Study of Dasatinib and Docetaxel in Metastatic Hormone Refractory Prostate Cancer

• Maximum Tolerated Dose (MTD) of Dasatinib Administered With Docetaxel [ Time Frame: From Day 3 of first 21-day cycle to Cycle 2 , Day 21 (or Study Day 42) ]
  MTD was defined by dose-limiting toxicity (DLT) criteria. DLT was defined as grade 4 neutropenia causing treatment interruption for >14 days, febrile neutropenia, grade 4 thrombocytopenia, grade 3 thrombocytopenia with a bleeding episode requiring platelet transfusion, nausea and/or vomiting despite medical intervention/prophylaxis causing treatment interruption for >14 days, grade 3-4 asthenia/fatigue, any other grade >=3 nonhematologic toxicity except alopecia or transient arthralgia/myalgia (unless unresponsive to intervention), or interruption of study drug for >14 days due to toxicity. When defined, the MTD would serve as recommended Phase 2 dose of each drug in the combination of oral dasatinib and intravenous docetaxel.
• Recommended Phase 2 Dose of Dasatinib Administered With Docetaxel, 75 mg/m^2 [ Time Frame: From Day 3 of first 21-day cycle to Cycle 2 , Day 21 (or Study Day 42) ]
  Because no dose-limiting toxicities occurred, the recommended dose of dasatinib used in Phase 2 was based on findings from ongoing studies in chronic myelogenous leukemia and experience from the previous Phase 2 study of single-agent dasatinib in chronic refractory prostate cancer. The recommended Phase 2 dose of docetaxel (75 mg/m^2) was based on the docetaxel package insert.

• Continuous safety assessment throughout treatment
• Pharmacokinetic data approximately at day 1, 14, and 21

• Percentage of Participants With a Prostate Specific Antigen (PSA) Response [ Time Frame: At pretreatment visit, and on Day 1 of Cycles 2 through 12, then every other cycle, where investigator deems appropriate, and at end of treatment (up to 51.6 months) ]
  PSA response rate is defined as a decrease of >=50% in PSA levels from baseline, sustained for at least 6 weeks and confirmed by at least 2 measurements
• Duration of Prostate Specific Antigen (PSA) Response [ Time Frame: At pretreatment visit, and on Day 1 of Cycles 2 through 12, then every other cycle, where investigator deems appropriate, and at end of treatment ]
  Duration of response is computed for participants with confirmed PSA response. It is measured in months from the time of the first of 2 consecutive measurements meeting the criteria for confirmed PSA response to the date of the first of 3 consecutive measurements that confirm PSA progression, the date of disease progression, or the date of death. Participants who neither progressed (PSA or disease) nor died were censored on the date of their last PSA assessment. PSA response is defined as a decrease of >=50% in PSA levels from baseline, sustained for at least 6 weeks and confirmed by at least 2 measurements. PSA progression is defined as 3 consecutive increases in PSA from baseline or nadir, each measurement at least 1 week apart. The final confirming PSA measurement had to be ≥5ng/mL higher than baseline or nadir and also represent at least a 50% increase from baseline or nadir (ie, the value is ≥1.5*baseline or nadir PSA).
• Number of Months of Progression-free Survival (PFS) [ Time Frame: Patients with an event: time from first dose to disease progression or death, whichever occurs first. Patients without an event: time to last on-study PSA measurement, tumor assessment, or radionuclide bone scan assessment, whichever occurs last ]

  PFS defined as time in months from the first dosing date to the date of disease progression or the date of death. Patients who neither progressed nor died were censored on the date of their last on-study prostate specific antigen (PSA) measurement, tumor assessment, or radionuclide bone scan assessment (whichever occurred last). Disease progression defined as either of the following: progression on radionuclide bone scan, death, or at least 2 of the following:

  tumor progression, as defined by modified Response Evaluation Criteria in Solid Tumors; PSA progression; or investigator-defined clinical progression based on physical examination, history, symptoms, and performance status.

• Percentage of Participants With an Objective Tumor Response by Response Evaluation Criteria in Solid Tumors (RECIST) [ Time Frame: Pretreatment visit then every 6 weeks thereafter (up to 51.6 months) ]
  Objective response rate is defined as the percentage of participants who have achieved best responses of confirmed Complete Response (CR) or Partial Response (PR) where confirmed requires repeat evaluations for a minimum of 4 weeks after the criteria for response are first met. RECIST: CR=disappearance of clinical and radiologic evidence of target lesions; PR=a 30% or greater decrease in the sum of the longest diameter (LD) of all lesions in reference to the baseline sum LD.
• Number of Participants by Best On-study Tumor Response by Response Evaluation Criteria in Solid Tumors (RECIST) [ Time Frame: Pretreatment visit then every 6 weeks thereafter (up to 51.6 months) ]

  RECIST for target lesions: Complete Response (CR)=disappearance of clinical and radiologic evidence of target lesions. Partial Response (PR)=a 30% or greater decrease in the sum of the longest diameter (LD) of all lesions in reference to the baseline sum LD. Stable disease (SD)=neither sufficient increase to qualify for Progressive Disease (PD) nor sufficient shrinkage to qualify for PR.

