Faculty Collaboration Database

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. Invest New Drugs 2014 Dec;32(6):1204-12

Date

06/13/2014

Pubmed ID

24919855

DOI

10.1007/s10637-014-0127-0

Scopus ID

2-s2.0-84938690353 (requires institutional sign-in at Scopus site)   56 Citations

Abstract

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.

Author List

Hong DS, Henary H, Falchook GS, Naing A, Fu S, Moulder S, Wheler JJ, Tsimberidou A, Durand JB, Khan R, Yang P, Johansen M, Newman RA, Kurzrock R

Author

Razelle Kurzrock MD Center Associate Director, Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adult
Aged
Antineoplastic Agents, Phytogenic
Cardenolides
Extracellular Signal-Regulated MAP Kinases
Female
Fibroblast Growth Factor 2
Humans
Leukocytes, Mononuclear
Male
Maximum Tolerated Dose
Middle Aged
NF-kappa B
Neoplasms
Nerium
Phytotherapy
Plant Extracts
Proto-Oncogene Proteins c-akt
Ribosomal Protein S6 Kinases, 70-kDa
Sodium-Potassium-Exchanging ATPase
TOR Serine-Threonine Kinases