title: A phase I, pharmacokinetic, and pharmacodynamic study of panobinostat, an HDAC inhibitor, combined with erlotinib in patients with advanced aerodigestive tract tumors.
abstract: OBJECTIVE
  Panobinostat, a histone deacetylase (HDAC) inhibitor, enhances antiproliferative activity in non-small cell lung cancer (NSCLC) cell lines when combined with erlotinib. We evaluated this combination in patients with advanced NSCLC and head and neck cancer.
  
  
  METHODS
  Eligible patients were enrolled in a 3+3 dose-escalation design to determine the maximum tolerated dose (MTD) of twice weekly panobinostat plus daily erlotinib at four planned dose levels (DL). Pharmacokinetics, blood, fat pad biopsies (FPB) for histone acetylation, and paired pre and posttherapy tumor biopsies for checkpoint kinase 1 (CHK1) expression were assessed.
  
  
  RESULTS
  Of 42 enrolled patients, 33 were evaluable for efficacy. Dose-limiting toxicities were prolonged-QTc and nausea at DL3. Adverse events included fatigue and nausea (grades 1-3), and rash and anorexia (grades 1-2). Disease control rates were 54% for NSCLC (n = 26) and 43% for head and neck cancer (n = 7). Of 7 patients with NSCLC with EGF receptor (EGFR) mutations, 3 had partial response, 3 had stable disease, and 1 progressed. For EGFR-mutant versus EGFR wild-type patients, progression-free survival (PFS) was 4.7 versus 1.9 months (P = 0.43) and overall survival was 41 (estimated) versus 5.2 months (P = 0.39). Erlotinib pharmacokinetics was not significantly affected. Correlative studies confirmed panobinostat's pharmacodynamic effect in blood, FPB, and tumor samples. Low CHK1 expression levels correlated with PFS (P = 0.006) and response (P = 0.02).
  
  
  CONCLUSIONS
  We determined MTD at 30 mg (panobinostat) and 100 mg (erlotinib). Further studies are needed to further explore the benefits of HDAC inhibitors in patients with EGFR-mutant NSCLC, investigate FPB as a potential surrogate source for biomarker investigations, and validate CHK1's predictive role.
authors.affiliation: Authors' Affiliations: Departments of Thoracic Oncology, Head and Neck Oncology, and Cutaneous Oncology; Chemical Biology and Molecular Medicine Program; Clinical Pharmacology Core; Biostatistics Core, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida; and Karmanos Cancer Institute, Detroit, Michigan.
authors.forename: Jhanelle E
authors.initials: JE
authors.lastname: Gray
authors.forename: Eric
authors.initials: E
authors.lastname: Haura
authors.forename: Alberto
authors.initials: A
authors.lastname: Chiappori
authors.forename: Tawee
authors.initials: T
authors.lastname: Tanvetyanon
authors.forename: Charles C
authors.initials: CC
authors.lastname: Williams
authors.forename: Mary
authors.initials: M
authors.lastname: Pinder-Schenck
authors.forename: Julie A
authors.initials: JA
authors.lastname: Kish
authors.forename: Jenny
authors.initials: J
authors.lastname: Kreahling
authors.forename: Richard
authors.initials: R
authors.lastname: Lush
authors.forename: Anthony
authors.initials: A
authors.lastname: Neuger
authors.forename: Leticia
authors.initials: L
authors.lastname: Tetteh
authors.forename: Angela
authors.initials: A
authors.lastname: Akar
authors.forename: Xiuhua
authors.initials: X
authors.lastname: Zhao
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Schell
authors.forename: Gerold
authors.initials: G
authors.lastname: Bepler
authors.forename: Soner
authors.initials: S
authors.lastname: Altiok
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000401:mortality; D018572:Disease-Free Survival; D000069347:Erlotinib Hydrochloride; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000401:mortality; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D007211:Indoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D000077767:Panobinostat; D011799:Quinazolines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D016896:Treatment Outcome
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D011799:Quinazolines; D000077767:Panobinostat; D000069347:Erlotinib Hydrochloride