A phase II trial of dasatinib in patients with metastatic castration-resistant prostate cancer treated previously with chemotherapy

Przemyslaw W. Twardowski, Jan H. Beumer, C. S. Chen, Andrew Kraft, Gurkamal S. Chatta, Masato Mitsuhashi, Wei Ye, Susan M. Christner, Michael B. Lilly

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

There is a need for efficacious therapies for metastatic castration-resistant prostate cancer (mCRPC) after disease progression on docetaxel. The SRC tyrosine kinase and its related family members may be important drivers of prostate cancer and can be inhibited by dasatinib. mCRPC patients, after one previous chemotherapy, started dasatinib at 70 mg twice daily, amended to 100 mg daily. The primary endpoint was the disease control (DC) rate, defined as complete response (CR), partial response (PR), or stable disease (SD) in prostate specific antigen (PSA), RECIST, bone scan, and FACT-P score. Up to 41 patients were to be accrued (two-stage design, 21+20) to rule out a null-hypothesized effect of 5 versus 20% (α=0.05, β=0.1). Secondary endpoints included progression-free survival, toxicity, and pharmacokinetic and pharmacodynamic correlatives. Of 38 patients, 27 were evaluable for response or toxicity. The median duration of therapy was 55 days (6-284). Five patients showed DC after 8 weeks of therapy (18.5% DC, 95% CI: 6.3-38.1%). One PR (3.7% response rate, 95% CI: 0.1-19.0%) was observed in a patient treated for 284 days. Twelve patients (43%) discontinued treatment for toxicity. Dasatinib induced a decrease in phytohemagglutinin-stimulated CSF2, CD40L, GZMB, and IL-2 mRNAs in blood cells, indicating target engagement. Decreases in plasma IL-6 and bone alkaline phosphatase, and in urinary N-telopeptide, were associated with DC. Dasatinib has definite but limited activity in advanced mCRPC, and was poorly tolerated. The observation of a patient with prolonged, objective, clinically significant benefit warrants molecular profiling to select the appropriate patient population.

Original languageEnglish (US)
Pages (from-to)743-753
Number of pages11
JournalAnti-Cancer Drugs
Volume24
Issue number7
DOIs
StatePublished - Aug 2013
Externally publishedYes

Fingerprint

Castration
Prostatic Neoplasms
Drug Therapy
docetaxel
Bone and Bones
CD40 Ligand
Dasatinib
Phytohemagglutinins
Therapeutics
Prostate-Specific Antigen
Protein-Tyrosine Kinases
Disease-Free Survival
Interleukin-2
Alkaline Phosphatase
Disease Progression
Interleukin-6
Blood Cells
Pharmacokinetics
Observation
Messenger RNA

Keywords

  • dasatinib
  • prostate cancer
  • SRC inhibition

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Cancer Research
  • Oncology

Cite this

A phase II trial of dasatinib in patients with metastatic castration-resistant prostate cancer treated previously with chemotherapy. / Twardowski, Przemyslaw W.; Beumer, Jan H.; Chen, C. S.; Kraft, Andrew; Chatta, Gurkamal S.; Mitsuhashi, Masato; Ye, Wei; Christner, Susan M.; Lilly, Michael B.

In: Anti-Cancer Drugs, Vol. 24, No. 7, 08.2013, p. 743-753.

Research output: Contribution to journalArticle

Twardowski, PW, Beumer, JH, Chen, CS, Kraft, A, Chatta, GS, Mitsuhashi, M, Ye, W, Christner, SM & Lilly, MB 2013, 'A phase II trial of dasatinib in patients with metastatic castration-resistant prostate cancer treated previously with chemotherapy', Anti-Cancer Drugs, vol. 24, no. 7, pp. 743-753. https://doi.org/10.1097/CAD.0b013e328361feb0
Twardowski, Przemyslaw W. ; Beumer, Jan H. ; Chen, C. S. ; Kraft, Andrew ; Chatta, Gurkamal S. ; Mitsuhashi, Masato ; Ye, Wei ; Christner, Susan M. ; Lilly, Michael B. / A phase II trial of dasatinib in patients with metastatic castration-resistant prostate cancer treated previously with chemotherapy. In: Anti-Cancer Drugs. 2013 ; Vol. 24, No. 7. pp. 743-753.
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