  PD=a 20% or greater increase in the sum of LD of all target lesions, taking as reference the smallest sum LD recorded at or following baseline; unequivocal progression of nonmeasurable disease/lesions as evaluated by CT scan or MRI (not as evaluated by radionuclide bone scan) and/or new lesions are present.

  To qualify as SD, patients had to exhibit SD for a minimum of 18 weeks. Those with evaluations noted as SD prior to 18 weeks and discontinued were reported as no change.

• Number of Participants by Best On-study Bone Scan Assessment From Baseline [ Time Frame: From Day 1 of therapy to last bone scan assessment (up to 51.6 months) ]
  Stable=no new lesions appeared at any 6-week assessment or new pain was not developed in an area that was previously visualized for a minimum of 18 weeks; no change=stable disease prior to 18 weeks and then discontinued treatment; progression=2 or more new areas of focal uptake or new adverse clinical symptoms in an area previously visualized; improved=disappearance of at least 1 lesion, no new lesions appearing since the most recent prior assessment, and new pain not developing in an area that was previously visualized.
• Percentage of Participants With Improvement on Bone Scan [ Time Frame: From Day 1 of therapy to last bone scan assessment (up to 51.6 months) ]
  Improvement=disappearance of at least 1 lesion, no new lesions appearing since the most recent prior assessment, and new pain not developing in an area that was previously visualized
• Baseline Scores and Changes in Pain Intensity From Baseline on the Brief Pain Inventory Short Form (BPI-sf) Scores Through Cycle 6 [ Time Frame: At pretreatment visit and on Day 1 of Cycles 2 through 6, then Day 1 of every other cycle, at end of treatment, and at follow-up visit ]
  The BPI-sf assessed intensity of pain in the last 24 hours as well as impact of pain on daily functions. Patients rated the severity of their pain at its worst, least, and average in the last 24 hours using an 11-point rating scale with endpoints of no pain (0 points) and pain as bad as you can imagine (11 points). They were asked to rate their present pain and pain at the time they completed the BPI-sf. Using an 11-point rating scale with endpoints of does not interfere (0 points) and completely interferes (11 points), the BPI-sf similarly assessed to what extent pain interfered with mood, walking, general activity, work, relations with others, sleep, and enjoyment of life. The BPI-sf also asked patients to mark the location of their pain on a body drawing and included other questions about pain treatment and the extent of pain relief. The BPI-sf was collected in the Phase 2 portion of the study only. For on-treatment visits, the BPI-sf was completed prior to the docetaxel infusion.
• Number of Participants With Death as Outcome, Serious Adverse Events (SAEs), Drug-related SAEs, Drug-related Adverse Events (AEs), Drug-related AEs Leading to Discontinuation, and Drug-related Grade 3 or 4 AEs in the Overall Population [ Time Frame: From first dose Day 1 through at least 30 days after last dose of either dasatinib or docetaxel, whichever was later (up to approximately 49 months) ]
  AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Drug-related=having certain, probable, possible, or missing relationship to study drug. Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Life-threatening or disabling, Grade 5=Leading to death.
• Number of Participants With Death as Outcome, Drug-related Serious Adverse Events (SAEs), Drug-related Adverse Events (AEs), Drug-related AEs Leading to Discontinuation, and Drug-related Grade 3 or 4 AEs in the Phase 2 Cohort [ Time Frame: From first dose Day 1 through at least 30 days after last dose of either dasatinib or docetaxel, whichever was later (up to approximately 49 months) ]
  AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Drug-related=having certain, probable, possible, or missing relationship to study drug. Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Life-threatening or disabling, Grade 5=Leading to death.
• Area Under the Concentration-time Curve (AUC) From 0 to 10 Hours Postdose (AUC [0-10])and AUC in 1 Dosing Interval, From Time 0 to 24 Hours (AUC[Tau])of Dasatinib Coadministered With Docetaxel [ Time Frame: Cycle 1, Day 14 at 0, 0.5 , 1, 2, 3, 4, 7, 10, and 24 hours postdose ]
• Maximum Observed Plasma Concentration (Cmax) of Dasatinib and of Docetaxel [ Time Frame: Docetaxel: Cycle 1, Day 1 at 0, 0.5, 1, 1.25, 1.5, 2, 3, 4, 7, 10, 24, and 48 hours postdose; dasatanib: Cycle 1, Day 14 at 0, .5, 1, 2, 3, 4, 7, 10, and 24 hours postdose ]
• Area Under the Concentration-time Curve (AUC) From Time 0 to Infinity (AUC[Inf]) of Docetaxel [ Time Frame: Cycle 1, Day 1 at 0, 0.5, 1, 1.25, 1.5, 2, 3, 4, 7, 10, 24, and 48 hours postdose ]
• Number of Participants Meeting the Criteria for On-study Abnormal Results Grade 3-4 of Clinical Laboratory Tests [ Time Frame: From Day 2 of Cycle 1 to up to 30 days after last dose of study drug (up to approximately 49 months) ]
  ULN=upper limit of normal. Graded by Common Toxicity Criteria: 1 (least severe) to 4 (life threatening ). Absolute neutrophil count (*10^9/L), Grade 3, <1.0-0.5; Grade 4, <0.5. Hemoglobin (mmol/L), Grade 3, <4.9-4.0; Grade 4, <4.0. Platelets (*10^9/L), Grade 3, <50.0-25.0; Grade 4, <25.0. Leukocytes (*10^9/L) Grade 3, <2.0-1.0; Grade 4, <1.0. ALP, ALT, and AST (*ULN), Grade 3, >5.0-20.0; Grade 4, >20.0. Total bilirubin (*ULN), Grade 3, >3.0-10.0; Grade 4, >10.0. Creatinine (*ULN), Grade 3, >3.0-6.0; Grade 4, >6.0. Hypercalcemia (mmol/L), Grade 3, >3.1-3.4; Grade 4, >3.4. Hypocalcemia mmol/L), Grade 3, <1.75-1.5; Grade 4, <1.5. Hyperkalemia (mmol/L), Grade 3, >6.0-7.0; Grade 4, >7.0. Hypokalemia (mmol/L), Grade 3, <3.0-2.5; Grade 4, <2.5. Hypernatremia (mmol/L), Grade 3, >155-160; Grade 4, >160. Hyponatremia (mmol/L), Grade 3, <130-120; Grade 4, <120. Phosphorus (mmol/L), Grade 3, <0.6-0.3; Grade 4, <0.3. Prothrombin time (seconds), Grade 3, >2.0; Grade 4, not defined.

