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.
- MeSH
- časové faktory MeSH
- dospělí MeSH
- dvojitá slepá metoda MeSH
- glutamáty aplikace a dávkování MeSH
- guanin aplikace a dávkování analogy a deriváty MeSH
- hodnocení rizik MeSH
- Kaplanův-Meierův odhad MeSH
- lidé středního věku MeSH
- lidé MeSH
- nádorové biomarkery krev MeSH
- nádory plic krev farmakoterapie mortalita patologie MeSH
- nemalobuněčný karcinom plic krev farmakoterapie mortalita sekundární MeSH
- pemetrexed MeSH
- přežití po terapii bez příznaků nemoci MeSH
- proporcionální rizikové modely MeSH
- protokoly antitumorózní kombinované chemoterapie škodlivé účinky farmakokinetika terapeutické užití MeSH
- rizikové faktory MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- sulfonamidy aplikace a dávkování MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze I MeSH
- klinické zkoušky, fáze II MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie MeSH
- srovnávací studie MeSH
- Geografické názvy
- Česká republika MeSH
- Spojené státy americké MeSH
