Phase I/II study of pemetrexed with or without ABT-751 in advanced or metastatic non - small-cell lung cancer

Charles M. Rudin, Ann Mauer, Martin Smakal, Rosalyn Juergens, Stanislav Spelda, Michael Wertheim, Andrew Coates, Evelyn McKeegan, Peter Ansell, Xiangdong Zhou, Jane Qian, Rajendra Pradhan, Barry Dowell, Andrew Krivoshik, Gary Gordon

Research output: Contribution to journalArticle

Abstract

Purpose: ABT-751 is an antimitotic and vascular disrupting agent with potent preclinical anticancer activity. We conducted a phase I and randomized double-blind phase II study of pemetrexed with ABT-751 or placebo in patients with recurrent advanced or metastatic non - small-cell lung cancer (NSCLC). Methods: One hundred seventy-one patients received intravenous pemetrexed 500 mg/m2 day 1 and oral ABT-751 or placebo days 1 to 14 of 21-day cycles. The primary end point was progression-free survival (PFS). Secondary end point included overall survival (OS); pharmacokinetic and pharmacodynamic parameters were also analyzed. Results: The recommended phase II dose of ABT-751 with pemetrexed is 200 mg. Fatigue, constipation, anemia, nausea, and diarrhea were the most common toxicities in both study arms. No pharmacokinetic interactions were observed. Median PFS in the ABT-751 arm was 2.3 months versus 1.9 for placebo (P = .819, log-rank) for the intention-to-treat population. However, differences in PFS (P = .112, log-rank) and OS (P = .034, log-rank; median 3.3 v 8.1 months) favoring ABT-751 were seen in the squamous NSCLC subgroup. Baseline circulating tumor cell concentrations were predictive of improved OS (P = .013). Changes from baseline of greater than 20% in plasma levels of placenta growth factor (P = .056), squamous cell carcinoma antigen (P = .03), and cytokeratin 19 fragment antigen 21-1 (P = .01) were markers best associated with improved OS. Conclusion: Addition of ABT-751 to pemetrexed is well-tolerated, but does not improve outcome in unselected patients with recurrent NSCLC. ABT-751 may have therapeutic potential in squamous NSCLC. Exploratory cellular and molecular analyses in this study identified biomarkers that may correlate with survival.

Original languageEnglish (US)
Pages (from-to)1075-1082
Number of pages8
JournalJournal of Clinical Oncology
Volume29
Issue number8
DOIs
StatePublished - Mar 10 2011
Externally publishedYes

Fingerprint

Pemetrexed
Non-Small Cell Lung Carcinoma
Survival
Disease-Free Survival
Placebos
Pharmacokinetics
Keratin-19
Antimitotic Agents
Circulating Neoplastic Cells
ABT751
Constipation
Nausea
Fatigue
Blood Vessels
Anemia
Diarrhea
Biomarkers

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Rudin, C. M., Mauer, A., Smakal, M., Juergens, R., Spelda, S., Wertheim, M., ... Gordon, G. (2011). Phase I/II study of pemetrexed with or without ABT-751 in advanced or metastatic non - small-cell lung cancer. Journal of Clinical Oncology, 29(8), 1075-1082. https://doi.org/10.1200/JCO.2010.32.5944

Phase I/II study of pemetrexed with or without ABT-751 in advanced or metastatic non - small-cell lung cancer. / Rudin, Charles M.; Mauer, Ann; Smakal, Martin; Juergens, Rosalyn; Spelda, Stanislav; Wertheim, Michael; Coates, Andrew; McKeegan, Evelyn; Ansell, Peter; Zhou, Xiangdong; Qian, Jane; Pradhan, Rajendra; Dowell, Barry; Krivoshik, Andrew; Gordon, Gary.

In: Journal of Clinical Oncology, Vol. 29, No. 8, 10.03.2011, p. 1075-1082.