• Assess safety and tolerability of combination
• Estimate efficacy (PSA, objective tumor response, progression free survival, bone scan changes)

• Drug: Dasatinib
  Tablets, Oral, 50, 70, 100, or 120 mg once daily; treatment may continue until disease progression
  Other Names:

  • Sprycel
  • BMS-354825
• Drug: Docetaxel
  Infusion, 60 or 75 mg/m^2, administered every 3 weeks.

• Active Comparator: Dasatinib, 50 mg + Docetaxel, 60 mg/m^2
  Participants received dasatinib, 50 mg, administered orally once daily. Docetaxel was administered every 3 weeks as an infusion at 60 mg/m^2.
  Interventions:

  • Drug: Dasatinib
  • Drug: Docetaxel
• Active Comparator: Dasatinib, 50 mg + Doxetaxel, 75 mg/m^2
  Participants received dasatinib, 50 mg administered orally once daily. Docetaxel was administered every 3 weeks as an infusion at 75 mg/m^2.
  Interventions:

  • Drug: Dasatinib
  • Drug: Docetaxel
• Active Comparator: Dasatinib, 70 mg + Docetaxel, 75 mg/m^2
  Participants received dasatinib, 70 mg, administered orally once daily. Docetaxel was administered every 3 weeks as an infusion at 75 mg/m^2.
  Interventions:

  • Drug: Dasatinib
  • Drug: Docetaxel
• Active Comparator: Dasatinib, 100 mg + Docetaxel, 75 mg/m^2
  Participants received dasatinib, 100 mg, administered orally once daily. Docetaxel was administered every 3 weeks as an infusion at 75 mg/m^2.
  Interventions:

  • Drug: Dasatinib
  • Drug: Docetaxel
• Active Comparator: Dasatinib, 120 mg + Docetaxel, 75 mg/m^2
  Participants received dasatinib, 120 mg, administered orally once daily. Docetaxel was administered every 3 weeks as an infusion at 75 mg/m^2.
  Interventions:

  • Drug: Dasatinib
  • Drug: Docetaxel

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