First-in-human study of pbi-05204, an oleander-derived inhibitor of akt, fgf-2, nf-κΒ and p70s6k, in patients with advanced solid tumors.

Abstract

BACKGROUND:

PBI-05204, a Nerium oleander extract (NOE) containing the cardiac glycoside oleandrin, inhibits the α-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 ≥ 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 μg/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.

• Authors: D S Hong, H Henary, G S Falchook, A Naing, S Fu, S Moulder, J J Wheler, A Tsimberidou, J B Durand, R Khan, P Yang, M Johansen, R A Newman, R Kurzrock
• Journal: Investigational new drugs (Invest New Drugs) Vol. 32 Issue 6 Pg. 1204-12 (Dec 2014) ISSN: 1573-0646 [Electronic] United States
• PMID: 24919855 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Antineoplastic Agents, Phytogenic
• Cardenolides
• NF-kappa B
• Plant Extracts
• Fibroblast Growth Factor 2
• MTOR protein, human
• Proto-Oncogene Proteins c-akt
• Ribosomal Protein S6 Kinases, 70-kDa
• TOR Serine-Threonine Kinases
• Extracellular Signal-Regulated MAP Kinases
• Sodium-Potassium-Exchanging ATPase
• oleandrin

Topics

• Adult
• Aged
• Antineoplastic Agents, Phytogenic (adverse effects, pharmacokinetics, pharmacology, therapeutic use)
• Cardenolides (adverse effects, blood, pharmacokinetics, pharmacology, therapeutic use)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Female
• Fibroblast Growth Factor 2 (antagonists & inhibitors)
• Humans
• Leukocytes, Mononuclear (metabolism)
• Male
• Maximum Tolerated Dose
• Middle Aged
• NF-kappa B (antagonists & inhibitors)
• Neoplasms (drug therapy, metabolism)
• Nerium
• Phytotherapy
• Plant Extracts (adverse effects, pharmacokinetics, pharmacology, therapeutic use)
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors, metabolism)
• Ribosomal Protein S6 Kinases, 70-kDa (antagonists & inhibitors, metabolism)
• Sodium-Potassium-Exchanging ATPase (metabolism)
• TOR Serine-Threonine Kinases (metabolism)