Phase II Study of Dasatinib (BMS-354825) for Androgen-deprived Progressive Prostate Cancer

Study Overview
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Brief Summary
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The purpose of this study is to learn if men with metastatic prostate cancer and rising Prostate Specific Antigen (PSA), who have been surgically castrated or are undergoing androgen deprivation with Luteinizing Hormone Releasing Hormone (LHRH) treatment, respond to dasatinib. The safety of this treatment will also be studied.

Official Title
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Phase II Study of Dasatinib (BMS-354825) for Androgen-deprived Progressive Prostate Cancer

Conditions
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Prostate Cancer

Intervention / Treatment
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* Drug: dasatinib
* Drug: dasatinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: males, 18 or older proven advanced prostate cancer documented metastatic disease rising PSA levels castrate levels of testosterone Exclusion Criteria: symptomatic CNS (brain or spinal cord) metastasis medical condition which may increase the risk of toxicity any prior or ongoing anti-cancer medical therapy or immunotherapy for prostate cancer other than primary androgen deprivation agents unable to take oral medication

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br> | Drug: dasatinib<br>* Tablets, Oral, 100 mg or 70 mg, twice daily, treatment may continue until disease progression<br>* Other names: BMS-354825;|
| Experimental: 2<br> | Drug: dasatinib<br>* Tablets, Oral, 100 mg, once daily (QD) treatment may continue until disease progression<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With a Response | Response = confirmed prostate specific antigen (PSA) response (decrease in PSA =>50% from baseline), confirmed improved bone scan (disappearance of => 1 lesion, no new lesions, new pain not developing), confirmed complete response (CR: disappearance of all lesions) or confirmed partial response (PR: =>30% in sum of longest diameter [LD] of all lesions compared to baseline sum LD), stable disease (SD: neither sufficient increase for progressive disease [PD: =>20% increase in sum of LD of all target lesions] nor sufficient shrinkage for PR), based on Response Criteria in Solid Tumors [RECIST]. | Within 2 weeks of first study drug administration, thereafter recorded every 4 weeks. | 
| Percentage of Participants With a Response | Response = confirmed PSA response (decrease in PSA =>50% from baseline), confirmed improved bone scan (disappearance of => 1 lesion, no new lesions, new pain not developing), confirmed CR (disappearance of all lesions) or confirmed PR (=>30% in sum of LD of all lesions compared to baseline sum LD), SD (neither sufficient increase for PD [=>20% increase in sum of LD of all target lesions] nor sufficient shrinkage for PR), based on RECIST. | Within 2 weeks of first study drug administration, thereafter recorded every 4 weeks. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With a Decrease in PSA by at Least 50% From Baseline | PSA is a marker of prostate cancer and a PSA response is defined as a decrease in the PSA value by at least 50% from baseline, for 2 successive evaluations, each at least 2 weeks apart, for a total of 3 measurements. | Prior to treatment with the study drug, Week 4, Week 8, Week 12 and every 4 weeks thereafter. | 
| Percentage of Participants With a Decrease in PSA by at Least 50% From Baseline | PSA is a marker of prostate cancer and a PSA response is defined as a decrease in the PSA value by at least 50% from baseline for 2 successive evaluations, each at least 2 weeks apart, for a total of 3 measurements. | Prior to treatment with the study drug, Week 4, Week 8, Week 12 and every 4 weeks thereafter. | 
| Number of Months of Decrease in PSA by at Least 50% From Baseline | PSA is a marker of prostate cancer. The duration of PSA response is measured from the time that the first of the 2 consecutive measurements met the criteria for confirmed PSA response, until the date of the first of the 3 consecutive measurements that confirm PSA progression, or the date of disease progression, or the date of death. | Prior to treatment with the study drug, Week 4, Week 8, Week 12 and every 4 weeks thereafter. | 
