Hormone Therapy Plus Chemotherapy as Initial Treatment for Local Failures or Advanced Prostate Cancer

Study Overview
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Brief Summary
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This study is for men who have prostate cancer and have failed local therapy or are not a candidate for prostatectomy or radiation therapy. The purpose of this research study is to assess the safety and benefit of androgen deprivation therapy (ADT, blocks hormones) plus chemotherapy. Degarelix is the hormone blocking drug that will be used. Doxorubicin, Ketoconazole, Docetaxel and Estramustine are the chemotherapy drugs that will be used. The drugs used in this study are approved by the Food and Drug Administration (FDA). Participants will be treated with ADT plus chemotherapy for three, four, or five 8-week cycles (12, 18, or 24 months). The number of cycles of chemotherapy they receive and the number of months they receive ADT will be based on their disease. The current standard treatment is ADT and chemotherapy. What differs in this research study is the cycling and combination of chemotherapy drugs chosen. The drugs chosen for this study have fewer side effects and are believed to provide maximum benefit.

Detailed Description
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As a working hypothesis, investigators suspect that the transformation from an androgen-dependent to an androgen-independent phenotype is mediated by expansion of an androgen-independent clone already present at the time of ADT that continues to grow while androgen-sensitive clones are being suppressed. It is thus desirable to bring treatment to bear on the androgen-independent component while the corresponding tumor burden remains minimal and prolong the time to hormone resistance. Investigators view the androgen-independent component as analogous to microscopic residual or micro-metastatic disease, for which adjuvant chemotherapy has been shown to be effective in other contexts, even when the same drugs had little or no impact on survival in the setting of more advanced disease. By treating all components of the tumor initially, investigators anticipate that the emergence of androgen-independent growth will be delayed, ultimately prolonging patient survival. Additionally, instead of treating patients empirically with an identical regimen, as in investigator's previous work, these patient subsets were designed to ensure a level of treatment appropriate to their individual disease, thus potentially lessening the burden of treatment (such as the long-term adverse effects of ADT). Investigators have chosen 3, 4, or 5 cycles of chemotherapy to be administered on the basis of tumor burden, a treatment selection method long established in germ cell tumors and used by this PI. Sub-analyses of previous data have raised the concern that treating patients with varying levels of disease the same way does not produce optimal results. Therefore, investigators seek to improve outcomes by tailoring treatment to tumor burden. In this study, patients with less tumor burden will receive 3 cycles of chemotherapy and 12 months of ADT, those with moderate tumor burden will receive 4 cycles and 18 months of treatment, and those with the greatest tumor burden will receive 5 cycles and 24 months of treatment. Additionally, this regimen of administering treatment sequentially, including a 2-week break, reduces toxicity.

Official Title
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Phase 2 Study of Androgen Deprivation Therapy (ADT) Plus Chemotherapy as Initial Treatment for Local Failures or Advanced Prostate Cancer

Conditions
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Prostatic Neoplasms

Intervention / Treatment
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* Drug: Doxorubicin
* Drug: Ketoconazole
* Drug: Docetaxel
* Drug: Estramustine
* Drug: Degarelix


