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

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.

Conflict of interest statement

Conflicts of Interest: WWT is a member of the Pharma-net data monitoring committee. JBA has no conflicts of interest to disclose. AMA has no conflicts of interest to disclose. DWN has no conflicts of interest to disclose. JNI has no conflicts of interest to disclose. MPG has no conflicts of interest to disclose. EAP’s research receives funding from Genentech, GlaxoSmithKline, and Genomic Health.

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