title: Phase I Study of Panobinostat (LBH589) and Letrozole in Postmenopausal Metastatic Breast Cancer Patients.
abstract: BACKGROUND
  Histone deacetylase inhibitors have been found to restore sensitivity to the estrogen receptor in endocrine-resistant and triple-negative breast cancer cell lines. We decided to test panobinostat, a pan-histone deacetylase inhibitor, because of preclinical data, combined with letrozole in a phase I study.
  
  
  METHODS
  We enrolled patients with metastatic breast cancer to determine the safety and tumor response using Response Evaluation Criteria In Solid Tumors. Dose level 1 was panobinostat 20 mg orally 3 times weekly with oral letrozole 2.5 mg daily. Dose level 2 was panobinostat 30 mg orally 3 times weekly, with the same dose of letrozole.
  
  
  RESULTS
  A total of 12 patients (6 at each dose level) were enrolled, and 43 cycles of treatment were given. Of the 6 patients at dose level 1, 1 experienced dose-limiting toxicity (20-mg dose level; an increase in creatinine). At the 30-mg dose level, 3 of 6 patients experienced dose-limiting toxicity, 1 each of grade 3 thrombocytopenia with bleeding, grade 4 thrombocytopenia, and grade 3 diarrhea. The maximum tolerated dose was 20 mg. Of the 12 patients, 2 experienced a partial response, and 5 had stable disease. The most common severe adverse event was thrombocytopenia, occurring in 4 of 12 patients.
  
  
  CONCLUSIONS
  The recommended phase II starting dose is panobinostat 20 mg orally 3 times weekly (eg, Monday, Wednesday, Friday) and oral letrozole 2.5 mg daily. This dose should be escalated to 30 mg orally 3 times weekly if no grade 3 toxicity has developed, because the partial responses occurred in patients receiving the 30-mg dose.
authors.affiliation: Department of Hematology/Oncology, Mayo Clinic, Jacksonville, FL. Electronic address: tan.winston@mayo.edu.
authors.forename: Winston W
authors.initials: WW
authors.lastname: Tan
authors.affiliation: Department of Biostatistics, Mayo Clinic, Rochester, MN.
authors.forename: Jacob B
authors.initials: JB
authors.lastname: Allred
authors.affiliation: Department of Hematology/Oncology, Mayo Clinic, Jacksonville, FL.
authors.forename: Alvaro
authors.initials: A
authors.lastname: Moreno-Aspitia
authors.affiliation: Department of Medical Oncology, Mayo Clinic, Scottsdale, AZ.
authors.forename: Donald W
authors.initials: DW
authors.lastname: Northfelt
authors.affiliation: Department of Medical Oncology, Mayo Clinic, Rochester, MN.
authors.forename: James N
authors.initials: JN
authors.lastname: Ingle
authors.affiliation: Department of Medical Oncology, Mayo Clinic, Rochester, MN.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Goetz
authors.affiliation: Department of Hematology/Oncology, Mayo Clinic, Jacksonville, FL.
authors.forename: Edith A
authors.initials: EA
authors.lastname: Perez
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D018275:Carcinoma, Lobular / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage; D007124:Immunoenzyme Techniques; D007211:Indoles / Q000008:administration & dosage; D000077289:Letrozole; D008207:Lymphatic Metastasis; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D009570:Nitriles / Q000008:administration & dosage; D000077767:Panobinostat; D017698:Postmenopause; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D015996:Survival Rate; D014230:Triazoles / Q000008:administration & dosage
chemical_list: D014408:Biomarkers, Tumor; D006877:Hydroxamic Acids; D007211:Indoles; D000077289:Letrozole; D009570:Nitriles; D000077767:Panobinostat; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D014230:Triazoles; C508053:ERBB2 protein, human
keywords: Aromatase refractory; Endocrine resistant breast cancer; Histone deacetylase inhibitors; Phase I study