5--oleoyl-cytarabine and Lung-Neoplasms

Cytarabine (ara-C) has limited activity in solid tumours. CP-4055 (ELACYT) is a novel ara-C-5'-elaidic acid ester that may circumvent this limitation. CP-4055 maximum tolerated dose (MTD), pharmacokinetics and antitumor activity have been investigated in patients with solid tumours.. Thirty-four patients (19 malignant melanoma, 8 ovarian cancers and 7 NSCLC) received CP-4055 as a 30 min, or 2 hr intravenous (IV) infusion daily for 5 consecutive days every 3 or 4 weeks (D1-5 q3w or D1-5 q4w) in a dose escalation designed study with doses ranging from 30 to 240 mg/m(2)/day.. The most frequent CTC grade 1-2 adverse events (AEs) were nausea, fatigue, vomiting, anorexia and pyrexia. Most of the grade 3-4 AEs were neutropenia. The MTD was 200 mg/m(2)/day and 240 mg/m(2)/day for D1-5 q3w and D1-5 q4w, respectively. The MTD was independent of infusion time in the 4 week schedule. CP-4055 was maintained in plasma for up to 5-10 hr at dose levels >150 mg/m(2)/day. One objective partial response (PR) with time to progression (TTP) of 22 months was reported in an advanced malignant melanoma patient.. CP-4055 was well tolerated; the majority of the AEs were of CTC grade 1. The 3 week schedule was not recommended due to neutropenic nadir between days 18-26. The recommended dose was 200 mg/m(2)/day in a D1-5 q4w schedule. Efficacy data suggest that CP-4055 might be active in treatment of solid tumours.

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Carcinoma, Non-Small-Cell Lung; Cytarabine; Dose-Response Relationship, Drug; Female; Humans; Infusions, Intravenous; Lung Neoplasms; Melanoma; Middle Aged; Neoplasms; Ovarian Neoplasms

The objective of the present study was to determine the in vivo antitumor activity of elacytarabine, the 5'-elaidic acid ester of arabinofuranosyl cytidine, alone and in combination with bevacizumab, cetuximab and trastuzumab in Vascular endothelial growth factor (VEGF), Epidermal growth factor receptor (EGFR)- and Human epidermal growth factor receptor 2 (HER2)-expressing non-small cell lung cancer xenografts.. The antitumor activity of elacytarabine, was tested at the maximal tolerable dose (MTD; 50 mg/kg) and half MTD (25 mg/kg), alone and in combination with the antibodies bevacizumab (5 mg/kg), cetuximab (20 mg/kg) and trastuzumab (4 mg/kg) in two human non-small cell lung cancer xenografts.. Elacytarabine exhibited very high activity in the EKVX xenograft at both dose levels, but was inactive in MAKSAX. Neither of the two xenografts were sensitive to bevacizumab or trastuzumab, but the MAKSAX xenograft showed intermediate response to cetuximab. The high sensitivity of EKVX to elacytarabine precluded the assessment of a potential benefit of the combinations with the antibodies. In the elacytarabine-, bevacizumab- and trastuzumab-insensitive MAKSAX xenograft, the combination of either bevacizumab or trastuzumab with elacytarabine at the MTD or half MTD resulted in intermediate activity, suggesting a beneficial effect of the combinations, whereas for cetuximab, the effect was enhanced when combined with elacytarabine given at the MTD, but not half-MTD.. The results suggest that elacytarabine could be active in some cases of non-small cell lung cancer, and that the combination of elacytarabine and tyrosine kinase inhibitors may exert important additive or possibly synergistic effects of potential clinical benefit.

Topics: Animals; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoma, Non-Small-Cell Lung; Cetuximab; Cytarabine; Female; Humans; Lung Neoplasms; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Trastuzumab; Xenograft Model Antitumor Assays