title: Phase I study of bevacizumab, everolimus, and panobinostat (LBH-589) in advanced solid tumors.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors: Duke University Medical Center, Durham, NC 27710, USA.
authors: John H
authors: JH
authors: Strickler
authors: Alexander N
authors: AN
authors: Starodub
authors: Jingquan
authors: J
authors: Jia
authors: Kellen L
authors: KL
authors: Meadows
authors: Andrew B
authors: AB
authors: Nixon
authors: Andrew
authors: A
authors: Dellinger
authors: Michael A
authors: MA
authors: Morse
authors: Hope E
authors: HE
authors: Uronis
authors: P Kelly
authors: PK
authors: Marcom
authors: S Yousuf
authors: SY
authors: Zafar
authors: Sherri T
authors: ST
authors: Haley
authors: Herbert I
authors: HI
authors: Hurwitz
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000068258:Bevacizumab; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D000068338:Everolimus; D005260:Female; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage; D007211:Indoles; D007275:Injections, Intravenous; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D000077767:Panobinostat; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D006877:Hydroxamic Acids; D007211:Indoles; D000068258:Bevacizumab; D000077767:Panobinostat; D000068338:Everolimus; D020123:Sirolimus