title: A phase 1 study of intermittently administered pazopanib in combination with continuous daily dosing of lapatinib in patients with solid tumors.
abstract: OBJECTIVE
  Preclinically, pazopanib/lapatinib combination acted synergistically to suppress the activity of multiple tyrosine kinases, including VEGFR-1, 2, 3, PDGFR and c-kit (pazopanib), HER1/EGFR and HER2 (lapatinib), and several other tyrosine kinases including c-Met through, plausibly, network inhibition effects. Clinically, continuous dosing of pazopanib/lapatinib combination was associated with a higher response rate than with lapatinib monotherapy, with poor tolerance. We explored multiple intermittent dose levels of pazopanib combined with continuous daily dosing of lapatinib in patients with solid tumors.
  
  
  METHODS
  The present study used a phase 1, modified 3 + 3, dose-escalation design to evaluate the safety and tolerability of the combination of orally received pazopanib once every other day with continuous daily dosing of lapatinib for 28 days. In the expansion phase, tumor response was evaluated in patients with specific genetic alterations (HER2 amplification, HER2 mutation, c-Met amplification, c-Met mutation, and EGFR mutation).
  
  
  RESULTS
  Twenty-four patients were treated. The most common drug-related adverse events were fatigue 7/24 (29%), skin rash 5/21 (21%), and diarrhea 3/24 (17%), with 4/24 (16%) patients experiencing grade ≥3 drug-related adverse events. Escalation to the FDA-approved dose (800 mg daily for pazopanib and 1500 mg every day for lapatinib) was not feasible due to toxicities. Pazopanib 200 mg every other day + lapatinib 500 mg daily was considered the maximum tolerated dose (MTD). No tumor response was observed, including in patients with the specific molecular genetic alterations tested.
  
  
  CONCLUSIONS
  Every other day dosing of pazopanib combined with daily lapatinib was tolerated at the established MTD, but no complete or partial tumor responses were observed at these dose levels.
authors.affiliation: Departments of Investigational Cancer Therapeutics (Phase I Program), Clinical Center for Targeted Therapy, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Box 455, Houston, TX, 77030, USA.
authors.forename: H
authors.initials: H
authors.lastname: Henary
authors.forename: G C
authors.initials: GC
authors.lastname: George
authors.forename: J
authors.initials: J
authors.lastname: Wheler
authors.forename: A
authors.initials: A
authors.lastname: Naing
authors.forename: S
authors.initials: S
authors.lastname: Piha-Paul
authors.forename: S
authors.initials: S
authors.lastname: Fu
authors.forename: R
authors.initials: R
authors.lastname: Mistry
authors.forename: R
authors.initials: R
authors.lastname: Zinner
authors.forename: R
authors.initials: R
authors.lastname: Kurzrock
authors.forename: D S
authors.initials: DS
authors.lastname: Hong
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D005784:Gene Amplification; D006801:Humans; D007191:Indazoles; D000077341:Lapatinib; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects
chemical_list: D066246:ErbB Receptors; D007191:Indazoles; D000077341:Lapatinib; D019859:Proto-Oncogene Proteins c-met; D011743:Pyrimidines; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D013449:Sulfonamides; C516667:pazopanib; C512478:EGFR protein, human; C508053:ERBB2 protein, human