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Published on: August 19, 2025
Phase I Study of Panobinostat (LBH589) and Letrozole in Postmenopausal Metastatic Breast Cancer Patients
Winston W Tan1, Jacob B Allred2, Alvaro Moreno-Aspitia1
1Department of Hematology/Oncology, Mayo Clinic, Jacksonville, FL.
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.
Insights
Panobinostat combined with letrozole showed promise in metastatic breast cancer. The recommended Phase II dose is 20 mg panobinostat three times weekly with letrozole, with potential escalation to 30 mg.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- Histone deacetylase inhibitors can restore estrogen receptor sensitivity in endocrine-resistant and triple-negative breast cancer.
- Preclinical data supported the investigation of panobinostat, a pan-histone deacetylase inhibitor, in combination with letrozole.
Purpose of the Study:
- To determine the safety and tumor response of panobinostat combined with letrozole in patients with metastatic breast cancer.
- To establish the maximum tolerated dose (MTD) and recommended Phase II starting dose for this combination therapy.
Main Methods:
- A Phase I clinical trial enrolled patients with metastatic breast cancer.
- Two dose levels were tested: Dose Level 1 (20 mg panobinostat 3x/week + 2.5 mg letrozole daily) and Dose Level 2 (30 mg panobinostat 3x/week + 2.5 mg letrozole daily).
- Safety was assessed by dose-limiting toxicities (DLTs), and tumor response was evaluated using Response Evaluation Criteria In Solid Tumors (RECIST).
Main Results:
- Twelve patients were enrolled, receiving a total of 43 cycles.
- The maximum tolerated dose was determined to be 20 mg of panobinostat.
- Two patients (16.7%) achieved a partial response, and five (41.7%) had stable disease. Thrombocytopenia was the most common severe adverse event.
Conclusions:
- The recommended Phase II starting dose is 20 mg of panobinostat orally three times weekly with 2.5 mg of oral letrozole daily.
- Dose escalation to 30 mg panobinostat three times weekly is suggested if no grade 3 toxicity occurs, given that partial responses were observed at this higher dose.
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