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Investigational New Drugs

, Volume 32, Issue 5, pp 1005–1016 | Cite as

A randomized phase II study of cediranib alone versus cediranib in combination with dasatinib in docetaxel resistant, castration resistant prostate cancer patients

  • Anna Spreafico
  • Kim N. Chi
  • Srikala S. Sridhar
  • David C. Smith
  • Michael A. Carducci
  • Peter Kavsak
  • Tracy S. Wong
  • Lisa Wang
  • S. Percy Ivy
  • Som Dave Mukherjee
  • Christian K. Kollmannsberger
  • Mahadeo A. Sukhai
  • Naoko Takebe
  • Suzanne Kamel-Reid
  • Lillian L. Siu
  • Sebastien J. HotteEmail author
PHASE II STUDIES

Summary

Background Activation of the vascular endothelial growth factor receptor (VEGFR) and the oncogenic Src pathway has been implicated in the development of castration-resistant prostate cancer (CRPC) in preclinical models. Cediranib and dasatinib are multi-kinase inhibitors targeting VEGFR and Src respectively. Phase II studies of cediranib and dasatinib in CRPC have shown single agent activity. Methods Docetaxel-pretreated CRPC patients were randomized to arm A: cediranib alone (20 mg/day) versus arm B: cediranib (20 mg/day) plus dasatinib (100 mg/day) given orally on 4-week cycles. Primary endpoint was 12-week progression-free survival (PFS) as per the Prostate Cancer Clinical Trials Working Group (PCWG2). Patient reported outcomes were evaluated using Functional Assessment of Cancer Therapy-Prostate (FACT-P) and Present Pain Intensity (PPI) scales. Correlative studies of bone turnover markers (BTM), including bone alkaline phosphate (BAP) and serum beta-C telopeptide (B-CTx) were serially assayed. Results A total of 22 patients, 11 per arm, were enrolled. Baseline demographics were similar in both arms. Median number of cycles =4 in arm A (range 1–12) and 2 in arm B (range 1–9). Twelve-week PFS was 73 % in arm A versus 18 % in arm B (p = 0.03). Median PFS in months (arm A versus B) was: 5.2 versus 2.6 (95 % CI: 1.9–6.5 versus 1.4-not reached). Most common grade 3 toxicities were hypertension, anemia and thrombocytopenia in arm A and hypertension, diarrhea and fatigue in arm B. One treatment-related death (retroperitoneal hemorrhage) was seen in arm A. FACT-P and PPI scores did not significantly change in either arm. No correlation between BTM and PFS was seen in either arm. Conclusions Although limited by small numbers, this randomized study showed that the combination of VEGFR and Src targeted therapy did not result in improved efficacy and may be associated with a worse outcome than VEGFR targeted therapy alone in patients with CRPC. ClinicalTrials.gov number: NCT01260688.

Keywords

Cediranib Dasatinib Castration resistant prostate cancer Quality of life Bone turnover marker 

Notes

Acknowledgments

This study (PJC-002/CTEP 8476), supported by the US National Cancer Institute, is led by the Princess Margaret Hospital Phase I Consortium (U01-CA132123), with participation from the University of Chicago Phase II Consortium (N01-CM-2011-00071) and the Johns Hopkins Kimmel Cancer Center Phase I Consortium (U01-CA70095).

Supplementary material

10637_2014_106_MOESM1_ESM.doc (1.6 mb)
ESM 1 (DOC 1603 kb)

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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Anna Spreafico
    • 1
  • Kim N. Chi
    • 2
  • Srikala S. Sridhar
    • 1
  • David C. Smith
    • 3
  • Michael A. Carducci
    • 4
  • Peter Kavsak
    • 5
  • Tracy S. Wong
    • 1
  • Lisa Wang
    • 1
  • S. Percy Ivy
    • 6
  • Som Dave Mukherjee
    • 5
  • Christian K. Kollmannsberger
    • 2
  • Mahadeo A. Sukhai
    • 1
  • Naoko Takebe
    • 7
  • Suzanne Kamel-Reid
    • 1
  • Lillian L. Siu
    • 1
  • Sebastien J. Hotte
    • 5
    Email author
  1. 1.Princess Margaret Cancer CenterTorontoCanada
  2. 2.British Columbia Cancer AgencyVancouverCanada
  3. 3.University of MichiganAnn ArborUSA
  4. 4.Johns Hopkins School of Medicine, Sidney Kimmel Comprehensive Cancer CenterBaltimoreUSA
  5. 5.Juravinski Cancer CentreHamiltonCanada
  6. 6.Cancer Therapy Evaluation ProgramNational Cancer InstituteBethesdaUSA
  7. 7.Division of Cancer Treatment and DiagnosisNational Cancer Institute NIHBethesdaUSA

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