Research output: Contribution to journalArticle

Rudin, CM, Mauer, A, Smakal, M, Juergens, R, Spelda, S, Wertheim, M, Coates, A, McKeegan, E, Ansell, P, Zhou, X, Qian, J, Pradhan, R, Dowell, B, Krivoshik, A & Gordon, G 2011, 'Phase I/II study of pemetrexed with or without ABT-751 in advanced or metastatic non - small-cell lung cancer', Journal of Clinical Oncology, vol. 29, no. 8, pp. 1075-1082. https://doi.org/10.1200/JCO.2010.32.5944
Rudin, Charles M. ; Mauer, Ann ; Smakal, Martin ; Juergens, Rosalyn ; Spelda, Stanislav ; Wertheim, Michael ; Coates, Andrew ; McKeegan, Evelyn ; Ansell, Peter ; Zhou, Xiangdong ; Qian, Jane ; Pradhan, Rajendra ; Dowell, Barry ; Krivoshik, Andrew ; Gordon, Gary. / Phase I/II study of pemetrexed with or without ABT-751 in advanced or metastatic non - small-cell lung cancer. In: Journal of Clinical Oncology. 2011 ; Vol. 29, No. 8. pp. 1075-1082.
@article{a8a77c85ac2446d5af5521349286de67,
title = "Phase I/II study of pemetrexed with or without ABT-751 in advanced or metastatic non - small-cell lung cancer",
abstract = "Purpose: ABT-751 is an antimitotic and vascular disrupting agent with potent preclinical anticancer activity. We conducted a phase I and randomized double-blind phase II study of pemetrexed with ABT-751 or placebo in patients with recurrent advanced or metastatic non - small-cell lung cancer (NSCLC). Methods: One hundred seventy-one patients received intravenous pemetrexed 500 mg/m2 day 1 and oral ABT-751 or placebo days 1 to 14 of 21-day cycles. The primary end point was progression-free survival (PFS). Secondary end point included overall survival (OS); pharmacokinetic and pharmacodynamic parameters were also analyzed. Results: The recommended phase II dose of ABT-751 with pemetrexed is 200 mg. Fatigue, constipation, anemia, nausea, and diarrhea were the most common toxicities in both study arms. No pharmacokinetic interactions were observed. Median PFS in the ABT-751 arm was 2.3 months versus 1.9 for placebo (P = .819, log-rank) for the intention-to-treat population. However, differences in PFS (P = .112, log-rank) and OS (P = .034, log-rank; median 3.3 v 8.1 months) favoring ABT-751 were seen in the squamous NSCLC subgroup. Baseline circulating tumor cell concentrations were predictive of improved OS (P = .013). Changes from baseline of greater than 20{\%} in plasma levels of placenta growth factor (P = .056), squamous cell carcinoma antigen (P = .03), and cytokeratin 19 fragment antigen 21-1 (P = .01) were markers best associated with improved OS. Conclusion: Addition of ABT-751 to pemetrexed is well-tolerated, but does not improve outcome in unselected patients with recurrent NSCLC. ABT-751 may have therapeutic potential in squamous NSCLC. Exploratory cellular and molecular analyses in this study identified biomarkers that may correlate with survival.",
author = "Rudin, {Charles M.} and Ann Mauer and Martin Smakal and Rosalyn Juergens and Stanislav Spelda and Michael Wertheim and Andrew Coates and Evelyn McKeegan and Peter Ansell and Xiangdong Zhou and Jane Qian and Rajendra Pradhan and Barry Dowell and Andrew Krivoshik and Gary Gordon",
year = "2011",
month = "3",
day = "10",
doi = "10.1200/JCO.2010.32.5944",
language = "English (US)",
volume = "29",
pages = "1075--1082",
journal = "Journal of Clinical Oncology",
issn = "0732-183X",
publisher = "American Society of Clinical Oncology",
number = "8",

}

TY - JOUR

T1 - Phase I/II study of pemetrexed with or without ABT-751 in advanced or metastatic non - small-cell lung cancer

AU - Rudin, Charles M.

