Study of Dasatinib and Docetaxel in Metastatic Hormone Refractory Prostate Cancer

Phase I/II Study of Dasatinib and Docetaxel in Metastatic Hormone Refractory Prostate Cancer

The purpose of this study is to find the recommended doses of dasatinib and docetaxel given in combination to men with metastatic hormone refractory prostate cancer and to assess the pharmacokinetic interactions between the 2 drugs.

Key Inclusion Criteria:

• Histologically or cytologically confirmed adenocarcinoma of the prostate that was clinically refractory to hormone therapy

• Eastern Cooperative Oncology Group performance status of 0 - 2

• Evidence of progressive metastatic disease at time of enrollment

• Measurable disease on either computer tomography scan or magnetic resonance imaging or positive bone scan with any level of serum prostate specific antigen (PSA) ≥5 ng/ml. Patients with PSA ≥5 ng/ml only and no other radiographic evidence of metastatic prostate cancer were not eligible

• Evidence of progressive disease since the most recent change in therapy. Progressive disease was defined as any one of the following:

  • Objective disease progression: Objective evidence of increase in radiographic lesions or the appearance of 1 or more new lesions
  • Bone scan progression: Appearance of either of the following: 2 or more new lesions on bone scan attributable to prostate cancer or 1 new lesion on bone scan attributable to prostate cancer in conjunction with a rising PSA
  • PSA progression: 2 consecutively rising PSA levels (≥5 ng/mL) separated by 2 weeks with a testosterone concentration of ≤50 ng/dL at 2 week intervals

• Serum testosterone levels ≤50 ng/dL, determined within 2 weeks prior to starting treatment

• Maintaining castrate status: patients who had not undergone surgical orchiectomy must have continued on medical therapies, such as gonadotropin-releasing hormone analogs, to maintain castrate levels of serum testosterone. Those receiving an antiandrogen as part of their first-line hormonal therapy must have shown progression of disease off of the antiandrogen prior to enrollment (6 weeks withdrawal for bicalutamide; 4 weeks for flutamide)

Key Exclusion Criteria:

• Sexually active fertile men not using effective birth control if their partners were women of child-bearing potential

• Known brain metastases

• Clinically-significant cardiovascular disease, including myocardial infarction or ventricular tachyarrhythmia within 6 months; prolonged heart rate-corrected QT interval (QTc) >450 msec; ejection fraction <40%, or major conduction abnormality (unless a cardiac pacemaker was present)

• Pleural or pericardial effusion, due to concerns that the combination of docetaxel and dasatinib could worsen these events

• Uncontrolled intercurrent illness including, ongoing or active infection, cardiac arrhythmia, or psychiatric illness/social situations that limit compliance with study requirements

• Participants were permitted to continue on a daily multivitamin but all other herbal, alternative, and food supplements must have been discontinued before enrollment into the study

• Ketoconazole must have been discontinued 4 weeks prior to enrollment

• Patients were not permitted to receive radioactive bone targeting agents, such as Strontium or Samarian ,while on study treatment

• The following restrictions on prior therapy for metastatic disease applied:

  • One chemotherapy regimen was permitted as long as docetaxel resistance or intolerance was not demonstrated. Docetaxel resistance was defined as objective disease progression or confirmed PSA progression during docetaxel therapy or within 3 months of treatment completion. Docetaxel intolerance was defined as toxicity requiring docetaxel interruption >4 weeks or dose modification below approved doses
  • No more than 1 prior course of palliative radiotherapy
  • Up to 1 prior treatment with a nonchemotherapeutic agent was permitted as treatment for metastatic prostate cancer
  • No prior radioisotope therapy with Strontium-89, Samarium, or similar agents
  • No limitation on prior hormonal therapy
  • QTc prolonging agents strongly associated with Torsade de Pointes arrhythmia