Phase I study of bevacizumab, everolimus, and panobinostat (LBH-589) in advanced solid tumors.
Journal Article (Journal Article)
PURPOSE: To define the maximum tolerated dose, clinical toxicities, and pharmacodynamics of bevacizumab, everolimus, and panobinostat (LBH-589) when administered in combination to patients with advanced solid tumor malignancies. EXPERIMENT DESIGN: Subjects received 10 mg of panobinostat three times weekly, 5 or 10 mg everolimus daily, and bevacizumab at 10 mg/kg every 2 weeks. Dose-limiting toxicities (DLTs) were assessed in cycle 1; toxicity evaluation was closely monitored throughout treatment. Treatment continued until disease progression or undesirable toxicity. Protein acetylation was assessed in peripheral blood mononuclear cells (PBMC) both at baseline and on treatment. RESULTS: Twelve subjects were evaluable for toxicity and nine subjects for response. DLTs in cohort 1 included grade 2 esophagitis and grade 3 oral mucositis; DLTs in cohort -1 were grade 2 ventricular arrhythmia and grade 2 intolerable skin rash. Common adverse events were diarrhea (50 %), headache (33 %), mucositis/stomatitis (25 %), hyperlipidemia (25 %), and thrombocytopenia (25 %). There was 1 partial response; an additional 2 subjects had stable disease as best response. No consistent changes in protein acetylation in PBMC were observed in samples available from eight patients on treatment compared with baseline. CONCLUSIONS: Bevacizumab, everolimus, and panobinostat in combination at the lowest proposed doses did not have an acceptable safety and tolerability profile and did not consistently inhibit HDAC activity; therefore, we do not recommend further evaluation.
Full Text
Duke Authors
- Hurwitz, Herbert Ira
- Marcom, Paul Kelly
- Morse, Michael Aaron
- Nixon, Andrew Benjamin
- Strickler, John
- Uronis, Hope Elizabeth
- Zafar, Syed Yousuf
Cited Authors
- Strickler, JH; Starodub, AN; Jia, J; Meadows, KL; Nixon, AB; Dellinger, A; Morse, MA; Uronis, HE; Marcom, PK; Zafar, SY; Haley, ST; Hurwitz, HI
Published Date
- August 2012
Published In
Volume / Issue
- 70 / 2
Start / End Page
- 251 - 258
PubMed ID
- 22744359
Pubmed Central ID
- PMC3793400
Electronic International Standard Serial Number (EISSN)
- 1432-0843
Digital Object Identifier (DOI)
- 10.1007/s00280-012-1911-1
Language
- eng
Conference Location
- Germany