| Number of Participants With Decrease in PSA Velocity | PSA is a marker of prostate cancer. PSA velocity measures the rate of change of PSA values. A decrease in PSA values and hence PSA velocity is an early indicator of potential anti-tumor activity. | Prior to treatment with the study drug, Week 4, Week 8, Week 12 and every 4 weeks thereafter. | 
| Number of Participants With Decrease in PSA Log Slope | PSA is a marker of prostate cancer. A decrease in PSA value is an early indicator of potential anti-tumor activity. Log (PSA) is assumed to have a linear relationship with time. The PSA log slope is defined as the slope of the log PSA line. | Prior to treatment with the study drug, Week 4, Week 8, Week 12 and every 4 weeks thereafter. | 
| Number of Participants With Increase in PSA Doubling Time | PSA is a marker of prostate cancer. PSA doubling time is defined as log 2 divided by the slope of the log PSA line. An increase in PSA doubling time indicates improvement in anti-tumor activity. | Prior to treatment with the study drug, Week 4, Week 8, Week 12 and every 4 weeks thereafter. | 
| Number of Participants With CR or PR | Tumor response was defined as the number of participants whose best response was CR or PR, per RECIST: CR: disappearance of all target/non-target lesions; PR: >= 30% decrease in the sum of the LDs of target lesions relative to the baseline sum LD | Prior to treatment with the study drug, Week 12, every 12 weeks thereafter and at the end of the treatment. | 
| Number of Participants With CR, PR or SD | Disease control rate is defined as the number of participants whose best response was CR, PR or SD, per RECIST: CR: disappearance of all target/non-target lesions; PR: >= 30% decrease in the sum of the LDs of target lesions relative to the baseline sum LD; SD: neither sufficient increase to qualify for PD nor sufficient shrinkage to qualify for PR; PD: defined as appearance of new lesion/s, or >=20% increase in the sum of the LD of target lesions, relative to the smallest sum LD recorded since treatment start, or unequivocal progression of existing non-target lesions. | Prior to treatment with the study drug, Week 12, every 12 weeks thereafter and at the end of the treatment. | 
| Number of Participants With a Confirmed Improved Bone Scan | An improved bone scan was defined as 1 or more of the following: disappearance of at least 1 lesion, no new lesions appearing since the most recent prior assessment, or new pain not developing in an area that was previously visualized. A response is considered confirmed if it is noted on 2 examinations at least 4 weeks apart. | Prior to treatment with the study drug, Week 12, every 12 weeks thereafter and at the end of the treatment. | 
| Percentage of Participants With Confirmed Improved Bone Scan | An improved bone scan was defined as 1 or more of the following: disappearance of at least 1 lesion, no new lesions appearing since the most recent prior assessment, or new pain not developing in an area that was previously visualized. A response is considered confirmed if it is noted on 2 examinations at least 4 weeks apart. | Prior to treatment with the study drug, Week 12, every 12 weeks thereafter and at the end of the treatment. | 
| Number of Participants With Disease Progression | Disease progression: progression of target lesions or unequivocal progression of non-measurable lesions/disease as evaluated by computed tomography (CT) scan or magnetic resonance imaging (MRI), not as evaluated by bone scan (non-measurable lesions included visceral and bone lesions), loss of PSA response (only for participants who achieved a PSA response) or Investigator-defined clinical progression based on physical examination, history, symptoms, and ECOG-PS. For participants who did not progress or die, date of last PSA measurement or tumor assessment was used, whichever occurred first. | Prior to treatment with the study drug, Week 12 and every 12 weeks thereafter and at the end of the treatment. | 
