title: A Phase I/II Trial of BNC105P with Everolimus in Metastatic Renal Cell Carcinoma.
abstract: OBJECTIVE
  BNC105P inhibits tubulin polymerization, and preclinical studies suggest possible synergy with everolimus. In this phase I/II study, efficacy and safety of the combination were explored in patients with metastatic renal cell carcinoma (mRCC).
  
  
  METHODS
  A phase I study in patients with clear cell mRCC and any prior number of therapies was conducted using a classical 3 + 3 design to evaluate standard doses of everolimus with increasing doses of BNC105P. At the recommended phase II dose (RP2D), patients with clear cell mRCC and one to two prior therapies (including ≥ 1 VEGF-TKI) were randomized to BNC105P with everolimus (arm A) or everolimus alone (arm B). The primary endpoint of the study was 6-month progression-free survival (6MPFS). Secondary endpoints included response rate, PFS, overall survival, and exploratory biomarker analyses.
  
  
  RESULTS
  In the phase I study (N = 15), a dose of BNC105P at 16 mg/m(2) with everolimus at 10 mg daily was identified as the RP2D. In the phase II study, 139 patients were randomized, with 69 and 67 evaluable patients in arms A and B, respectively. 6MPFS was similar in the treatment arms (arm A: 33.82% vs. arm B: 30.30%, P = 0.66) and no difference in median PFS was observed (arm A: 4.7 mos vs. arm B: 4.1 mos; P = 0.49). Changes in matrix metalloproteinase-9, stem cell factor, sex hormone-binding globulin, and serum amyloid A protein were associated with clinical outcome with BNC105P.
  
  
  CONCLUSIONS
  Although the primary endpoint was not met in an unselected population, correlative studies suggest several biomarkers that warrant further prospective evaluation.
authors: City of Hope Medical Center, Duarte, California. spal@coh.org.
authors: Sumanta
authors: S
authors: Pal
authors: BC Cancer Agency, Vancouver, British Columbia, Canada.
authors: Arun
authors: A
authors: Azad
authors: University of Washington, Seattle, Washington.
authors: Shailender
authors: S
authors: Bhatia
authors: Medical University of South Carolina, Charleston, South Carolina.
authors: Harry
authors: H
authors: Drabkin
authors: Mayo Clinic, Rochester, Minnesota.
authors: Brian
authors: B
authors: Costello
authors: University of Texas Health Science Center, San Antonio, Texas.
authors: John
authors: J
authors: Sarantopoulos
authors: National Cancer Center, Singapore.
authors: Ravindran
authors: R
authors: Kanesvaran
authors: University of New Mexico Cancer Center, Albuquerque, New Mexico.
authors: Richard
authors: R
authors: Lauer
authors: Indiana University Health Goshen Center for Cancer Care, Goshen, Indiana.
authors: Alexander
authors: A
authors: Starodub
authors: Nebraska Cancer Specialists/Nebraska Methodist Hospital, Omaha, Nebraska.
authors: Ralph
authors: R
authors: Hauke
authors: Dana-Farber Cancer Center, Boston, Massachusetts.
authors: Christopher J
authors: CJ
authors: Sweeney
authors: Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland.
authors: Noah M
authors: NM
authors: Hahn
authors: University of Alabama, Birmingham, Alabama.
authors: Guru
authors: G
authors: Sonpavde
authors: Texas Oncology, Fort Worth, Texas.
authors: Stephen
authors: S
authors: Richey
authors: Hoosier Cancer Research Network, Indianapolis, Indiana.
authors: Timothy
authors: T
authors: Breen
authors: Bionomics, Thebarton, South Australia, Australia.
authors: Gabriel
authors: G
authors: Kremmidiotis
authors: Bionomics, Thebarton, South Australia, Australia.
authors: Annabell
authors: A
authors: Leske
authors: Bionomics, Thebarton, South Australia, Australia.
authors: Elizabeth
authors: E
authors: Doolin
authors: Bionomics, Thebarton, South Australia, Australia.
authors: David C
authors: DC
authors: Bibby
authors: Bionomics, Thebarton, South Australia, Australia.
authors: Jeremy
authors: J
authors: Simpson
authors: Bionomics, Thebarton, South Australia, Australia.
authors: Jose
authors: J
authors: Iglesias
authors: Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas.
authors: Thomas
authors: T
authors: Hutson
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D001572:Benzofurans / Q000008:administration & dosage* / Q000009:adverse effects; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018572:Disease-Free Survival; D000068338:Everolimus / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D008875:Middle Aged; D010755:Organophosphates / Q000008:administration & dosage* / Q000009:adverse effects; D012738:Sex Hormone-Binding Globulin / Q000096:biosynthesis; D016896:Treatment Outcome
chemical_list: C568089:BNC 105P; D001572:Benzofurans; D010755:Organophosphates; D012738:Sex Hormone-Binding Globulin; D000068338:Everolimus; D020780:Matrix Metalloproteinase 9