Phase I Study of Panobinostat (LBH589) and Letrozole in Postmenopausal Metastatic Breast Cancer Patients

Clin Breast Cancer. 2016 Apr;16(2):82-6. doi: 10.1016/j.clbc.2015.11.003. Epub 2015 Nov 17.

Abstract

Introduction: 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.

Patients and 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.

Conclusion: 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.

Trial registration: ClinicalTrials.gov NCT01105312.

Keywords: Aromatase refractory; Endocrine resistant breast cancer; Histone deacetylase inhibitors; Phase I study.

Publication types

  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adult
  • Aged
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Biomarkers, Tumor / metabolism
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Carcinoma, Ductal, Breast / drug therapy*
  • Carcinoma, Ductal, Breast / metabolism
  • Carcinoma, Ductal, Breast / secondary
  • Carcinoma, Lobular / drug therapy*
  • Carcinoma, Lobular / metabolism
  • Carcinoma, Lobular / secondary
  • Drug Administration Schedule
  • Female
  • Follow-Up Studies
  • Humans
  • Hydroxamic Acids / administration & dosage
  • Immunoenzyme Techniques
  • Indoles / administration & dosage
  • Letrozole
  • Lymphatic Metastasis
  • Maximum Tolerated Dose
  • Middle Aged
  • Neoplasm Invasiveness
  • Neoplasm Staging
  • Nitriles / administration & dosage
  • Panobinostat
  • Postmenopause
  • Prognosis
  • Receptor, ErbB-2 / metabolism
  • Receptors, Estrogen / metabolism
  • Receptors, Progesterone / metabolism
  • Survival Rate
  • Triazoles / administration & dosage

Substances

  • Biomarkers, Tumor
  • Hydroxamic Acids
  • Indoles
  • Nitriles
  • Receptors, Estrogen
  • Receptors, Progesterone
  • Triazoles
  • Letrozole
  • Panobinostat
  • ERBB2 protein, human
  • Receptor, ErbB-2

Associated data

  • ClinicalTrials.gov/NCT01105312