title: Phase II trial of lapatinib and topotecan (LapTop) in patients with platinum-refractory/resistant ovarian and primary peritoneal carcinoma.
abstract: OBJECTIVE
  Resistance to chemotherapy is a major challenge in the treatment of ovarian/peritoneal cancer. One purported mechanism of topotecan resistance is the breast cancer resistance protein (BCRP) and P-glycoprotein (Pgp). We designed a phase II clinical trial evaluating the efficacy and adverse event profile of concomitant topotecan and lapatinib, a small molecule pan-erbB inhibitor that can block BCRP/Pgp efflux of topotecan.
  
  
  METHODS
  Patients with platinum-refractory or resistant epithelial ovarian/peritoneal cancer were treated with topotecan 3.2 mg/m² IV on Day 1, 8 and 15 and lapatinib 1250 mg PO daily, continuously in 28 day cycles. The primary endpoint was response rate. For correlative studies, archived tissue was assessed for expression of EGFR, HER2, HIF-1α, CD31, and BCRP.
  
  
  RESULTS
  Eighteen patients were enrolled and treated. Four experienced evidence of clinical benefit: one partial response and three with stable disease. Using a two-stage Simon design, the trial was stopped after the first stage due to insufficient activity. Grades 3+ and 4+ adverse events (AE) were experienced in 14 and 4 patients, respectively. The most common grade 3/4 AE were neutropenia (56%), thrombocytopenia (28%), and diarrhea (22%).
  
  
  CONCLUSIONS
  The combination of lapatinib plus topotecan for the treatment of platinum refractory/resistant epithelial ovarian cancer lacks sufficient activity to warrant further investigation. In particular, hematologic adverse events were substantial. Expression of correlative study markers did not reveal patterns of predicted benefit or toxicity. Disruption of erbB signaling and BCRP/Pgp efflux with lapatinib was insufficient for overcoming topotecan resistance, suggesting alternative mechanisms of resistance are involved.
authors.affiliation: Department of Medical Oncology, Mayo, Rochester, MN 55905, USA.
authors.forename: S John
authors.initials: SJ
authors.lastname: Weroha
authors.forename: Ann L
authors.initials: AL
authors.lastname: Oberg
authors.forename: Katie L Allen
authors.initials: KL
authors.lastname: Ziegler
authors.forename: Shaker R
authors.initials: SR
authors.lastname: Dakhilm
authors.forename: Kendrith M
authors.initials: KM
authors.lastname: Rowland
authors.forename: Lynn C
authors.initials: LC
authors.lastname: Hartmann
authors.forename: Dennis F
authors.initials: DF
authors.lastname: Moore
authors.forename: Gary L
authors.initials: GL
authors.lastname: Keeney
authors.forename: Prema P
authors.initials: PP
authors.lastname: Peethambaram
authors.forename: Paul
authors.initials: P
authors.lastname: Haluska
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use*; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000096:biosynthesis; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis; D000077341:Lapatinib; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000096:biosynthesis; D009944:Organoplatinum Compounds / Q000494:pharmacology; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D010534:Peritoneal Neoplasms / Q000188:drug therapy*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000096:biosynthesis; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis; D015996:Survival Rate; D019772:Topotecan / Q000008:administration & dosage / Q000009:adverse effects
chemical_list: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D066246:ErbB Receptors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000077341:Lapatinib; D009363:Neoplasm Proteins; D009944:Organoplatinum Compounds; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D019772:Topotecan; C116614:ABCG2 protein, human; C497442:HIF1A protein, human