Phase i pharmacokinetic and pharmacodynamic study of the pan-PI3K/mTORC vascular targeted pro-drug SF1126 in patients with advanced solid tumours and B-cell malignancies

D. Mahadevan, E. G. Chiorean, W. B. Harris, D. D. Von Hoff, A. Stejskal-Barnett, W. Qi, S. P. Anthony, A. E. Younger, D. M. Rensvold, F. Cordova, C. F. Shelton, M. D. Becker, J. R. Garlich, Donald L Durden, R. K. Ramanathan

Research output: Contribution to journalArticle

66 Citations (Scopus)

Abstract

Background: SF1126 is a peptidic pro-drug inhibitor of pan-PI3K/mTORC. A first-in-human study evaluated safety, dose limiting toxicities (DLT), maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics (PD) and efficacy of SF1126, in patients with advanced solid and B-cell malignancies. Patients and methods: SF1126 was administered IV days 1 and 4, weekly in 28 day-cycles. Dose escalation utilised modified Fibonacci 3+3. Samples to monitor PK and PD were obtained. Results: Forty four patients were treated at 9 dose levels (90-1110 mg/m2/day). Most toxicity was grade 1 and 2 with a single DLT at180 mg/m2 (diarrhoea). Exposure measured by peak concentration (C max) and area under the time-concentration curve (AUC 0-t) was dose proportional. Stable disease (SD) was the best response in 19 of 33 (58%) evaluable patients. MTD was not reached but the maximum administered dose (MAD) was 1110 mg/m2. The protocol was amended to enrol patients with CD20+ B-cell malignancies at 1110 mg/m 2. A CLL patient who progressed on rituximab [R] achieved SD after 2 months on SF1126 alone but in combination with R achieved a 55% decrease in absolute lymphocyte count and a lymph node response. PD studies of CLL cells demonstrated SF1126 reduced p-AKT and increased apoptosis indicating inhibition of activated PI3K signalling. Conclusion: SF1126 is well tolerated with SD as the best response in patients with advanced malignancies.

Original languageEnglish (US)
Pages (from-to)3319-3327
Number of pages9
JournalEuropean Journal of Cancer
Volume48
Issue number18
DOIs
StatePublished - Dec 1 2012

Fingerprint

Prodrugs
Phosphatidylinositol 3-Kinases
Blood Vessels
B-Lymphocytes
Pharmacokinetics
Neoplasms
Maximum Tolerated Dose
Lymphocyte Count
SF 1126
Area Under Curve
Diarrhea
Lymph Nodes
Apoptosis
Safety

Keywords

  • B-cell malignancies
  • PI3K/mTORC pathway
  • Pharmacodynamics
  • Pharmacokinetics
  • Refractory solid tumours
  • SF1126

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Phase i pharmacokinetic and pharmacodynamic study of the pan-PI3K/mTORC vascular targeted pro-drug SF1126 in patients with advanced solid tumours and B-cell malignancies. / Mahadevan, D.; Chiorean, E. G.; Harris, W. B.; Von Hoff, D. D.; Stejskal-Barnett, A.; Qi, W.; Anthony, S. P.; Younger, A. E.; Rensvold, D. M.; Cordova, F.; Shelton, C. F.; Becker, M. D.; Garlich, J. R.; Durden, Donald L; Ramanathan, R. K.

In: European Journal of Cancer, Vol. 48, No. 18, 01.12.2012, p. 3319-3327.