AU - Mauer, Ann

AU - Smakal, Martin

AU - Juergens, Rosalyn

AU - Spelda, Stanislav

AU - Wertheim, Michael

AU - Coates, Andrew

AU - McKeegan, Evelyn

AU - Ansell, Peter

AU - Zhou, Xiangdong

AU - Qian, Jane

AU - Pradhan, Rajendra

AU - Dowell, Barry

AU - Krivoshik, Andrew

AU - Gordon, Gary

PY - 2011/3/10

Y1 - 2011/3/10

N2 - Purpose: ABT-751 is an antimitotic and vascular disrupting agent with potent preclinical anticancer activity. We conducted a phase I and randomized double-blind phase II study of pemetrexed with ABT-751 or placebo in patients with recurrent advanced or metastatic non - small-cell lung cancer (NSCLC). Methods: One hundred seventy-one patients received intravenous pemetrexed 500 mg/m2 day 1 and oral ABT-751 or placebo days 1 to 14 of 21-day cycles. The primary end point was progression-free survival (PFS). Secondary end point included overall survival (OS); pharmacokinetic and pharmacodynamic parameters were also analyzed. Results: The recommended phase II dose of ABT-751 with pemetrexed is 200 mg. Fatigue, constipation, anemia, nausea, and diarrhea were the most common toxicities in both study arms. No pharmacokinetic interactions were observed. Median PFS in the ABT-751 arm was 2.3 months versus 1.9 for placebo (P = .819, log-rank) for the intention-to-treat population. However, differences in PFS (P = .112, log-rank) and OS (P = .034, log-rank; median 3.3 v 8.1 months) favoring ABT-751 were seen in the squamous NSCLC subgroup. Baseline circulating tumor cell concentrations were predictive of improved OS (P = .013). Changes from baseline of greater than 20% in plasma levels of placenta growth factor (P = .056), squamous cell carcinoma antigen (P = .03), and cytokeratin 19 fragment antigen 21-1 (P = .01) were markers best associated with improved OS. Conclusion: Addition of ABT-751 to pemetrexed is well-tolerated, but does not improve outcome in unselected patients with recurrent NSCLC. ABT-751 may have therapeutic potential in squamous NSCLC. Exploratory cellular and molecular analyses in this study identified biomarkers that may correlate with survival.

AB - Purpose: ABT-751 is an antimitotic and vascular disrupting agent with potent preclinical anticancer activity. We conducted a phase I and randomized double-blind phase II study of pemetrexed with ABT-751 or placebo in patients with recurrent advanced or metastatic non - small-cell lung cancer (NSCLC). Methods: One hundred seventy-one patients received intravenous pemetrexed 500 mg/m2 day 1 and oral ABT-751 or placebo days 1 to 14 of 21-day cycles. The primary end point was progression-free survival (PFS). Secondary end point included overall survival (OS); pharmacokinetic and pharmacodynamic parameters were also analyzed. Results: The recommended phase II dose of ABT-751 with pemetrexed is 200 mg. Fatigue, constipation, anemia, nausea, and diarrhea were the most common toxicities in both study arms. No pharmacokinetic interactions were observed. Median PFS in the ABT-751 arm was 2.3 months versus 1.9 for placebo (P = .819, log-rank) for the intention-to-treat population. However, differences in PFS (P = .112, log-rank) and OS (P = .034, log-rank; median 3.3 v 8.1 months) favoring ABT-751 were seen in the squamous NSCLC subgroup. Baseline circulating tumor cell concentrations were predictive of improved OS (P = .013). Changes from baseline of greater than 20% in plasma levels of placenta growth factor (P = .056), squamous cell carcinoma antigen (P = .03), and cytokeratin 19 fragment antigen 21-1 (P = .01) were markers best associated with improved OS. Conclusion: Addition of ABT-751 to pemetrexed is well-tolerated, but does not improve outcome in unselected patients with recurrent NSCLC. ABT-751 may have therapeutic potential in squamous NSCLC. Exploratory cellular and molecular analyses in this study identified biomarkers that may correlate with survival.

UR - http://www.scopus.com/inward/record.url?scp=79952764349&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79952764349&partnerID=8YFLogxK

U2 - 10.1200/JCO.2010.32.5944

DO - 10.1200/JCO.2010.32.5944

M3 - Article

VL - 29

SP - 1075

EP - 1082

JO - Journal of Clinical Oncology

JF - Journal of Clinical Oncology

SN - 0732-183X

IS - 8

ER -