| Median Number of Months to Disease Progression | Measured from date of first dose to date of first 3 consecutive measurements that confirm PSA progression, date of disease progression,or death date.Disease progression:progression of target lesions or unequivocal progression of non-measurable lesions/disease as evaluated by computed tomography (CT) scan or magnetic resonance imaging (MRI),loss of PSA response or Investigator-defined clinical progression based on physical examination,history,symptoms,and ECOG-PS.For participants who did not progress or die,date of last PSA measurement or tumor assessment was used, whichever occurred first. | Prior to treatment with the study drug, Week 12 and every 12 weeks thereafter and at the end of the treatment. | 
| Median Change From Baseline in Individual FAPSI Scores at Week 12 | FAPSI-8:symptom index of important clinician-rated symptoms/concerns to monitor when assessing value of treatment for advanced prostate cancer. Participants respond to each item on a 5-point Likert-type scale from 0 (not at all) to 4 (very much). GP1:I have lack of energy, GP4:I have pain, GE6:I worry that my condition will get worse, C2: I am losing weight, P2:I have certain areas in my body where I experience significant pain,P3:My pain keeps me from doing things I want to do, P7:I have difficulty urinating, P8:My problems with urinating limit my activities. | Prior to treatment with the study drug, Week 12, every 12 weeks thereafter and at the end of the treatment. | 
| Median Change From Baseline in Total FAPSI-8 Scores at Weeks 12, 24 and 36 | The FAPSI-8 is a symptom index comprised of the most important clinician-rated symptoms or concerns to monitor when assessing the value of treatment for advanced prostate cancer. It includes 8 items developed to measure symptoms/concerns specific to prostate cancer such as fatigue, pain (3-items), weight loss, difficulty with urination (2-items) and concerns about the condition becoming worse. Participants respond to each item on a 5-point Likert-type scale from 0 (not at all) to 4 (very much). | Prior to treatment with the study drug, Week 12, every 12 weeks thereafter and at the end of the treatment. | 
| Median Change From Baseline in Individual FAPSI Scores at Week 24 | FAPSI-8:symptom index of important clinician-rated symptoms/concerns to monitor when assessing value of treatment for advanced prostate cancer. Participants respond to each item on a 5-point Likert-type scale from 0 (not at all) to 4 (very much). GP1:I have lack of energy, GP4:I have pain, GE6:I worry that my condition will get worse, C2: I am losing weight, P2:I have certain areas in my body where I experience significant pain,P3:My pain keeps me from doing things I want to do, P7:I have difficulty urinating, P8:My problems with urinating limit my activities. | Prior to treatment with the study drug, Week 12, every 12 weeks thereafter and at the end of the treatment. | 
| Median Change From Baseline in Individual FAPSI Scores at Week 36 | FAPSI-8:index of symptoms/concerns when assessing value of treatment for advanced prostate cancer.Participants respond to each item on 5-point Likert-type scale:0 (not at all) to 4 (very much).GP1:I have lack of energy,GP4:I have pain,GE6:I worry that my condition will get worse,C2:I am losing weight,P2:I have certain areas in my body where I experience significant pain,P3:My pain keeps me from doing things I want to do,P7:I have difficulty urinating,P8:My problems with urinating limit my activities. The number of participants for whom these data are available is too small for analysis. | Prior to treatment with the study drug, Week 12, every 12 weeks thereafter and at the end of the treatment. | 
| Number of Participants Who Died, Experienced Serious Adverse Events (SAEs), Adverse Events (AEs) or Discontinuations Due to AEs | AE: any new untoward medical occurrence/worsening of pre-existing medical condition, whether or not related to study drug. SAE: any AE that resulted in death; was life threatening; resulted in persistent/significant disability/incapacity; resulted in/prolonged an existing in-patient hospitalization; was a congenital anomaly/birth defect; or was an overdose. Participants who discontinued the study due to any AEs were recorded. | From start of study drug therapy up to 30 days after the last dose. | 
