title: First-in-human study of CH5132799, an oral class I PI3K inhibitor, studying toxicity, pharmacokinetics, and pharmacodynamics, in patients with metastatic cancer.
abstract: OBJECTIVE
  This phase I dose-escalation study investigated the maximum-tolerated dose (MTD), dose-limiting toxicities (DLT), safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary clinical activity of CH5132799.
  
  
  METHODS
  Patients with metastatic solid tumors were eligible for the study. CH5132799 was administered orally once daily or twice daily in 28-day cycles.
  
  
  RESULTS
  Thirty-eight patients with solid tumors received CH5132799 at 2 to 96 mg once daily or 48 to 72 mg twice daily. The MTD was 48 mg on the twice-daily schedule but was not reached on the once daily schedule. DLTs were grade 3 elevated liver function tests (LFT), grade 3 fatigue, grade 3 encephalopathy, grade 3 diarrhea, and grade 3 diarrhea with grade 3 stomatitis; all DLTs were reversible. Most drug-related adverse events were grade 1/2. Diarrhea (34%) and nausea (32%) were the most common events. Mean Cmax and AUC0-24 in steady state at MTD were 175 ng/mL and 1,550 ng·h/mL, respectively, consistent with efficacious exposure based on preclinical modeling. Reduction in SUVmax with [(18)F] fluorodeoxyglucose positron emission tomography (FDG-PET) was observed in 5 of 7 patients at MTD. A patient with PIK3CA-mutated clear cell carcinoma of the ovary achieved a partial response by GCIG CA125 criteria and further, a heavily pretreated patient with triple-negative breast cancer had marked improvement in her cutaneous skin lesions lasting six cycles.
  
  
  CONCLUSIONS
  CH5132799 is well tolerated at the MTD dose of 48 mg twice daily. At this dose, the drug had a favorable PK and PD profile and preliminary evidence of clinical activity.
authors.affiliation: Imperial NIHR/Wellcome Trust Imperial Clinical Research Facility, Imperial College and Hammersmith Hospital Healthcare NHS Trust, London, United Kingdom.
authors.forename: Sarah
authors.initials: S
authors.lastname: Blagden
authors.forename: Aurelius
authors.initials: A
authors.lastname: Omlin
authors.affiliation: The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, United Kingdom.
authors.forename: Aurelius
authors.initials: A
authors.lastname: Olmin
authors.affiliation: King's College London and Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom.
authors.forename: Debra
authors.initials: D
authors.lastname: Josephs
authors.affiliation: Imperial NIHR/Wellcome Trust Imperial Clinical Research Facility, Imperial College and Hammersmith Hospital Healthcare NHS Trust, London, United Kingdom.
authors.forename: Chara
authors.initials: C
authors.lastname: Stavraka
authors.affiliation: The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, United Kingdom.
authors.forename: Andrea
authors.initials: A
authors.lastname: Zivi
authors.affiliation: Imperial NIHR/Wellcome Trust Imperial Clinical Research Facility, Imperial College and Hammersmith Hospital Healthcare NHS Trust, London, United Kingdom.
authors.forename: David J
authors.initials: DJ
authors.lastname: Pinato
authors.affiliation: Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom.
authors.forename: Alan
authors.initials: A
authors.lastname: Anthoney
authors.affiliation: The Institute of Cancer Research, London, United Kingdom.
authors.forename: Shaun
authors.initials: S
authors.lastname: Decordova
authors.affiliation: The Institute of Cancer Research, London, United Kingdom.
authors.forename: Karen
authors.initials: K
authors.lastname: Swales
authors.affiliation: The Institute of Cancer Research, London, United Kingdom.
authors.forename: Ruth
authors.initials: R
authors.lastname: Riisnaes
authors.affiliation: The Institute of Cancer Research, London, United Kingdom.
authors.forename: Lorna
authors.initials: L
authors.lastname: Pope
authors.affiliation: Chugai Pharmaceutical Co. Ltd., Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Noguchi
authors.affiliation: Chugai Pharmaceutical Co. Ltd., Japan.
authors.forename: Rie
authors.initials: R
authors.lastname: Shiokawa
authors.affiliation: Chugai Pharmaceutical Co. Ltd., Japan.
authors.forename: Michiyasu
authors.initials: M
authors.lastname: Inatani
authors.affiliation: Chugai Pharma Europe Ltd., London, United Kingdom.
authors.forename: Jenny
authors.initials: J
authors.lastname: Prince
authors.affiliation: Chugai Pharma Europe Ltd., London, United Kingdom.
authors.forename: Keith
authors.initials: K
authors.lastname: Jones
authors.affiliation: Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom.
authors.forename: Chris
authors.initials: C
authors.lastname: Twelves
authors.affiliation: King's College London and Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom.
authors.forename: James
authors.initials: J
authors.lastname: Spicer
authors.affiliation: The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, United Kingdom. udai.banerji@icr.ac.uk.
authors.forename: Udai
authors.initials: U
authors.lastname: Banerji
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D058534:Class I Phosphatidylinositol 3-Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D049268:Positron-Emission Tomography; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use*; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use*; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D011743:Pyrimidines; D013449:Sulfonamides; D058534:Class I Phosphatidylinositol 3-Kinases; C559137:CH 5132799