 120 mg (n=3), 180 mg (n=3), 270 mg (n=5), 400 mg (n=9), and 600 mg (n=5). Two patients experienced DLTs (one each in the 80 mg and 600 mg dose groups). The MTD for PF-04449913 was established to be 400 mg once daily. Of the 47 patients enrolled, 28 (60%) experienced treatment-related adverse events, three of which were grade 4 in severity. The most common treatment-related adverse events included dysgeusia (13 [28%] patients), decreased appetite (nine [19%]), and alopecia (seven [15%]). None of the 15 deaths reported were treatment related. Pharmacokinetics seemed to be dose proportional. The mean half-life was 23·9 h (SD 14·0) in the MTD group. Some suggestion of clinical activity was noted in 23 (49%) of 47 patients with haematological malignancies. Based on these results, the recommended phase 2 dose was 200 mg or lower once daily. INTERPRETATION: Based on these findings, PF-04449913 is being tested in phase 2 studies in patients with myelodysplastic syndrome, acute myeloid leukaemia, and myelofibrosis. FUNDING: Pfizer.

Original languageEnglish (US)
Pages (from-to)e339-e346
JournalThe Lancet Haematology
Volume2
Issue number8
DOIs
StatePublished - Jan 1 2015
Externally publishedYes

Fingerprint

Pharmacokinetics
Safety
Neoplasms
Primary Myelofibrosis
Maximum Tolerated Dose
Myelodysplastic Syndromes
Therapeutics
Acute Myeloid Leukemia
Leukemia, Myelomonocytic, Chronic
Poisons
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
1-(2-(1H-benzo(d)imidazol-2-yl)-1-methylpiperidin-4-yl)-3-(4-cyanophenyl)urea
Dysgeusia
Myeloid Progenitor Cells
Blast Crisis
Myeloid Leukemia
Alopecia
Appetite
Hematologic Neoplasms
Italy

ASJC Scopus subject areas

  • Hematology

Cite this

Treatment with PF-04449913, an oral smoothened antagonist, in patients with myeloid malignancies : A phase 1 safety and pharmacokinetics study. / Martinelli, Giovanni; Oehler, Vivian G.; Papayannidis, Cristina; Courtney, Rachel; Shaik, M. Naveed; Zhang, Xiaoxi; O'Connell, Ashleigh; McLachlan, Karen R.; Zheng, Xianxian; Radich, Jerald; Baccarani, Michele; Kantarjian, Hagop M.; Levin, Wendy J.; Cortes, Jorge E.; Jamieson, Catriona.

In: The Lancet Haematology, Vol. 2, No. 8, 01.01.2015, p. e339-e346.

