Multimodality Phase II Study in Prostate Cancer

Study Overview
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Brief Summary
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This is a single arm phase II study of docetaxel, prednisone, and sunitinib systemic therapy followed by salvage external beam radiation therapy for men who have experienced PSA recurrence following initial radical prostatectomy for prostate cancer. The primary aim is the rate of progression-free survival at 2 years as measured by lack of PSA progression and no evidence of disease. We hypothesize that this aggressive initial systemic therapy will improve the long term remission rates for men who are undergoing salvage radiation therapy for PSA recurrence in the absence of metastatic disease.

Detailed Description
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In many common malignancies such as breast cancer, trimodality therapy represents the standard-of-care approach, including initial surgical resection followed by systemic chemotherapy followed by radiotherapy for optimal local control, and targeted hormonal or biologic therapy for a period of time to reduce the ongoing risk of systemic disease recurrence. These approaches have reduced recurrence rates and improved overall survival in the adjuvant setting in breast cancer; however, the treatment of men with PSA recurrence following radical prostatectomy has generally been unsatisfying, given the high rates of persistent or recurrent disease despite salvage radiotherapy. The primary purpose of the study is to determine the rate of biochemical (PSA) progression free survival (bPFS) in men with PSA recurrent non-metastatic prostate cancer following radical prostatectomy, who receive multimodality therapy consisting of local salvage external beam radiotherapy and systemic docetaxel-based chemotherapy plus the targeted anti-VEGF biologic therapy sunitinib. Biochemical PFS will be defined as the proportion of subjects at 24 months, post-registration, with one of the following: 1) a serum PSA value of 0.2 ng/ml or more above the post-radiotherapy PSA nadir and confirmed 4 weeks later by a second PSA measurement that was higher than the first by any amount, 2) a continued rise in the PSA level following study treatment if no nadir is experienced, defined as 2 rising values greater than the baseline PSA and separated by at least 4 weeks, 3) evidence of clinical progression or initiation of systemic therapy for progressive disease, or 4) death. Secondary objectives include finding the rate of biochemical (PSA) disease free survival over time, Two-, three-, five-, and six- year risk of local recurrence (proportion), two-, three-, five-, and six-year risk of metastases and metastasis-free survival, two-, three-, five-, and six-year risk of metastases and metastasis-free survival, Safety, feasibility, and tolerability as assessed by NCI Common Toxicity Scales (v3.0), quality of life questionnaire (EPIC-short form surveys), achievement of accrual goals. Finally, a comparison of RNA expression profiles from original prostate radical prostatectomy specimen among those with PSA relapse at 2 and 5 years as compared to those without PSA relapse at the primary endpoint.

Official Title
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Multimodality Therapy for Recurrent High Risk Prostate Cancer: A Phase II Study

Conditions
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Prostate Cancer

Intervention / Treatment
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* Drug: Docetaxel
* Drug: Sunitinib
* Radiation: EBXRT


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Prostate adenocarcinoma with evidence of recurrent disease as measured only by rising PSA, without evidence of metastatic disease by bone scan or CT scan within 4 weeks of entry PSA ≤ 3.0 ng/ml and ≥ 0.1 ng/ml within 2 weeks of registration Radical prostatectomy within 4 years of registration. Rising PSA as defined by 1 or more PSA values greater than the nadir value after radical prostatectomy, separated by at least 4 weeks. Gleason sum at radical prostatectomy of 7-10 (4+3 or 3+4 allowed) Informed consent Age > 18 years. Adequate laboratory parameters: leukocytes ≥ 3,000/uL absolute neutrophil count ≥ 1,500/uL platelets ≥ 75,000/uL hemoglobin > 9.0 g/dl total bilirubin within normal institutional limit AST(SGOT)/ALT(SGPT) < 2.5x institutional upper limit creatinine < 2.0x institutional upper limit Karnofsky Performance Status ≥ 80 (Attachment 2). Written, signed, dated, and witnessed IRB approved informed consent form (ICF) before any screening procedures are performed. Peripheral neuropathy ≤ grade 1 Exclusion Criteria: Evidence of metastatic disease by CT scan, physical exam, or bone scan within 4 weeks of registration History of bleeding disorders or medical comorbidities that in the opinion of the investigator would preclude the use of systemic chemotherapy Prior systemic or biologic therapy, including pre-operative therapies or adjuvant chemotherapy, biologic therapy, or hormonal therapy Life expectancy of less than 5 years from medical co-morbidities by physician judgment Non-adenocarcinoma prostate cancer pathology at radical prostatectomy Prior radiotherapy to the abdomen or pelvis Less than or equal to 6 weeks from prior major surgery, including radical prostatectomy, open biopsy, or traumatic injury. Recent cardiovascular event (within 12 months) including unstable angina, myocardial infarction, severe or at rest claudication, or stroke/CVA. Subjects receiving known strong CYP3A4 isoenzyme inhibitors and/or inducers. Subjects on acceptable CYP3A4 isoenzyme inhibitors and/or inducers are eligible, provided they have been taking a stable regimen for at least 4 weeks prior to screening. Presence of a non-healing wound or ulcer. Grade >= 3 hemorrhage within the past month. Hypertension with systolic blood pressure of >140 mm Hg and/or diastolic pressure >90 mm Hg at the time of screening. Anti-hypertensive medications are permitted. Subjects with American Heart Association (AHA) Class 2-4 heart disease or any history of congestive heart failure with an ejection fraction <50%. Subjects with inability to tolerate or absorb oral medications. QTc interval >480 msec on baseline EKG. Subjects may not be taking a medication known to significantly prolong the QTc interval. Subjects who have not recovered from prior biopsy, surgery, traumatic injury, and/or radiation therapy. Anticoagulation with warfarin (therapeutic doses of warfarin for catheter patency are permitted). Low molecular weight heparin is permitted. Active infection(s), active antimicrobial therapy or serious intercurrent illness. Any other major medical or psychiatric illness that, in the investigator's judgment, will substantially increase the risk associated with the subject's participation in this study, including inability to absorb oral medications. Any history of hemoptysis within the past 12 months

