Study Of SU011248 In Combination With Docetaxel (Taxotere) And Prednisone In Patients With Prostate Cancer

Study Overview
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Brief Summary
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This is a multi-center, open-label, Phase 1/2 study of SU011248 (sunitinib malate, SUTENT) in combination with docetaxel and prednisone for the first-line treatment of metastatic hormone-refractory prostate cancer (mHRPC).

Official Title
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A Phase 1/2 Safety And Pharmacokinetic Study Of SU011248 In Combination With Docetaxel (Taxotere) And Prednisone In Patients With Metastatic Hormone Refractory Prostate Cancer (HRPC)

Conditions
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Prostatic Neoplasms

Intervention / Treatment
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* Drug: Docetaxel
* Drug: Prednisone
* Drug: SU011248


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed adenocarcinoma of the prostate Patients must have progressive hormone-refractory prostate cancer (HRPC): patients must have undergone primary hormone treatment (e.g. orchiectomy or gonadotropin releasing hormone analog with or without antiandrogens). For patients who received antiandrogen therapy, disease progression must have been determined after antiandrogen discontinuation Progressive disease based on either non-measurable disease and an elevated PSA OR measurable disease Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 Exclusion Criteria: Prior thalidomide, anti-vascular endothelial growth factor (VEGF) therapy, VEGF receptor inhibitor, platelet-derived growth factor (PDGF) receptor inhibitor or anti-angiogenic treatment of any kind including investigational therapy Prior chemotherapy Uncontrolled pain at baseline, impending complication from bone metastasis (fracture and/or compression) and/or presence of urinary obstruction (urinary retention, hydronephrosis) History of cardiac dysfunction, QT interval corrected for heart rate (QTc) >450 msec Central Nervous System (CNS) involvement

