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.

The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins David H Koch Cancer Research Building 2 1550 Orleans St Rm 544 Baltimore MD 21231 USA

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Indianapolis, IN: Eli Lilly and Company; ALIMTA (pemetrexed) package insert.

Bridgewater, NJ: sanofi-aventis; TAXOTERE (docetaxel) package insert.

Melville, NY: OSI Pharmaceuticals; TARCEVA (erlotinib) package insert.

Hanna N, Shepherd FA, Fossella FV, et al. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol. 2004;22:1589–1597. PubMed

Kubota K, Niho S, Enatsu S, et al. Efficacy differences of pemetrexed by histology in pretreated patients with stage IIIB/IV non-small cell lung cancer: Review of results from an open-label randomized phase II study. J Thorac Oncol. 2009;4:1530–1536. PubMed

Scagliotti G, Hanna N, Fossella F, et al. The differential efficacy of pemetrexed according to NSCLC histology: A review of two phase III studies. Oncologist. 2009;14:253–263. PubMed

Scagliotti GV, Parikh P, von Pawel J, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol. 2008;26:3543–3551. PubMed

Cohen MH, Justice R, Pazdur R. Approval summary: Pemetrexed in the initial treatment of advanced/metastatic non-small cell lung cancer. Oncologist. 2009;14:930–935. PubMed

Yoshimatsu K, Yamaguchi A, Yoshino H, et al. Mechanism of action of E7010, an orally active sulfonamide antitumor agent: Inhibition of mitosis by binding to the colchicine site of tubulin. Cancer Res. 1997;57:3208–3213. PubMed

Galmarini CM. ABT-751 (Abbott) Curr Opin Investig Drugs. 2005;6:623–630. PubMed

Segreti JA, Polakowski JS, Koch KA, et al. Tumor selective antivascular effects of the novel antimitotic compound ABT-751: An in vivo rat regional hemodynamic study. Cancer Chemother Pharmacol. 2004;54:273–281. PubMed

Koyanagi N, Nagasu T, Fujita F, et al. In vivo tumor growth inhibition produced by a novel sulfonamide, E7010, against rodent and human tumors. Cancer Res. 1994;54:1702–1706. PubMed

Jorgensen TJ, Tian H, Joseph IB, et al. Chemosensitization and radiosensitization of human lung and colon cancers by antimitotic agent, ABT-751, in athymic murine xenograft models of subcutaneous tumor growth. Cancer Chemother Pharmacol. 2007;59:725–732. PubMed

Yamamoto K, Noda K, Yoshimura A, et al. Phase I study of E7010. Cancer Chemother Pharmacol. 1998;42:127–134. PubMed

Hande KR, Hagey A, Berlin J, et al. The pharmacokinetics and safety of ABT-751, a novel, orally bioavailable sulfonamide antimitotic agent: Results of a phase I study. Clin Cancer Res. 2006;12:2834–2840. PubMed

Mauer AM, Szeto L, Belt RJ, et al. Preliminary results of a phase 2 study of ABT-751 in patients (pts) with taxane-refractory non-small cell lung carcinoma (NSCLC) J Clin Oncol. 2005;23(suppl):654s. abstr 7137.

Mauer AM, Cohen EE, Ma PC, et al. A phase II study of ABT-751 in patients with advanced non-small cell lung cancer. J Thorac Oncol. 2008;3:631–636. PubMed

Benson AB, Kindler HL, Jodrell D, et al. Phase 2 study of ABT-751 in patients with refractory metastatic colorectal carcinoma (CRC) J Clin Oncol. 2005;23(suppl):255s. abstr 3537.

Hagey AE, Figlin RA, Moldawer N, et al. Preliminary phase 2 results of ABT-751 in subjects with advanced renal cell carcinoma (RCC) J Clin Oncol. 2005;23(suppl):403s. abstr 4603.

Washington DK, Storniolo AV, Saleh M, et al. Phase 2 results of ABT-751 in subjects with taxane-refractory breast cancer: Interim analysis. J Clin Oncol. 2005;23(suppl):59s. abstr 724.

Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors: European Organisation for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000;92:205–216. PubMed

Rudek MA, Zhao M, He P, et al. Validation and implementation of a liquid chromatography/tandem mass spectrometry assay to quantitate ABT-751, ABT-751 glucuronide, and ABT-751 sulfate in human plasma for clinical pharmacology studies. J Pharm Biomed Anal. 2006;42:253–260. PubMed

Haas M, Laubender RP, Stieber P, et al. Prognostic relevance of CA 19-9, CEA, CRP, and LDH kinetics in patients treated with palliative second-line therapy for advanced pancreatic cancer. Tumour Biol. 2010;31:351–357. PubMed

Holdenrieder S, von Pawel J, Dankelmann E, et al. Nucleosomes, ProGRP, NSE, CYFRA 21-1, and CEA in monitoring first-line chemotherapy of small cell lung cancer. Clin Cancer Res. 2008;14:7813–7821. PubMed

Molina R, Auge JM, Bosch X, et al. Usefulness of serum tumor markers, including progastrin-releasing peptide, in patients with lung cancer: Correlation with histology. Tumour Biol. 2009;30:121–129. PubMed

Molina R, Filella X, Auge JM, et al. Tumor markers (CEA, CA 125, CYFRA 21-1, SCC and NSE) in patients with non-small cell lung cancer as an aid in histological diagnosis and prognosis: Comparison with the main clinical and pathological prognostic factors. Tumour Biol. 2003;24:209–218. PubMed

Ardizzoni A, Cafferata MA, Tiseo M, et al. Decline in serum carcinoembryonic antigen and cytokeratin 19 fragment during chemotherapy predicts objective response and survival in patients with advanced nonsmall cell lung cancer. Cancer. 2006;107:2842–2849. PubMed

Boulder, CO: OSI Pharmaceuticals; 2001. OSI-774 Investigators Brochure.

Cristofanilli M, Budd GT, Ellis MJ, et al. Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med. 2004;351:781–791. PubMed

Molina R, Auge JM, Filella X, et al. Pro-gastrin-releasing peptide (proGRP) in patients with benign and malignant diseases: Comparison with CEA, SCC, CYFRA 21-1 and NSE in patients with lung cancer. Anticancer Res. 2005;25:1773–1778. PubMed

Zhang L, Chen J, Ke Y, et al. Expression of placenta growth factor (PlGF) in non-small cell lung cancer (NSCLC) and the clinical and prognostic significance. World J Surg Oncol. 2005;3:68. PubMed PMC

Randomized phase II study of carboplatin and paclitaxel with either linifanib or placebo for advanced nonsquamous non-small-cell lung cancer

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ClinicalTrials.gov
NCT00297089