Study of Dasatinib and Docetaxel in Metastatic Hormone Refractory Prostate Cancer

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.

Time frame: From Day 3 of first 21-day cycle to Cycle 2 , Day 21 (or Study Day 42)

Population: All patients who received at least 1 dose of dasatinib in Phase 1

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.

Time frame: From Day 3 of first 21-day cycle to Cycle 2 , Day 21 (or Study Day 42)

Population: All patients who received at least 1 dose of dasatinib in Phase 1

Time frame: Cycle 1, Day 14 at 0, 0.5 , 1, 2, 3, 4, 7, 10, and 24 hours postdose

Population: All patients who received at least 1 dose of dasatinib; n=number of patients who were evaluable

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

Population: All patients who received at least 1 dose of dasatinib

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.

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

Population: All patients who received dasatinib, 100 mg + docetaxel, 75 mg/m\^2, in the Phase 2 portion of the study and completed the BPI-sf at baseline. n=evaluable participants in that cycle.

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).

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

Population: All participants who received dasatinib, 100 mg + docetaxel, 75 mg/m\^2 and who had a PSA response

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

Population: All patients who received at least 1 dose of dasatinib; n=number of patients who were evaluable

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.

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

Population: All patients who received dasatinib, 100 mg + docetaxel, 75 mg/m\^2

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.

Time frame: From Day 1 of therapy to last bone scan assessment (up to 51.6 months)

Population: All patients who received dasatinib, 100 mg + docetaxel, 75 mg/m\^2

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.

Time frame: Pretreatment visit then every 6 weeks thereafter (up to 51.6 months)

Population: All patients who received dasatinib, 100 mg + docetaxel, 75 mg/m\^2

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.

Time frame: From Day 2 of Cycle 1 to up to 30 days after last dose of study drug (up to approximately 49 months)

Population: All participants who received at least 1 dose of study drug

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.

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)

Population: All patients who received dasatinib, 100 mg + docetaxel, 75 mg/m\^2

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.

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)

Population: All participants who received at least 1 dose of dasatinib

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.

Time frame: Pretreatment visit then every 6 weeks thereafter (up to 51.6 months)

Population: All patients who received dasatinib, 100 mg + docetaxel, 75 mg/m\^2

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

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)

Population: All patients who received dasatinib, 100 mg + docetaxel, 75 mg/m\^2

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

Time frame: From Day 1 of therapy to last bone scan assessment (up to 51.6 months)

Population: All patients who received dasatinib, 100 mg + docetaxel, 75 mg/m\^2