Research output: Contribution to journalArticle

Mahadevan, D, Chiorean, EG, Harris, WB, Von Hoff, DD, Stejskal-Barnett, A, Qi, W, Anthony, SP, Younger, AE, Rensvold, DM, Cordova, F, Shelton, CF, Becker, MD, Garlich, JR, Durden, DL & Ramanathan, RK 2012, 'Phase i pharmacokinetic and pharmacodynamic study of the pan-PI3K/mTORC vascular targeted pro-drug SF1126 in patients with advanced solid tumours and B-cell malignancies', European Journal of Cancer, vol. 48, no. 18, pp. 3319-3327. https://doi.org/10.1016/j.ejca.2012.06.027
Mahadevan, D. ; Chiorean, E. G. ; Harris, W. B. ; Von Hoff, D. D. ; Stejskal-Barnett, A. ; Qi, W. ; Anthony, S. P. ; Younger, A. E. ; Rensvold, D. M. ; Cordova, F. ; Shelton, C. F. ; Becker, M. D. ; Garlich, J. R. ; Durden, Donald L ; Ramanathan, R. K. / Phase i pharmacokinetic and pharmacodynamic study of the pan-PI3K/mTORC vascular targeted pro-drug SF1126 in patients with advanced solid tumours and B-cell malignancies. In: European Journal of Cancer. 2012 ; Vol. 48, No. 18. pp. 3319-3327.
@article{872bc5f12f864c7cb8258e699eb58c31,
title = "Phase i pharmacokinetic and pharmacodynamic study of the pan-PI3K/mTORC vascular targeted pro-drug SF1126 in patients with advanced solid tumours and B-cell malignancies",
abstract = "Background: SF1126 is a peptidic pro-drug inhibitor of pan-PI3K/mTORC. A first-in-human study evaluated safety, dose limiting toxicities (DLT), maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics (PD) and efficacy of SF1126, in patients with advanced solid and B-cell malignancies. Patients and methods: SF1126 was administered IV days 1 and 4, weekly in 28 day-cycles. Dose escalation utilised modified Fibonacci 3+3. Samples to monitor PK and PD were obtained. Results: Forty four patients were treated at 9 dose levels (90-1110 mg/m2/day). Most toxicity was grade 1 and 2 with a single DLT at180 mg/m2 (diarrhoea). Exposure measured by peak concentration (C max) and area under the time-concentration curve (AUC 0-t) was dose proportional. Stable disease (SD) was the best response in 19 of 33 (58{\%}) evaluable patients. MTD was not reached but the maximum administered dose (MAD) was 1110 mg/m2. The protocol was amended to enrol patients with CD20+ B-cell malignancies at 1110 mg/m 2. A CLL patient who progressed on rituximab [R] achieved SD after 2 months on SF1126 alone but in combination with R achieved a 55{\%} decrease in absolute lymphocyte count and a lymph node response. PD studies of CLL cells demonstrated SF1126 reduced p-AKT and increased apoptosis indicating inhibition of activated PI3K signalling. Conclusion: SF1126 is well tolerated with SD as the best response in patients with advanced malignancies.",
keywords = "B-cell malignancies, PI3K/mTORC pathway, Pharmacodynamics, Pharmacokinetics, Refractory solid tumours, SF1126",
author = "D. Mahadevan and Chiorean, {E. G.} and Harris, {W. B.} and {Von Hoff}, {D. D.} and A. Stejskal-Barnett and W. Qi and Anthony, {S. P.} and Younger, {A. E.} and Rensvold, {D. M.} and F. Cordova and Shelton, {C. F.} and Becker, {M. D.} and Garlich, {J. R.} and Durden, {Donald L} and Ramanathan, {R. K.}",
year = "2012",
month = "12",
day = "1",
doi = "10.1016/j.ejca.2012.06.027",
language = "English (US)",
volume = "48",
pages = "3319--3327",
journal = "European Journal of Cancer",
issn = "0959-8049",
publisher = "Elsevier Limited",
number = "18",

}

TY - JOUR

T1 - Phase i pharmacokinetic and pharmacodynamic study of the pan-PI3K/mTORC vascular targeted pro-drug SF1126 in patients with advanced solid tumours and B-cell malignancies

AU - Mahadevan, D.

AU - Chiorean, E. G.

AU - Harris, W. B.

AU - Von Hoff, D. D.