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Pathologic proof of adenocarcinoma of the prostate. Patients must belong to one of the following subsets: Prior local therapy Patients with Prostate Specific Antigen (PSA) recurrence following prostatectomy or radiation therapy who have no radiographic involvement. PSA doubling time ≤6 months. Nodal involvement only. Low volume bone disease: ≤3 metastases. Nodal involvement with associated bone involvement. High volume bone-visceral disease: Patients with >3 metastatic bone sites or visceral metastases. No prior definitive local therapy Tumors felt to be unresectable, not candidates for radiation therapy, and PSA elevated with biopsy-proven disease. Metastatic disease at presentation. Patients may have started ADT within 3 months of study entry. No previous cytotoxic therapy is allowed, including systemic irradiation with strontium-89, samarium, or radium-223. Previous definitive radiotherapy to one metastatic site is acceptable, provided that unirradiated sites remain. At least 8 weeks must have elapsed since radiation therapy to the pelvis. Patients having limited irradiation of a metastatic site are eligible 4 weeks following radiation. Patients may have had previous exposure to ADT if it was given for ≤6 months to downstage the primary and provided that such therapy was completed at least 12 months prior to entry into this study with a return of serum testosterone to ≥200 ng/dL. Patients must be free of serious comorbidity and have a life expectancy of ≥3 years. Patients must have adequate physiologic reserves as evidenced by: Eastern Cooperative Oncology Group (ECOG) status of ≤2. Patients must have adequate bone marrow function: Platelets ≥100,000 cells/mm3, Hemoglobin ≥9.0 g/dL, and Absolute Neutrophil Count (ANC) ≥1,500 cells/mm3. Patients must have adequate renal function: creatinine ≤2 × upper limit of normal (ULN). Patients must have adequate liver function: Aspartate aminotransferase (AST) / Alanine transaminase (ALT) ≤2.5 × ULN; alkaline phosphatase <2.5 × ULN, unless bone metastasis is present in the absence of liver metastasis; and bilirubin < ULN or 1.5 mg/dl. No evidence of active ischemia on electrocardiogram (ECG) and documentation of ejection fraction (EF) ≥50%. Exclusion criteria: Patients must not have a second malignancy unless there is confidence of previous curative therapy. Patients with a recent history of transient ischemic attack (TIA) (within 6 months), who are requiring regular antianginal therapy, or who are having claudication sufficient to limit activity are not eligible. Patients with a previous history of deep venous thrombosis or pulmonary embolism (within 12 months) are not eligible Patients must not have a serious intercurrent medical or psychiatric illness, including serious active infection. Patients must not have sensory neuropathy > grade 1.