Research output: Contribution to journalArticle

Martinelli, G, Oehler, VG, Papayannidis, C, Courtney, R, Shaik, MN, Zhang, X, O'Connell, A, McLachlan, KR, Zheng, X, Radich, J, Baccarani, M, Kantarjian, HM, Levin, WJ, Cortes, JE & Jamieson, C 2015, 'Treatment with PF-04449913, an oral smoothened antagonist, in patients with myeloid malignancies: A phase 1 safety and pharmacokinetics study', The Lancet Haematology, vol. 2, no. 8, pp. e339-e346. https://doi.org/10.1016/S2352-3026(15)00096-4
Martinelli, Giovanni ; Oehler, Vivian G. ; Papayannidis, Cristina ; Courtney, Rachel ; Shaik, M. Naveed ; Zhang, Xiaoxi ; O'Connell, Ashleigh ; McLachlan, Karen R. ; Zheng, Xianxian ; Radich, Jerald ; Baccarani, Michele ; Kantarjian, Hagop M. ; Levin, Wendy J. ; Cortes, Jorge E. ; Jamieson, Catriona. / Treatment with PF-04449913, an oral smoothened antagonist, in patients with myeloid malignancies : A phase 1 safety and pharmacokinetics study. In: The Lancet Haematology. 2015 ; Vol. 2, No. 8. pp. e339-e346.
@article{36218e6665e344289b8f644e81a242a0,
title = "Treatment with PF-04449913, an oral smoothened antagonist, in patients with myeloid malignancies: A phase 1 safety and pharmacokinetics study",
abstract = "BACKGROUND: Activation of the Hedgehog signalling pathway contributes to cancer progression and the development of myeloid leukaemia stem cell therapeutic resistance. We aimed to identify the maximum tolerated dose (MTD) and the recommended phase 2 dose of the selective Hedgehog antagonist PF-04449913 in myeloid malignancies. METHODS: We undertook an open-label, dose-finding, standard 3+3 design phase 1 study of PF-04449913 in adult patients with acute myeloid leukaemia, chronic myeloid leukaemia, chronic myelomonocytic leukaemia, myelodysplastic syndrome, or myelofibrosis who were refractory, resistant, or intolerant to previous treatments, at three centres in the USA and one in Italy. Patients who had newly diagnosed, untreated disease were included if they were not eligible for standard treatment options or if standard treatments were not deemed appropriate. Patients received PF-04449913 once daily continuously until disease progression, unacceptable toxic effects, or patient withdrawal for up to 12 28-day cycles. Additional cycles were given if patients showed evidence of clinical benefit. The starting dose was 5 mg and was increased by 100{\%} until the first dose-limiting toxic effect (DLT) and by 50{\%} thereafter, in keeping with a 3+3 clinical trial statistical design. The primary endpoint was first-cycle DLTs. Secondary endpoints were safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary clinical activity. This trial is registered with ClinicalTrials.gov, number NCT00953758. FINDINGS: Between March 24, 2010, and Sept 7, 2012, 47 patients were enrolled and included in the study: 28 with acute myeloid leukaemia, six with myelodysplastic syndrome, five with chronic myeloid leukaemia (two with chronic-phase and three with blast-phase disease), one with chronic myelomonocytic leukaemia, and seven with myelofibrosis. Patients received PF-04449913 once daily at 5 mg (n=3), 10 mg (n=3), 20 mg (n=4), 40 mg (n=4), 80 mg (n=8), 120 mg (n=3), 180 mg (n=3), 270 mg (n=5), 400 mg (n=9), and 600 mg (n=5). Two patients experienced DLTs (one each in the 80 mg and 600 mg dose groups). The MTD for PF-04449913 was established to be 400 mg once daily. Of the 47 patients enrolled, 28 (60{\%}) experienced treatment-related adverse events, three of which were grade 4 in severity. The most common treatment-related adverse events included dysgeusia (13 [28{\%}] patients), decreased appetite (nine [19{\%}]), and alopecia (seven [15{\%}]). None of the 15 deaths reported were treatment related. Pharmacokinetics seemed to be dose proportional. The mean half-life was 23·9 h (SD 14·0) in the MTD group. Some suggestion of clinical activity was noted in 23 (49{\%}) of 47 patients with haematological malignancies. Based on these results, the recommended phase 2 dose was 200 mg or lower once daily. INTERPRETATION: Based on these findings, PF-04449913 is being tested in phase 2 studies in patients with myelodysplastic syndrome, acute myeloid leukaemia, and myelofibrosis. FUNDING: Pfizer.",
author = "Giovanni Martinelli and Oehler, {Vivian G.} and Cristina Papayannidis and Rachel Courtney and Shaik, {M. Naveed} and Xiaoxi Zhang and Ashleigh O'Connell and McLachlan, {Karen R.} and Xianxian Zheng and Jerald Radich and Michele Baccarani and Kantarjian, {Hagop M.} and Levin, {Wendy J.} and Cortes, {Jorge E.} and Catriona Jamieson",
year = "2015",
month = "1",
day = "1",
doi = "10.1016/S2352-3026(15)00096-4",
language = "English (US)",
volume = "2",
pages = "e339--e346",
journal = "The Lancet Haematology",
issn = "2352-3026",
publisher = "Lancet Publishing Group",
number = "8",

}

TY - JOUR

T1 - Treatment with PF-04449913, an oral smoothened antagonist, in patients with myeloid malignancies

T2 - A phase 1 safety and pharmacokinetics study

AU - Martinelli, Giovanni

AU - Oehler, Vivian G.

AU - Papayannidis, Cristina

AU - Courtney, Rachel

AU - Shaik, M. Naveed

AU - Zhang, Xiaoxi

AU - O'Connell, Ashleigh

AU - McLachlan, Karen R.

AU - Zheng, Xianxian

AU - Radich, Jerald

AU - Baccarani, Michele

AU - Kantarjian, Hagop M.

AU - Levin, Wendy J.

AU - Cortes, Jorge E.