AU - Stejskal-Barnett, A.

AU - Qi, W.

AU - Anthony, S. P.

AU - Younger, A. E.

AU - Rensvold, D. M.

AU - Cordova, F.

AU - Shelton, C. F.

AU - Becker, M. D.

AU - Garlich, J. R.

AU - Durden, Donald L

AU - Ramanathan, R. K.

PY - 2012/12/1

Y1 - 2012/12/1

N2 - Background: SF1126 is a peptidic pro-drug inhibitor of pan-PI3K/mTORC. A first-in-human study evaluated safety, dose limiting toxicities (DLT), maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics (PD) and efficacy of SF1126, in patients with advanced solid and B-cell malignancies. Patients and methods: SF1126 was administered IV days 1 and 4, weekly in 28 day-cycles. Dose escalation utilised modified Fibonacci 3+3. Samples to monitor PK and PD were obtained. Results: Forty four patients were treated at 9 dose levels (90-1110 mg/m2/day). Most toxicity was grade 1 and 2 with a single DLT at180 mg/m2 (diarrhoea). Exposure measured by peak concentration (C max) and area under the time-concentration curve (AUC 0-t) was dose proportional. Stable disease (SD) was the best response in 19 of 33 (58%) evaluable patients. MTD was not reached but the maximum administered dose (MAD) was 1110 mg/m2. The protocol was amended to enrol patients with CD20+ B-cell malignancies at 1110 mg/m 2. A CLL patient who progressed on rituximab [R] achieved SD after 2 months on SF1126 alone but in combination with R achieved a 55% decrease in absolute lymphocyte count and a lymph node response. PD studies of CLL cells demonstrated SF1126 reduced p-AKT and increased apoptosis indicating inhibition of activated PI3K signalling. Conclusion: SF1126 is well tolerated with SD as the best response in patients with advanced malignancies.

AB - Background: SF1126 is a peptidic pro-drug inhibitor of pan-PI3K/mTORC. A first-in-human study evaluated safety, dose limiting toxicities (DLT), maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics (PD) and efficacy of SF1126, in patients with advanced solid and B-cell malignancies. Patients and methods: SF1126 was administered IV days 1 and 4, weekly in 28 day-cycles. Dose escalation utilised modified Fibonacci 3+3. Samples to monitor PK and PD were obtained. Results: Forty four patients were treated at 9 dose levels (90-1110 mg/m2/day). Most toxicity was grade 1 and 2 with a single DLT at180 mg/m2 (diarrhoea). Exposure measured by peak concentration (C max) and area under the time-concentration curve (AUC 0-t) was dose proportional. Stable disease (SD) was the best response in 19 of 33 (58%) evaluable patients. MTD was not reached but the maximum administered dose (MAD) was 1110 mg/m2. The protocol was amended to enrol patients with CD20+ B-cell malignancies at 1110 mg/m 2. A CLL patient who progressed on rituximab [R] achieved SD after 2 months on SF1126 alone but in combination with R achieved a 55% decrease in absolute lymphocyte count and a lymph node response. PD studies of CLL cells demonstrated SF1126 reduced p-AKT and increased apoptosis indicating inhibition of activated PI3K signalling. Conclusion: SF1126 is well tolerated with SD as the best response in patients with advanced malignancies.

KW - B-cell malignancies

KW - PI3K/mTORC pathway

KW - Pharmacodynamics

KW - Pharmacokinetics

KW - Refractory solid tumours

KW - SF1126

UR - http://www.scopus.com/inward/record.url?scp=84869505566&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84869505566&partnerID=8YFLogxK

U2 - 10.1016/j.ejca.2012.06.027

DO - 10.1016/j.ejca.2012.06.027

M3 - Article

VL - 48

SP - 3319

EP - 3327

JO - European Journal of Cancer

JF - European Journal of Cancer

SN - 0959-8049

IS - 18

ER -