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Multimodality<br>4 cycles of 70 mg/m2 Docetaxel + 37.5 mg daily Sunitinib for 14 days followed by a 7 day break for 3 cycles + external beam radiotherapy to 66 Gray over 6-7 weeks | Drug: Docetaxel<br>* Docetaxel 70 mg/m2 day 1 every 3 weeks for 4 cycles with prednisone 5 mg orally twice daily<br>* Other names: Taxotere;Drug: Sunitinib<br>* Sunitinib 37.5 mg orally once daily for 14 days followed by 7 days off, for 4 cycles, concurrent with docetaxel and prednisone<br>* Other names: Sutent;Radiation: EBXRT<br>* External beam radiotherapy to the prostate bed, started on day 100, after completion of chemotherapy. 66 Gy over 6-7 weeks.<br>* Other names: IMRT;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Rate of Progression Free Survival (PFS) at 24 Months | Percentage of participants surviving 24 months from the start of study treatment without progression of disease. PFS was defined as the time from the date of study treatment initiation to the date of the first documented progression. Progression will be defined as having experienced any of the following: a serum prostate specific antigen (PSA) value of 0.2 ng/mL or more above the post-radiotherapy PSA nadir and confirmed 4 weeks later by a second PSA measurement that was higher than the first by any amount, a continued rise in the PSA level following study treatment if no nadir is experienced, defined as 2 rising values greater than the baseline PSA and separated by at least 4 weeks, or evidence of clinical progression or initiation of systemic therapy for progressive disease. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Biochemical Progression (bPFS Proportion) at 2 and 3 Years. | Percentage of participants surviving 24 and 36 months from the start of study treatment without progression of disease. PFS was defined as the time from the date of study treatment initiation to the date of the first documented progression. Progression will be defined as having experienced any of the following: a serum prostate specific antigen (PSA) value of 0.2 ng/mL or more above the post-radiotherapy PSA nadir and confirmed 4 weeks later by a second PSA measurement that was higher than the first by any amount or a continued rise in the PSA level following study treatment if no nadir is experienced, defined as 2 rising values greater than the baseline PSA and separated by at least 4 weeks. Please note: bPFS is identical to PFS but includes only PSA-based endpoints or death. | 24 months and 36 months | 
| Rate of Local Recurrence at 2 and 3 Years | Local recurrence is defined as men with locally recurrent disease confirmed pathologically within the radiation field, and is estimated at 2 and 3 years. | 24 months and 36 months | 
| Metastasis-free Survival (MFS) Rates at 2 and 3 Years. | MFS is defined as the length of time between the date of start of treatment and the date of evidence of systemic disease on bone scan or cross sectional imaging or death, whichever occurs first. | 2 and 3 years | 
| Change in Quality of Life (QoL) After 1 Year | A validated scale of prostate-cancer specific quality of life will be measured using the Expanded Prostate Cancer Index Composite (EPIC) short form survey. This survey is standardized into subscale, 4 of which were examined on this study. These subscales are the urinary irritative domain, urinary incontinence domain, bowel domain, and sexual function domain, each standardized on a scale of 0-100, where higher score indicate a higher level of QoL. The survey was performed at baseline, at 3 months after completing radiotherapy, at 12 months, and at 2 and 3 years of follow-up for a total of 5 possible surveys per patient. Due to a low number of completed surveys at the fourth and fifth time point, the difference between the 12 month time point and baseline is summarized. Negative values indicate a decrease in QoL, while positive numbers represent an increase. | baseline and 1 year | 
| Change in Quality of Life (QoL) After 3 Month | A validated scale of prostate-cancer specific quality of life will be measured using the Expanded Prostate Cancer Index Composite (EPIC) short form survey. This survey is standardized into subscale, 4 of which were examined on this study. These subscales are the urinary irritative domain, urinary incontinence domain, bowel domain, and sexual function domain, each standardized on a scale of 0-100, where higher score indicate a higher level of QoL. The survey was performed at baseline and 3 months after completing radiotherapy. Negative values indicate a decrease in QoL, while positive numbers represent an increase. | baseline and 3 months | 
| Comparison of RNA Expression Profile From Original Prostate Radical Prostatectomy Specimen Among Those With PSA Relapse at 2 and 3 Years as Compared to Those Without PSA Relapse at the Primary Endpoint. | Prospective collection of prostate tissue at the time of radical prostatectomy is routinely performed at Duke. These samples will be analyzed by laser capture microdissection (LCM) for genomic profiling by RNA expression analysis for all subjects with tissue available. The expression profiles of subjects who experience PSA recurrence after protocol therapy by the 24 month endpoint will be compared with the expression profiles of subjects without recurrence at this time point as an exploratory measure to predict aggressive prostate cancer and those subjects who are unlikely to benefit from this approach. Baseline prostate tumor biomarkers in the form of RNA expression profiles will be correlated with 2 year PFS in an exploratory analysis. The median bPFS of those with detectable biomarker expression is reported. | 2 and 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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prostate cancer, sunitinib, docetaxel, PSA, radiation, PSA recurrence, No metastatic disease