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 |
| --- | --- |
| Active Comparator: Definitive local therapy<br>3 cycles of chemotherapy (doxorubicin, ketoconazole, docetaxel and estramustine) + 12 months ADT (degarelix) | Drug: Doxorubicin<br>* In weeks 1, 3, and 5 of each 8-week cycle, participants will receive doxorubicin (20 mg/m2 as a 24-hour intravenous infusion on day 1 of each applicable week)<br>* Other names: Rubex;Drug: Ketoconazole<br>* In weeks 1, 3, and 5 of each 8-week cycle, participants will receive ketoconazole (400 mg orally 3 times daily for 7 days)<br>* Other names: Nizoral;Drug: Docetaxel<br>* In weeks 2, 4, and 6 of each 8-week cycle, participants will receive docetaxel (35 mg/m2 intravenously on day 1 of each applicable week)<br>* Other names: Docecad;Drug: Estramustine<br>* In weeks 2, 4, and 6 of each 8-week cycle, participants will receive estramustine (280 mg orally 3 times daily for 7 days)<br>* Other names: Emcyt;Drug: Degarelix<br>* The starting dose (240 mg given as two injections of 120 mg each) is followed by maintenance doses of 80 mg administered as a single injection every 28 days<br>* Other names: Firmagon;|
| Active Comparator: Nodal only/Low-volume bone<br>4 cycles of chemotherapy (doxorubicin, ketoconazole, docetaxel and estramustine) + 18 months ADT (degarelix) | Drug: Doxorubicin<br>* In weeks 1, 3, and 5 of each 8-week cycle, participants will receive doxorubicin (20 mg/m2 as a 24-hour intravenous infusion on day 1 of each applicable week)<br>* Other names: Rubex;Drug: Ketoconazole<br>* In weeks 1, 3, and 5 of each 8-week cycle, participants will receive ketoconazole (400 mg orally 3 times daily for 7 days)<br>* Other names: Nizoral;Drug: Docetaxel<br>* In weeks 2, 4, and 6 of each 8-week cycle, participants will receive docetaxel (35 mg/m2 intravenously on day 1 of each applicable week)<br>* Other names: Docecad;Drug: Estramustine<br>* In weeks 2, 4, and 6 of each 8-week cycle, participants will receive estramustine (280 mg orally 3 times daily for 7 days)<br>* Other names: Emcyt;Drug: Degarelix<br>* The starting dose (240 mg given as two injections of 120 mg each) is followed by maintenance doses of 80 mg administered as a single injection every 28 days<br>* Other names: Firmagon;|
| Active Comparator: High volume/no prior tx<br>5 cycles of chemotherapy (doxorubicin, ketoconazole, docetaxel and estramustine) + 24 months ADT (degarelix) | Drug: Doxorubicin<br>* In weeks 1, 3, and 5 of each 8-week cycle, participants will receive doxorubicin (20 mg/m2 as a 24-hour intravenous infusion on day 1 of each applicable week)<br>* Other names: Rubex;Drug: Ketoconazole<br>* In weeks 1, 3, and 5 of each 8-week cycle, participants will receive ketoconazole (400 mg orally 3 times daily for 7 days)<br>* Other names: Nizoral;Drug: Docetaxel<br>* In weeks 2, 4, and 6 of each 8-week cycle, participants will receive docetaxel (35 mg/m2 intravenously on day 1 of each applicable week)<br>* Other names: Docecad;Drug: Estramustine<br>* In weeks 2, 4, and 6 of each 8-week cycle, participants will receive estramustine (280 mg orally 3 times daily for 7 days)<br>* Other names: Emcyt;Drug: Degarelix<br>* The starting dose (240 mg given as two injections of 120 mg each) is followed by maintenance doses of 80 mg administered as a single injection every 28 days<br>* Other names: Firmagon;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy as Measured by Number Who Progressed | Progression defined as increase in Prostate Specific Antigen (PSA) >0.3 ng/mL over 2 measurements or larger/new lesion | From the time the participant signs the informed consent until the participant was taken off-study or the study was stopped, an average of 10 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy as Measured by Number of Participants With Pathology/Biopsy Positive for Disease |  | about 10 months after treatment initiation | 
| Efficacy as Measured by PSA Level | Prostate-specific antigen, or PSA, is a protein produced by normal, as well as malignant, cells of the prostate gland. The PSA test measures the level of PSA in a man's blood. For this test, a blood sample is sent to a laboratory for analysis. The results are reported as nanograms of PSA per milliliter (ng/mL) of blood. | baseline | 
| Efficacy as Measured by PSA Level | Prostate-specific antigen, or PSA, is a protein produced by normal, as well as malignant, cells of the prostate gland. The PSA test measures the level of PSA in a man's blood. For this test, a blood sample is sent to a laboratory for analysis. The results are reported as nanograms of PSA per milliliter (ng/mL) of blood. | Cycle 1 Day 1, which is the day of treatment initiation | 
| Efficacy as Measured by PSA Level | Prostate-specific antigen, or PSA, is a protein produced by normal, as well as malignant, cells of the prostate gland. The PSA test measures the level of PSA in a man's blood. For this test, a blood sample is sent to a laboratory for analysis. The results are reported as nanograms of PSA per milliliter (ng/mL) of blood. | Cycle 2 Day 1, which is about 8 weeks after treatment initiation | 
| Efficacy as Measured by PSA Level | Prostate-specific antigen, or PSA, is a protein produced by normal, as well as malignant, cells of the prostate gland. The PSA test measures the level of PSA in a man's blood. For this test, a blood sample is sent to a laboratory for analysis. The results are reported as nanograms of PSA per milliliter (ng/mL) of blood. | Cycle 3 Day 1, which is about 16 weeks after treatment initiation | 
| Efficacy as Measured by PSA Level | Prostate-specific antigen, or PSA, is a protein produced by normal, as well as malignant, cells of the prostate gland. The PSA test measures the level of PSA in a man's blood. For this test, a blood sample is sent to a laboratory for analysis. The results are reported as nanograms of PSA per milliliter (ng/mL) of blood. | Cycle 4 Day 1, which is about 24 weeks after treatment initiation | 