| Number of Participants Who Experienced Drug-related SAEs, Drug-related AEs, Drug-related Grade 3/4 AEs and Discontinuations Due to Drug-related AEs. | Drug-related AEs are those events with a relationship to the study therapy of certain; probable; possible; or missing. Drug-related SAEs are those events with any relationship to the study therapy. Drug-related AEs were graded using the National Cancer Institute (NCI) Common Toxicity Criteria (CTC), version 3.0: Grade 1=mild, 2=moderate, 3=severe, 4=life threatening, 5=death. Participants who discontinued the study due to any drug-related AEs were also recorded. | From start of study drug therapy up to 30 days after the last dose. | 
| Number of Participants With Grade 3-4 Hematology Abnormalities | Abnormalities were graded per the NCI CTC, version 3.0 criteria (Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = life threatening). Grade 3 and 4 criteria are as follows: Hemoglobin: Grade 3:6.5 - <8.0g/dL, Grade 4: <6.5g/dL. Platelets: Grade 3: 25.0 - <50.0*10^9/L, Grade 4: <25.0*10. Absolute Neutrophil Count (ANC): Grade 3: 0.5 - <1.0*10^9/L, Grade 4: <0.5*10^9/L. Leukocytes: Grade 3: 1.0 - <2.0*10^9/L, Grade 4: <1.0*10^9/L. | Data was collected prior treatment with the study drug, Week 2, Week 4, Week 8, Week 12 , every 4 weeks thereafter and at the end of the treatment. | 
| Number of Participants With Grade 3-4 Serum Chemistry Abnormalities in Alanine Aminotransferase, Aspartate Aminotransferase, Alkaline Phosphatase, Bilirubin and Calcium | Abnormalities were graded according to the NCI CTC, version 3.0 (Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = life threatening). Grade 3 and 4 criteria are as follows: alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase: Grade 3: 5.0-20.0 * ULN (upper limit of normal), Grade 4: >20.0 * ULN; calcium: Grade 3: 6.0-<7.0 or >12.5-13.5 mg/dL, Grade 4: <0.6->13.5 mg/dL; bilirubin: Grade 3: >3-10 * ULN, Grade 4: >10 * ULN. | Data was collected prior treatment with the study drug, Week 2, Week 4, Week 8, Week 12 , every 4 weeks thereafter and at the end of the treatment. | 
| Number of Participants With Grade 3-4 Serum Chemistry Abnormalities in Creatinine, Potassium, Sodium and Phosphorous | Abnormalities were graded per the NCI CTC, version 3.0 (Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = life threatening). Grade 3 and 4 criteria are as follows: phosphorous: Grade 3: 1.0-<2.0 mg/dL, Grade 4: <1.0 mg/dL; sodium: Grade 3: 120-<130 or >155-160mEq/L, Grade 4: <120 or >160 mEq/L; creatinine: Grade 3: >3.0-6.0 * ULN, Grade 4: >6.0 * ULN; potassium: Grade 3: 2.5 -<3.0 or >6.0 -7.0 mEq/L, Grade 4: < 2.5 or >7.0 mEq/L. | Data was collected prior treatment with the study drug, Week 2, Week 4, Week 8, Week 12 , every 4 weeks thereafter and at the end of the treatment. | 
| Number of Participants With Abnormal Lactate Dehydrogenase (LD) | LDH is a laboratory safety parameter. Normal ranges for LD vary with both age and disease status, and another reason for variation in upper limit of normal (ULN) and lower limit of normal (LLN) is that LD was measured via a local (versus a standardized) laboratory. It is therefore not possible to provide one ULN and LLN for the population. | Data was collected prior treatment with the study drug, Week 2, Week 4, Week 8, Week 12, every 4 weeks thereafter and at the end of the treatment. | 
| Number of Participants With Positive Urinalysis | Participants' urine samples were tested for the presence of blood, glucose and protein. If these substances were present in a participant's urine, the results were given as positive. | Data was collected prior treatment with the study drug, Week 2, Week 4, Week 8, Week 12 , every 4 weeks thereafter and at the end of the treatment. | 
| Number of Participants With QTc Prolongation | The QT interval is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle. QTc is the QT interval corrected for heart rate. A prolonged QT interval is a risk factor for ventricular tachyarrhythmias and sudden death. | From start of study drug therapy up to 30 days after the last dose. | 
| Number of Participants With a Baseline uNTx Value <=ULN, With a Decrease, Increase or no Change in uNTx | uNTx is a measure of bone metabolism. A decrease in the marker relative to baseline indicates a decrease in bone metabolism. | Prior to treatment with the study drug, Week 4, Week 8, Week 12 and every 4 weeks thereafter. | 
| Number of Participants With a Baseline uNTx Value >ULN, With a Decrease, Increase or no Change in uNTx | uNTx is a measure of bone metabolism. A decrease in the marker relative to baseline indicates a decrease in bone metabolism. | Prior to treatment with the study drug, Week 4, Week 8, Week 12 and every 4 weeks thereafter. | 
