TY - JOUR
T1 - Phase i Study of Panobinostat (LBH589) and Letrozole in Postmenopausal Metastatic Breast Cancer Patients
AU - Tan, Winston W.
AU - Allred, Jacob B.
AU - Moreno-Aspitia, Alvaro
AU - Northfelt, Donald W.
AU - Ingle, James N.
AU - Goetz, Matthew P.
AU - Perez, Edith A.
N1 - Funding Information:
W.W. Tan is a member of the Pharma-net data monitoring committee. E.A. Perez's research receives funding from Genentech , GlaxoSmithKline , and Genomic Health . The remaining authors declare that they have no competing interests.
Funding Information:
W.W. Tan is the primary investigator for the North Central Cancer Treatment Group N093B phase I/II study of panobinostat (LBH589) and letrozole in patients with triple negative metastatic breast cancer ( ClinicalTrials.gov identifier, NCT01105312 ). The present study was sponsored by Novartis .
PY - 2016/4/1
Y1 - 2016/4/1
N2 - 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.
AB - 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.
KW - Aromatase refractory
KW - Endocrine resistant breast cancer
KW - Histone deacetylase inhibitors
KW - Phase I study
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U2 - 10.1016/j.clbc.2015.11.003
DO - 10.1016/j.clbc.2015.11.003
M3 - Article
C2 - 26774555
AN - SCOPUS:84960290488
VL - 16
SP - 82
EP - 86
JO - Clinical Breast Cancer
JF - Clinical Breast Cancer
SN - 1526-8209
IS - 2
ER -