Journal
INVESTIGATIONAL NEW DRUGS
Volume 32, Issue 6, Pages 1204-1212Publisher
SPRINGER
DOI: 10.1007/s10637-014-0127-0
Keywords
PBI-05204; Nerium oleander; Phase I; AKT; Oleandrin,NF-kB
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Funding
- NIH/NCI Cancer Center Support Grant (CCSG) [P30CA016672]
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Background PBI-05204, a Nerium oleander extract (NOE) containing the cardiac glycoside oleandrin, inhibits the alpha-3 subunit of Na-K ATPase, as well as FGF-2 export, Akt and p70S6K, hence attenuating mTOR activity. This first-in-human study determined the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of PBI-05204 in patients with advanced cancer. Methods Forty-six patients received PBI-05204 by mouth for 21 of 28 days (3 + 3 trial design). Dose was escalated 100 % using an accelerated titration design until grade 2 toxicity was observed. Plasma PK and mTOR effector (p70S6K and pS6) protein expressions were evaluated. Results Dose-limiting toxicities (grade 3 proteinuria, fatigue) were observed at dose level 8 (0.3383 mg/kg/day). Common possible drug-related adverse were fatigue (26 patients, 56.5 %), nausea (19 patients, 41.3 %) and diarrhea (15 patients, 32.6 %). Electrocardiogram monitoring revealed grade 1 atrioventricular block (N = 10 patients) and grade 2 supraventricular tachycardia (N = 1). The MTD was DL7 (0.2255 mg/kg) where no toxicity of grade a parts per thousand yenaEuro parts per thousand 3 was observed in seven patients treated. Seven patients (15 %) had stable disease > 4 months. Mean peak oleandrin concentrations up to 2 ng/mL were achieved, with area under the curves 6.6 to 25.5 mu g/L*hr and a half-life range of 5-13 h. There was an average 10 % and 35 % reduction in the phosphorylation of Akt and pS6 in PBMC samples in 36 and 32 patients, respectively, tested between predose and 21 days of treatment. Conclusions PBI-05204 was well tolerated in heavily pretreated patients with advanced solid tumors. The recommended Phase II dose is 0.2255 mg/kg/day.
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