title: A phase I trial of combination trastuzumab, lapatinib, and bevacizumab in patients with advanced cancer.
abstract: OBJECTIVE
  Preclinical data indicate that combination HER2-directed and anti-VEGF therapy may bypass resistance to trastuzumab. A phase I trial was performed to assess safety, activity, and correlates.
  
  
  METHODS
  Patients with advanced, refractory malignancy were enrolled (modified 3 + 3 design with expansions for responding tumor types). Patients received lapatinib daily for 21 days, and bevacizumab and trastuzumab every 3 weeks. Correlates included HER2 extracellular domain levels (ECD) and single nucleotide polymorphisms (SNPs).
  
  
  RESULTS
  Ninety-four patients were treated (median = four prior systemic therapies). The most common related adverse events ≥ grade 2 were diarrhea (n = 33, 35 %) and hypertension (n = 10, 11 %). The recommended phase 2 dose was trastuzumab 6 mg/m(2) (loading = 8 mg/m(2)) and bevacizumab 15 mg/kg every 3 weeks, with lapatinib 1,250 mg daily (full FDA-approved dose of each drug). One patient (1 %) achieved a complete response (CR); eight (9 %), a partial response (PR) (includes breast (n = 7, one of which was HER2 2+ by IHC) and salivary ductal carcinoma (n = 1); and 14 (15 %), stable disease (SD) ≥6 months (total SD ≥ 6 months/PR/CR =23 (25 %). All patients with PR/CR received prior trastuzumab +/- lapatinib. SD ≥ 6 months/PR/CR rate and time to treatment failure (TTF) correlated with elevated baseline HER2 ECD (N = 75 patients tested) but not with HER2 SNPs.
  
  
  CONCLUSIONS
  Combination trastuzumab, lapatinib, and bevacizumab was well-tolerated and demonstrated antitumor activity in heavily pretreated patients with advanced malignancy.
authors.affiliation: Sarah Cannon Research Institute at HealthONE, Presbyterian/St. Luke's Medical Center, 1800 Williams Street, Suite 300, Denver, CO, 80218, USA, gerald.falchook@scresearch.net.
authors.forename: Gerald S
authors.initials: GS
authors.lastname: Falchook
authors.forename: Stacy
authors.initials: S
authors.lastname: Moulder
authors.forename: Aung
authors.initials: A
authors.lastname: Naing
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Wheler
authors.forename: David S
authors.initials: DS
authors.lastname: Hong
authors.forename: Sarina A
authors.initials: SA
authors.lastname: Piha-Paul
authors.forename: Apostolia M
authors.initials: AM
authors.lastname: Tsimberidou
authors.forename: Siqing
authors.initials: S
authors.lastname: Fu
authors.forename: Ralph
authors.initials: R
authors.lastname: Zinner
authors.forename: Filip
authors.initials: F
authors.lastname: Janku
authors.forename: Yunfang
authors.initials: Y
authors.lastname: Jiang
authors.forename: Mei
authors.initials: M
authors.lastname: Huang
authors.forename: Kristin L
authors.initials: KL
authors.lastname: Parkhurst
authors.forename: Razelle
authors.initials: R
authors.lastname: Kurzrock
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D000068258:Bevacizumab; D005260:Female; D006801:Humans; D000077341:Lapatinib; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D000068878:Trastuzumab; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D000077341:Lapatinib; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human