| Efficacy as Measured by PSA Level | Prostate-specific antigen, or PSA, is a protein produced by normal, as well as malignant, cells of the prostate gland. The PSA test measures the level of PSA in a man's blood. For this test, a blood sample is sent to a laboratory for analysis. The results are reported as nanograms of PSA per milliliter (ng/mL) of blood. | Cycle 5 Day 1, which is about about 32 weeks after treatment initiation | 
| Efficacy as Measured by PSA Level | Prostate-specific antigen, or PSA, is a protein produced by normal, as well as malignant, cells of the prostate gland. The PSA test measures the level of PSA in a man's blood. For this test, a blood sample is sent to a laboratory for analysis. The results are reported as nanograms of PSA per milliliter (ng/mL) of blood. The time point is the end of treatment, which is about about 8 weeks after the start of the last cycle. For the arm completing 3 cycles, the time point is 24 weeks after treatment initiation. For the arm completing 4 cycles, the time point is 32 weeks after treatment initiation. For the arm completing 5 cycles, the time point is 40 weeks after treatment initiation. | end of treatment, which is about about 8 weeks after the start of the last cycle | 
| Efficacy as Measured by Number Who PSA Progressed | PSA progression defined as increase in Prostate Specific Antigen (PSA) >0.3 ng/mL over 2 measurements | From the time the participant signs the informed consent until the participant was taken off-study or the study was stopped, an average of 10 months | 
| Quality of Life Measure by FACT-P Scale | The Functional Assessment of Cancer Therapy-Prostate (FACT-P) scale is a tool used for assessing the health-related quality of life (QoL) in men with prostate cancer. It consists of 27 core items which assess patient function in four domains (Physical, Social/Family, Emotional, and Functional well-being), and it is further supplemented by 12 site specific items to assess for prostate-related symptoms. Each item is rated on a 0 to 4 Likert type scale, and then combined to produce a global QoL score, with a range of scores of 0 to 156. Higher scores represent better QoL. | post cycle 1, which is about 8 weeks after treatment initiation | 
| Quality of Life Measure by FACT-P Scale | The Functional Assessment of Cancer Therapy-Prostate (FACT-P) scale is a tool used for assessing the health-related quality of life (QoL) in men with prostate cancer. It consists of 27 core items which assess patient function in four domains (Physical, Social/Family, Emotional, and Functional well-being), and it is further supplemented by 12 site specific items to assess for prostate-related symptoms. Each item is rated on a 0 to 4 Likert type scale, and then combined to produce a global QoL score, with a range of scores of 0 to 156. Higher scores represent better QoL. | post cycle 2, which is about 16 weeks after treatment initiation | 
| Quality of Life Measure by FACT-P Scale | The Functional Assessment of Cancer Therapy-Prostate (FACT-P) scale is a tool used for assessing the health-related quality of life (QoL) in men with prostate cancer. It consists of 27 core items which assess patient function in four domains (Physical, Social/Family, Emotional, and Functional well-being), and it is further supplemented by 12 site specific items to assess for prostate-related symptoms. Each item is rated on a 0 to 4 Likert type scale, and then combined to produce a global QoL score, with a range of scores of 0 to 156. Higher scores represent better QoL. | post cycle 3, which is about 24 weeks after treatment initiation | 
| Quality of Life Measure by FACT-P Scale | The Functional Assessment of Cancer Therapy-Prostate (FACT-P) scale is a tool used for assessing the health-related quality of life (QoL) in men with prostate cancer. It consists of 27 core items which assess patient function in four domains (Physical, Social/Family, Emotional, and Functional well-being), and it is further supplemented by 12 site specific items to assess for prostate-related symptoms. Each item is rated on a 0 to 4 Likert type scale, and then combined to produce a global QoL score, with a range of scores of 0 to 156. Higher scores represent better QoL. | post cycle 4, which is about 32 weeks after treatment initiation | 
| Quality of Life Measure by FACT-P Scale | The Functional Assessment of Cancer Therapy-Prostate (FACT-P) scale is a tool used for assessing the health-related quality of life (QoL) in men with prostate cancer. It consists of 27 core items which assess patient function in four domains (Physical, Social/Family, Emotional, and Functional well-being), and it is further supplemented by 12 site specific items to assess for prostate-related symptoms. Each item is rated on a 0 to 4 Likert type scale, and then combined to produce a global QoL score, with a range of scores of 0 to 156. Higher scores represent better QoL. | post cycle 5, which is about about 40 weeks after treatment initiation | 
| Quality of Life Measure by FACT-P Scale | The Functional Assessment of Cancer Therapy-Prostate (FACT-P) scale is a tool used for assessing the health-related quality of life (QoL) in men with prostate cancer. It consists of 27 core items which assess patient function in four domains (Physical, Social/Family, Emotional, and Functional well-being), and it is further supplemented by 12 site specific items to assess for prostate-related symptoms. Each item is rated on a 0 to 4 Likert type scale, and then combined to produce a global QoL score, with a range of scores of 0 to 156. Higher scores represent better QoL. The time point is about 12 weeks after completion of the last cycle. For the arm completing 3 cycles, the time point is 36 weeks after treatment initiation. For the arm completing 4 cycles, the time point is 44 weeks after treatment initiation. For the arm completing 5 cycles, the time point is 52 weeks after treatment initiation. | about 12 weeks after completion of the last cycle | 
| Safety of Drug Regimen as Measured by Number of Adverse Events |  | From the time the participant signs the informed consent until the participant was taken off-study or the study was stopped, an average of 10 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Advanced, Prostate Cancer, Local Failures