title: First-in-Human Study of PF-05212384 (PKI-587), a Small-Molecule, Intravenous, Dual Inhibitor of PI3K and mTOR in Patients with Advanced Cancer.
abstract: To evaluate safety (primary endpoint), tolerability, pharmacokinetics, pharmacodynamic profile, and preliminary activity of the intravenous, pan-class I isoform PI3K/mTOR inhibitor PF-05212384 in patients with advanced solid tumors.
  
  
  
  Part 1 of this open-label phase I study was designed to estimate the maximum-tolerated dose (MTD) in patients with nonselected solid tumors, using a modified continual reassessment method to guide dose escalation. Objectives of part 2 were MTD confirmation and assessment of preliminary activity in patients with selected tumor types and PI3K pathway dysregulation.
  
  
  
  Seventy-seven of the 78 enrolled patients received treatment. The MTD for PF-05212384, administered intravenously once weekly, was estimated to be 154 mg. The most common treatment-related adverse events (AE) were mucosal inflammation/stomatitis (58.4%), nausea (42.9%), hyperglycemia (26%), decreased appetite (24.7%), fatigue (24.7%), and vomiting (24.7%). The majority of patients treated at the MTD experienced only grade 1 treatment-related AEs. Grade 3 treatment-related AEs occurred in 23.8% of patients at the MTD. No treatment-related grade 4-5 AEs were reported at any dose level. Antitumor activity was noted in this heavily pretreated patient population, with two partial responses (PR) and an unconfirmed PR. Eight patients had long-lasting stable disease (>6 months). Pharmacokinetic analyses showed a biphasic concentration-time profile for PF-05212384 (half-life, 30-37 hours after multiple dosing). PF-05212384 inhibited downstream effectors of the PI3K pathway in paired tumor biopsies.
  
  
  
  These findings demonstrate the manageable safety profile and antitumor activity of the PI3K/mTOR inhibitor PF-05212384, supporting further clinical development for patients with advanced solid malignancies.
authors: Dana-Farber Cancer Institute, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts.
authors: Geoffrey I
authors: GI
authors: Shapiro
authors: Memorial Sloan Kettering Cancer Center, New York, New York.
authors: Katherine M
authors: KM
authors: Bell-McGuinn
authors: Mayo Clinic, Rochester, Minnesota.
authors: Julian R
authors: JR
authors: Molina
authors: Sarah Cannon Research Institute, Tennessee Oncology, Nashville, Tennessee.
authors: Johanna
authors: J
authors: Bendell
authors: King's College London, Guy's Hospital, London, United Kingdom.
authors: James
authors: J
authors: Spicer
authors: Massachusetts General Hospital Cancer Center, Boston, Massachusetts.
authors: Eunice L
authors: EL
authors: Kwak
authors: Beth Israel Medical Center, Boston, Massachusetts.
authors: Susan S
authors: SS
authors: Pandya
authors: Pfizer Oncology, Groton, Connecticut.
authors: Robert
authors: R
authors: Millham
authors: Pfizer Oncology, Groton, Connecticut.
authors: Gary
authors: G
authors: Borzillo
authors: Pfizer Oncology, Groton, Connecticut.
authors: Kristen J
authors: KJ
authors: Pierce
authors: Pfizer Oncology, Cambridge, Massachusetts.
authors: Lixin
authors: L
authors: Han
authors: Pfizer Oncology, La Jolla, California.
authors: Brett E
authors: BE
authors: Houk
authors: Pfizer Oncology, Milan, Italy.
authors: Jorge D
authors: JD
authors: Gallo
authors: Vall d'Hebron University Hospital and Institute of Oncology, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors: Maria
authors: M
authors: Alsina
authors: Vall d'Hebron University Hospital and Institute of Oncology, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors: Irene
authors: I
authors: Braña
authors: Vall d'Hebron University Hospital and Institute of Oncology, Universitat Autònoma de Barcelona, Barcelona, Spain. jtabernero@vhio.net.
authors: Josep
authors: J
authors: Tabernero
mesh_terms: D000328:Adult; D000368:Aged; D003131:Combined Modality Therapy; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009025:Morpholines / Q000494:pharmacology* / Q000627:therapeutic use*; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D019233:Retreatment; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D016896:Treatment Outcome; D014227:Triazines / Q000494:pharmacology* / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D014227:Triazines; C549060:gedatolisib; D058570:TOR Serine-Threonine Kinases
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