AU - Jamieson, Catriona

PY - 2015/1/1

Y1 - 2015/1/1

N2 - BACKGROUND: Activation of the Hedgehog signalling pathway contributes to cancer progression and the development of myeloid leukaemia stem cell therapeutic resistance. We aimed to identify the maximum tolerated dose (MTD) and the recommended phase 2 dose of the selective Hedgehog antagonist PF-04449913 in myeloid malignancies. METHODS: We undertook an open-label, dose-finding, standard 3+3 design phase 1 study of PF-04449913 in adult patients with acute myeloid leukaemia, chronic myeloid leukaemia, chronic myelomonocytic leukaemia, myelodysplastic syndrome, or myelofibrosis who were refractory, resistant, or intolerant to previous treatments, at three centres in the USA and one in Italy. Patients who had newly diagnosed, untreated disease were included if they were not eligible for standard treatment options or if standard treatments were not deemed appropriate. Patients received PF-04449913 once daily continuously until disease progression, unacceptable toxic effects, or patient withdrawal for up to 12 28-day cycles. Additional cycles were given if patients showed evidence of clinical benefit. The starting dose was 5 mg and was increased by 100% until the first dose-limiting toxic effect (DLT) and by 50% thereafter, in keeping with a 3+3 clinical trial statistical design. The primary endpoint was first-cycle DLTs. Secondary endpoints were safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary clinical activity. This trial is registered with ClinicalTrials.gov, number NCT00953758. FINDINGS: Between March 24, 2010, and Sept 7, 2012, 47 patients were enrolled and included in the study: 28 with acute myeloid leukaemia, six with myelodysplastic syndrome, five with chronic myeloid leukaemia (two with chronic-phase and three with blast-phase disease), one with chronic myelomonocytic leukaemia, and seven with myelofibrosis. Patients received PF-04449913 once daily at 5 mg (n=3), 10 mg (n=3), 20 mg (n=4), 40 mg (n=4), 80 mg (n=8), 120 mg (n=3), 180 mg (n=3), 270 mg (n=5), 400 mg (n=9), and 600 mg (n=5). Two patients experienced DLTs (one each in the 80 mg and 600 mg dose groups). The MTD for PF-04449913 was established to be 400 mg once daily. Of the 47 patients enrolled, 28 (60%) experienced treatment-related adverse events, three of which were grade 4 in severity. The most common treatment-related adverse events included dysgeusia (13 [28%] patients), decreased appetite (nine [19%]), and alopecia (seven [15%]). None of the 15 deaths reported were treatment related. Pharmacokinetics seemed to be dose proportional. The mean half-life was 23·9 h (SD 14·0) in the MTD group. Some suggestion of clinical activity was noted in 23 (49%) of 47 patients with haematological malignancies. Based on these results, the recommended phase 2 dose was 200 mg or lower once daily. INTERPRETATION: Based on these findings, PF-04449913 is being tested in phase 2 studies in patients with myelodysplastic syndrome, acute myeloid leukaemia, and myelofibrosis. FUNDING: Pfizer.

AB - BACKGROUND: Activation of the Hedgehog signalling pathway contributes to cancer progression and the development of myeloid leukaemia stem cell therapeutic resistance. We aimed to identify the maximum tolerated dose (MTD) and the recommended phase 2 dose of the selective Hedgehog antagonist PF-04449913 in myeloid malignancies. METHODS: We undertook an open-label, dose-finding, standard 3+3 design phase 1 study of PF-04449913 in adult patients with acute myeloid leukaemia, chronic myeloid leukaemia, chronic myelomonocytic leukaemia, myelodysplastic syndrome, or myelofibrosis who were refractory, resistant, or intolerant to previous treatments, at three centres in the USA and one in Italy. Patients who had newly diagnosed, untreated disease were included if they were not eligible for standard treatment options or if standard treatments were not deemed appropriate. Patients received PF-04449913 once daily continuously until disease progression, unacceptable toxic effects, or patient withdrawal for up to 12 28-day cycles. Additional cycles were given if patients showed evidence of clinical benefit. The starting dose was 5 mg and was increased by 100% until the first dose-limiting toxic effect (DLT) and by 50% thereafter, in keeping with a 3+3 clinical trial statistical design. The primary endpoint was first-cycle DLTs. Secondary endpoints were safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary clinical activity. This trial is registered with ClinicalTrials.gov, number NCT00953758. FINDINGS: Between March 24, 2010, and Sept 7, 2012, 47 patients were enrolled and included in the study: 28 with acute myeloid leukaemia, six with myelodysplastic syndrome, five with chronic myeloid leukaemia (two with chronic-phase and three with blast-phase disease), one with chronic myelomonocytic leukaemia, and seven with myelofibrosis. Patients received PF-04449913 once daily at 5 mg (n=3), 10 mg (n=3), 20 mg (n=4), 40 mg (n=4), 80 mg (n=8), 120 mg (n=3), 180 mg (n=3), 270 mg (n=5), 400 mg (n=9), and 600 mg (n=5). Two patients experienced DLTs (one each in the 80 mg and 600 mg dose groups). The MTD for PF-04449913 was established to be 400 mg once daily. Of the 47 patients enrolled, 28 (60%) experienced treatment-related adverse events, three of which were grade 4 in severity. The most common treatment-related adverse events included dysgeusia (13 [28%] patients), decreased appetite (nine [19%]), and alopecia (seven [15%]). None of the 15 deaths reported were treatment related. Pharmacokinetics seemed to be dose proportional. The mean half-life was 23·9 h (SD 14·0) in the MTD group. Some suggestion of clinical activity was noted in 23 (49%) of 47 patients with haematological malignancies. Based on these results, the recommended phase 2 dose was 200 mg or lower once daily. INTERPRETATION: Based on these findings, PF-04449913 is being tested in phase 2 studies in patients with myelodysplastic syndrome, acute myeloid leukaemia, and myelofibrosis. FUNDING: Pfizer.

UR - http://www.scopus.com/inward/record.url?scp=84955178161&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84955178161&partnerID=8YFLogxK

U2 - 10.1016/S2352-3026(15)00096-4

DO - 10.1016/S2352-3026(15)00096-4

M3 - Article

C2 - 26688487

AN - SCOPUS:84955178161

VL - 2

SP - e339-e346

JO - The Lancet Haematology

JF - The Lancet Haematology

SN - 2352-3026

IS - 8

ER -