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. doi: 10.1007/s10637-014-0127-0. Epub 2014 Jun 13.

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.

Publication types

  • Clinical Trial, Phase I
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Agents, Phytogenic / adverse effects
  • Antineoplastic Agents, Phytogenic / pharmacokinetics
  • Antineoplastic Agents, Phytogenic / pharmacology
  • Antineoplastic Agents, Phytogenic / therapeutic use*
  • Cardenolides / adverse effects
  • Cardenolides / blood
  • Cardenolides / pharmacokinetics
  • Cardenolides / pharmacology
  • Cardenolides / 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*
  • Neoplasms / metabolism
  • Nerium*
  • Phytotherapy
  • Plant Extracts / adverse effects
  • Plant Extracts / pharmacokinetics
  • Plant Extracts / pharmacology
  • Plant Extracts / therapeutic use*
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors
  • Proto-Oncogene Proteins c-akt / metabolism
  • Ribosomal Protein S6 Kinases, 70-kDa / antagonists & inhibitors
  • Ribosomal Protein S6 Kinases, 70-kDa / metabolism
  • Sodium-Potassium-Exchanging ATPase / metabolism
  • TOR Serine-Threonine Kinases / metabolism

Substances

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