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/m(2) 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.

• Authors: 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
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 29 Issue 8 Pg. 1075-82 (Mar 10 2011) ISSN: 1527-7755 [Electronic] United States
• PMID: 21300929 (Publication Type: Clinical Trial, Phase I, Clinical Trial, Phase II, Comparative Study, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• ABT751
• Biomarkers, Tumor
• Glutamates
• Sulfonamides
• Pemetrexed
• Guanine

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, pharmacokinetics, therapeutic use)
• Biomarkers, Tumor (blood)
• Carcinoma, Non-Small-Cell Lung (blood, drug therapy, mortality, secondary)
• Czech Republic
• Disease-Free Survival
• Double-Blind Method
• Female
• Glutamates (administration & dosage)
• Guanine (administration & dosage, analogs & derivatives)
• Humans
• Kaplan-Meier Estimate
• Lung Neoplasms (blood, drug therapy, mortality, pathology)
• Male
• Middle Aged
• Pemetrexed
• Proportional Hazards Models
• Risk Assessment
• Risk Factors
• Sulfonamides (administration & dosage)
• Time Factors
• Treatment Outcome
• United States