title: Phase I combination of pazopanib and everolimus in PIK3CA mutation positive/PTEN loss patients with advanced solid tumors refractory to standard therapy.
abstract: OBJECTIVE
  Combining agents that block both the VEGF and PI3K/AKT/mTOR pathways may be synergistic. We explored a novel dosing schedule to assess safety, toxicity and activity in patients with advanced solid tumors.
  
  
  METHODS
  Patients with refractory solid tumors were enrolled in a modified 3 + 3 Phase I dose escalation study to determine dose limiting toxicities (DLTs) and the maximum tolerated dose (MTD) of a combination of everolimus (mTOR inhibitor) and pazopanib (tyrosine kinase inhibitor with anti-VEGF activity). An expansion cohort selected for patients with molecular alterations in the PI3K/AKT/mTOR pathway.
  
  
  RESULTS
  Sixty-two patients were enrolled; median age was 60 years; 29 were women. The MTD was pazopanib 600 mg every other day (QOD) alternating with everolimus 10 mg PO QOD. DLTs were grade 3 thrombocytopenia and creatinine elevation. Most common toxicities of any grade were thrombocytopenia, transaminitis, leukopenia/neutropenia and lipid abnormalities. Among 52 patients evaluable for response, the clinical benefit rate (CBR) was 27 % (14/52) including four partial responses (PR), and 10 stable disease (SD) ≥6 months. 26 of 45 patients evaluated for molecular alterations had at least one alteration in the PI3K/AKT/mTOR pathway. CBR in patients with a matched alteration was 27 % (7/26) versus 26 % (5/19) for patients without an alteration (p = 0.764). However, 64% of those with CBR and molecular testing done for alteration in the PI3K/AKT/mTOR pathway were positive.
  
  
  CONCLUSIONS
  Combination treatment with pazopanib and everolimus was well tolerated and demonstrated activity in solid tumors. Further exploration of this combination and molecular correlation with treatment outcomes is warranted.
authors.affiliation: Centro de Oncologia e Hematologia do Hospital Israelita Albert Einstein, São Paulo, Brazil.
authors.forename: Heloisa Veasey
authors.initials: HV
authors.lastname: Rodrigues
authors.forename: Danxia
authors.initials: D
authors.lastname: Ke
authors.forename: JoAnn
authors.initials: J
authors.lastname: Lim
authors.forename: Bettzy
authors.initials: B
authors.lastname: Stephen
authors.forename: Jorge
authors.initials: J
authors.lastname: Bellido
authors.forename: Filip
authors.initials: F
authors.lastname: Janku
authors.forename: Ralph
authors.initials: R
authors.lastname: Zinner
authors.forename: Apostolia
authors.initials: A
authors.lastname: Tsimberidou
authors.forename: David
authors.initials: D
authors.lastname: Hong
authors.forename: Sarina
authors.initials: S
authors.lastname: Piha-Paul
authors.forename: Siqing
authors.initials: S
authors.lastname: Fu
authors.forename: Aung
authors.initials: A
authors.lastname: Naing
authors.forename: Vivek
authors.initials: V
authors.lastname: Subbiah
authors.forename: Daniel
authors.initials: D
authors.lastname: Karp
authors.forename: Gerald
authors.initials: G
authors.lastname: Falchook
authors.forename: Razelle
authors.initials: R
authors.lastname: Kurzrock
authors.forename: Jennifer
authors.initials: J
authors.lastname: Wheler
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D000068338:Everolimus / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007191:Indazoles; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D011743:Pyrimidines / Q000009:adverse effects / Q000627:therapeutic use*; D013449:Sulfonamides / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000068338:Everolimus; D007191:Indazoles; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D011743:Pyrimidines; D013449:Sulfonamides; C516667:pazopanib