title: 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: 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.affiliation: Department of Investigational Cancer Therapeutics (Phase I Program), University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Box 455, Houston, TX, 77030, USA, dshong@mdanderson.org.
authors.forename: D S
authors.initials: DS
authors.lastname: Hong
authors.forename: H
authors.initials: H
authors.lastname: Henary
authors.forename: G S
authors.initials: GS
authors.lastname: Falchook
authors.forename: A
authors.initials: A
authors.lastname: Naing
authors.forename: S
authors.initials: S
authors.lastname: Fu
authors.forename: S
authors.initials: S
authors.lastname: Moulder
authors.forename: J J
authors.initials: JJ
authors.lastname: Wheler
authors.forename: A
authors.initials: A
authors.lastname: Tsimberidou
authors.forename: J B
authors.initials: JB
authors.lastname: Durand
authors.forename: R
authors.initials: R
authors.lastname: Khan
authors.forename: P
authors.initials: P
authors.lastname: Yang
authors.forename: M
authors.initials: M
authors.lastname: Johansen
authors.forename: R A
authors.initials: RA
authors.lastname: Newman
authors.forename: R
authors.initials: R
authors.lastname: Kurzrock
mesh_terms: D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D002298:Cardenolides / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000037:antagonists & inhibitors; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D030007:Nerium; D008517:Phytotherapy; D010936:Plant Extracts / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000037:antagonists & inhibitors / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D002298:Cardenolides; D016328:NF-kappa B; D010936:Plant Extracts; D016222:Fibroblast Growth Factor 2; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D000254:Sodium-Potassium-Exchanging ATPase; C021065:oleandrin