| Number of Participants With a uNTx Response | uNTx is a measure of bone metabolism. uNTx response is defined for participants with baseline uNTx above ULN. It is defined as either on-study uNTx values decreasing to within normal limits or 35% or more decrease in uNTx from baseline, whichever happens first. | Prior to treatment with the study drug, Week 4, Week 8, Week 12 and every 4 weeks thereafter. | 
| Median Number of Months of uNTx Response | uNTx is a measure of bone metabolism.The median number of months of uNTx response was calculated for participants with baseline uNTx =< ULN and uNTx progression during treatment, from first dose of dasatinib to uNTx progression.For participant with baseline uNTx above ULN, it was time from uNTx response to uNTx progression.For participants with baseline uNTx equal to or below ULN or uNTx response and no uNTx progression, the date of last uNTx assessment was used. Duration of uNTx response was not defined for participants with baseline value greater than ULN who never achieved uNTx responses. | Prior to treatment with the study drug, Week 4, Week 8, Week 12 and every 4 weeks thereafter. | 
| Number of Participants With a Baseline BAP Value <= ULN, With a Decrease, Increase or no Change in BAP | BAP is a measure of bone metabolism. A decrease in BAP relative to the baseline indicates decrease in bone metabolism. | Prior to treatment with the study drug, Week 4, Week 8, Week 12 and every 4 weeks thereafter. | 
| Number of Participants With a Baseline BAP Value > ULN, With a Decrease, Increase or no Change in BAP | BAP is a measure of bone metabolism. A decrease in BAP relative to baseline indicates a decrease in bone metabolism. | Prior to treatment with the study drug, Week 4, Week 8, Week 12 and every 4 weeks thereafter. | 
| Number of Participants With BAP Response | BAP is a measure of bone metabolism. A BAP response is calculated for participants with a baseline BAP value > ULN. It is defined as on-study BAP values within normal limits. | Prior to treatment with the study drug, Week 4, Week 8, Week 12 and every 4 weeks thereafter. | 
| Median Number of Months of BAP Response | The median number of months of the BAP response was calculated for participants with baseline BAP <= ULN, from first dose of dasatinib to the first time BAP is above ULN. For participants with baseline BAP > ULN, it was the time from BAP response to the first time BAP was above ULN. For participants with baseline BAP =< ULN or BAP, and no BAP above ULN, last BAP assessment date was used. The median number of months of response was not defined for participants with baseline value > ULN, that never achieved BAP response. | Prior to treatment with the study drug, Week 4, Week 8, Week 12 and every 4 weeks thereafter. | 
| Mean Plasma Concentration at 100 mg Dasatinib Dose (Week 2) | Mean plasma concentration was obtained directly from the concentration-time data. | At pre-dose, 1 hour, 3 hours, 6 hours and at 12 hours after any dose for BID and QD group. | 
| Mean Plasma Concentration at 100 mg Dasatinib Dose (Week 6) | Mean plasma concentration was obtained directly from the concentration-time data. | At pre-dose, 1 hour, 3 hours, 6 hours and at 12 hours after any dose for BID and QD group. | 
| Mean Plasma Concentration at 70 mg Dasatinib Dose (Week 2) | Mean plasma concentration was obtained directly from the concentration-time data. | At pre-dose, 1 hour, 3 hours, 6 hours and at 12 hours after any dose for BID and QD group. | 
| Mean Plasma Concentration at 70 mg Dasatinib Dose (Week 6) | Mean plasma concentration was obtained directly from the concentration-time data. | At pre-dose, 1 hour, 3 hours, 6 hours and at 12 hours after any dose for BID group. | 
| Mean Plasma Concentration at 50 mg Dasatinib Dose (Week 2) | Mean plasma concentration was obtained directly from the concentration-time data. | At pre-dose, 1 hour, 3 hours, 6 hours and at 12 hours after any dose for BID and QD group. | 
| Mean Plasma Concentration at Dose 50 mg (Week 6) | Mean plasma concentration was obtained directly from the concentration-time data. | At pre-dose, 1 hour, 3 hours, 6 hours and at 12 hours after any dose for BID and QD group. |