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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A<br>SU011248 in combination with docetaxel and prednisone | Drug: Docetaxel<br>* Docetaxel Phase 1 - escalating doses (60 and 75 mg/m2), intravenous therapy (IV), administered every 3 weeks. Phase 2 - Phase 1 optimal combination dose (75 mg/m2, IV, every 3 weeks).<br>* Other names: Taxotere; Sunitinib malate; SUTENT;Drug: Prednisone<br>* Prednisone Phase1/2 - 5 mg twice a day (BID), oral.<br>Drug: SU011248<br>* SU011248 Phase 1 - escalating doses (12.5, 37.5, and 50 mg), oral, administered on a 2-weeks on, 1-week off daily regimen (Schedule 2/1). Phase 2 - Phase 1 optimal combination dose (37.5 mg/day, oral, Schedule 2/1).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Prostate Specific Antigen (PSA) Response | PSA response rate, which is defined as a greater than or equal to a 50% decrease in PSA from baseline, that is subsequently confirmed. | Baseline, Day 1 of each 21-day cycle | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to PSA Progression | Defined as the time from start of study treatment to first documentation of PSA progression using the PSA Working Group criteria calculated as (first event date - first dose date + 1)/7. PSA progression is defined for patients with a PSA response, as a 50% increase over nadir (lowest) and increase in absolute-value PSA level by at least 5 nanograms per milliliter (ng/mL) [or back to baseline] and for patients without a PSA response as a 25% increase over baseline [or nadir (lowest)] and increase in absolute-value PSA level by at least 5 ng/mL, both confirmed by a second value. | Baseline to first documentation of PSA progression up to 28 days after date of last dose | 
| Duration of PSA Response (DPR) | Defined as time from first documentation of PSA response (≥50% decrease in PSA from baseline that is subsequently confirmed) to first documentation of PSA progression (defined for patients with a PSA response as a 50% increase over nadir [lowest] and increase in absolute-value PSA level by at least 5 ng/mL [or back to baseline] and for patients without a PSA response as a 25% increase over baseline [or nadir / lowest] and increase in absolute-value PSA level by at least 5 ng/mL, both confirmed by a second value). Calculated as (end date for DPR - first PSA response + 1)/7. | Baseline to first documentation of PSA progression up to 28 days after date of last dose | 
| Percentage of Participants With Objective Response Rate (ORR) | Defined as confirmed complete response (CR: disappearance of all target lesions) or confirmed partial response (PR: ≥30% decrease in sum of the longest dimensions (LD) of the target lesions taking as a reference the baseline sum LD) according to response evaluation criteria in solid tumors (RECIST). Confirmed responses are those that persist on repeat imaging study ≥4 weeks after initial documentation of response. | Baseline to first documentation of PSA progression up to 28 days after date of last dose | 
| Ratio to Baseline (Bsl) in Median Levels of Soluble Protein Biomarkers by Prostate Specific Antigen (PSA) Response: VEGFC | Soluble protein biomarker Vascular Endothelial Growth Factor C (VEGFC) measured as picograms per milliliter (pg/mL). PSA responders are participants with a confirmed PSA response as per the Working Group criteria (>50% decrease from baseline) and non-responders are those not meeting the definition of responder. Ratio=value of soluble protein biomarkers at each time point to the value at baseline (C1D14 : C1D1). | Baseline (Cycle 1 Day 1 [C1.D1]), C1.D14, C2.D1, C2.D14, C3.D1, C3.D14 | 
| Ratio to Baseline in Median Levels of Soluble Protein Biomarkers by Prostate Specific Antigen (PSA) Response: VEGFR2 | Soluble protein biomarker Vascular Endothelial Growth Factor receptor 2 (VEGFR2) measured as pg/mL. PSA responders are participants with a confirmed PSA response as per the Working Group criteria (>50% decrease from baseline) and non-responders are those not meeting the definition of responder. Ratio=value of soluble protein biomarkers at each time point to the value at baseline (C1D14 : C1D1). | Baseline (C1.D1), C1.D14, C2.D1, C2.D14, C3.D1, C3.D14 | 
| Ratio to Baseline in Median Levels of Soluble Protein Biomarkers by Prostate Specific Antigen (PSA) Response: VEGFR3 | Soluble protein biomarker Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) measured as picograms per milliliter (pg/mL). PSA responders are participants with a confirmed PSA response as per the Working Group criteria (>50% decrease from baseline) and non-responders are those not meeting the definition of responder. Ratio=value of soluble protein biomarkers at each time point to the value at baseline (C1D14 : C1D1). | Baseline (C1.D1), C1.D14, C2.D1, C2.D14, C3.D1, C3.D14 | 
| Ratio to Baseline in Median Levels of Soluble Protein Biomarkers by Clinical Benefit Response (CBR): VEGFC | Soluble protein biomarker VEGFC measured as pg/mL. CBR defined as confirmed CR (disappearance of all target lesions) or confirmed PR (≥30% decrease in sum of longest dimensions [LD] of target lesions taking as reference the baseline sum LD) or SD (neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease) ≥3 months versus PD (≥20% increase in sum LD of target lesions taking as reference the smallest sum LD recorded since treatment started, unequivocal progression of existing non-target lesions, or appearance of ≥1 new lesions) or SD <3 months. | Baseline (C1.D1), C1.D14, C2.D1, C2.D14, C3.D14 | 
| Ratio to Baseline in Median Levels of Soluble Protein Biomarkers by Clinical Benefit Response (CBR): VEGFR2 | Soluble protein biomarker VEGFR2 measured as pg/mL. CBR defined as confirmed CR (disappearance of all target lesions) or confirmed PR (≥30% decrease in sum of longest dimensions [LD] of target lesions taking as reference the baseline sum LD) or SD (neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease) ≥3 months versus PD (≥20% increase in sum LD of target lesions taking as reference the smallest sum LD recorded since treatment started, unequivocal progression of existing non-target lesions, or appearance of ≥1 new lesions) or SD <3 months. | Baseline (C1.D1), C1.D14, C2.D1, C2.D14, C3.D14 | 
| Ratio to Baseline in Median Levels of Soluble Protein Biomarkers by Clinical Benefit Response (CBR): VEGFR3 | Soluble protein biomarker VEGFR3 measured as pg/mL. CBR defined as confirmed CR (disappearance of all target lesions) or confirmed PR (≥30% decrease in sum of longest dimensions [LD] of target lesions taking as reference the baseline sum LD) or SD (neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease) ≥3 months versus PD (≥20% increase in sum LD of target lesions taking as reference the smallest sum LD recorded since treatment started, unequivocal progression of existing non-target lesions, or appearance of ≥1 new lesions) or SD <3 months. | Baseline (C1.D1), C1.D14, C2.D1, C2.D14, C3.D14 | 
| Change From Baseline in Modified Brief Pain Inventory-Short Form (mBPI-sf) : Pain Intensity (Questions 2-5) | The questionnaire assesses pain intensity (worst, least, average, and right now), level of relief in the last 24 hours, and the impact of pain on daily functions (general activity, mood, walking ability, normal work, relations with other people, sleep, and enjoyment of life). The pain intensity index score was derived from Questions 2-5 with range from 0 to 10 (0: no pain; 1-4: mild pain; 5-6: moderate pain; 7-10: severe pain); higher scores indicate worse health status. | Baseline (C1.D1), Day 1 of Cycles 2 through 16, and End of Treatment (EOT=following Cycle 16 or within 7 days of withdrawal from study) | 
| Change From Baseline in Modified Brief Pain Inventory-Short Form (mBPI-sf): Pain Interference (Questions 7A Through 7G) | The questionnaire assesses pain intensity (worst, least, average, and right now), level of relief in the last 24 hours, and the impact of pain on daily functions (general activity, mood, walking ability, normal work, relations with other people, sleep, and enjoyment of life). The pain interference index score (to measure how much pain had interfered with daily activities) was derived from Questions 7A-7G with a range from 0 (no interference) to 10 (completely interferes); higher scores indicate more interference. | Baseline (C1.D1), Day 1 of Cycles 2 through 16, and End of Treatment (EOT=following Cycle 16 or within 7 days of withdrawal from study) | 
| Change From Baseline in Functional Assessment of Cancer Therapy-Prostate (FACT-P) Questionnaire (FACT-General and Prostate Cancer Subscale) | Assesses health related quality of life and advanced prostate cancer specific symptoms. FACT-General (FACT-G) assesses 4 domains: physical, social and family, emotional, and functional well-being. The prostate cancer subscale assesses prostate cancer symptoms focusing on pain, urination problems, and sexual functions. Individual scores range from 0 (not at all) to 4 (very much). Scores for some of the individual questions are reverse-coded in order for higher scores to correspond to better health status. FACT-P overall score range is 0 to 156; higher scores indicate better health status. | Baseline (C1.D1), Day 1 of Cycles 2 through 16, and End of Treatment (EOT=following Cycle 16 or within 7 days of withdrawal from study) | 
| Preliminary Assessment of PSA Modulation by SU011248 | PSA modulation analyzed by the mean change in PSA response measured as ng/mL. | Baseline to Day 28 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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First-line treatment of metastatic hormone-refractory prostate cancer SUTENT in combination with docetaxel and prednisone