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

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.

• Doxorubicin (Drug), also known as Adriamycin, Rubex: 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)
• Ketoconazole (Drug), also known as Nizoral: In weeks 1, 3, and 5 of each 8-week cycle, participants will receive ketoconazole (400 mg orally 3 times daily for 7 days)
• Docetaxel (Drug), also known as Taxotere, Docecad: 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)
• Estramustine (Drug), also known as Emcyt: In weeks 2, 4, and 6 of each 8-week cycle, participants will receive estramustine (280 mg orally 3 times daily for 7 days)
• Degarelix (Drug), also known as Firmagon: 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

Primary outcomes

• Efficacy as Measured by Number Who Progressed [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]: Progression defined as increase in Prostate Specific Antigen (PSA) >0.3 ng/mL over 2 measurements or larger/new lesion

Secondary outcomes

• 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 [baseline]: 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.
• Efficacy as Measured by PSA Level [Cycle 1 Day 1, which is the day of treatment initiation]: 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.
• Efficacy as Measured by PSA Level [Cycle 2 Day 1, which is about 8 weeks after treatment initiation]: 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.
• Efficacy as Measured by PSA Level [Cycle 3 Day 1, which is about 16 weeks after treatment initiation]: 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.
• Efficacy as Measured by PSA Level [Cycle 4 Day 1, which is about 24 weeks after treatment initiation]: 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.
• Efficacy as Measured by PSA Level [Cycle 5 Day 1, which is about about 32 weeks after treatment initiation]: 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.
• Efficacy as Measured by PSA Level [end of treatment, which is about about 8 weeks after the start of the last cycle]: 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.
• Efficacy as Measured by Number Who PSA Progressed [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]: PSA progression defined as increase in Prostate Specific Antigen (PSA) >0.3 ng/mL over 2 measurements
• Quality of Life Measure by FACT-P Scale [post cycle 1, which is about 8 weeks after treatment initiation]: 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.
• Quality of Life Measure by FACT-P Scale [post cycle 2, which is about 16 weeks after treatment initiation]: 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.
• Quality of Life Measure by FACT-P Scale [post cycle 3, which is about 24 weeks after treatment initiation]: 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.
• Quality of Life Measure by FACT-P Scale [post cycle 4, which is about 32 weeks after treatment initiation]: 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.
• Quality of Life Measure by FACT-P Scale [post cycle 5, which is about about 40 weeks after treatment initiation]: 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.
• Quality of Life Measure by FACT-P Scale [about 12 weeks after completion of the last cycle]: 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.
• 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]

Sex: Male, ages: 18 Years to any

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.

Participant flow

Outcome results

• Efficacy as Measured by Number Who Progressed (Primary), Count of participants, Participants: Definitive Local Therapy 0; Nodal Only/Low-volume Bone 0; High Volume/no Prior tx 2
• Efficacy as Measured by Number of Participants With Pathology/Biopsy Positive for Disease (Secondary), Count of participants, Participants: Definitive Local Therapy 0; Nodal Only/Low-volume Bone 3; High Volume/no Prior tx 3
• Efficacy as Measured by PSA Level (Secondary), Median, ng/mL: Definitive Local Therapy 5.7 (0.1 to 27.7); Nodal Only/Low-volume Bone 15.8 (0.8 to 46.6); High Volume/no Prior tx 90.7 (17.5 to 2191)
• Efficacy as Measured by PSA Level (Secondary), Median, ng/mL: Definitive Local Therapy 5.7 (0.01 to 27.7); Nodal Only/Low-volume Bone 9.7 (0.8 to 46.6); High Volume/no Prior tx 90.7 (17.5 to 90.7)
• Efficacy as Measured by PSA Level (Secondary), Median, ng/mL: Definitive Local Therapy 0.01 (0.01 to 0.3); Nodal Only/Low-volume Bone 0.3 (0.1 to 0.6); High Volume/no Prior tx 3.8 (0.6 to 68.1)
• Efficacy as Measured by PSA Level (Secondary), Median, ng/mL: Definitive Local Therapy 0.01 (0.01 to 0.3); Nodal Only/Low-volume Bone 0.1 (0.1 to 0.8); High Volume/no Prior tx 0.9 (0.3 to 7.0)
• Efficacy as Measured by PSA Level (Secondary), Median, ng/mL: Definitive Local Therapy ; Nodal Only/Low-volume Bone 0.01 (0.01 to 0.1); High Volume/no Prior tx 0.55 (0.2 to 4.1)
• Efficacy as Measured by PSA Level (Secondary), Median, ng/mL: Definitive Local Therapy ; Nodal Only/Low-volume Bone ; High Volume/no Prior tx 0.5 (0.1 to 2.6)
• Efficacy as Measured by PSA Level (Secondary), Median, ng/mL: Definitive Local Therapy 0.01 (0.01 to 0.2); Nodal Only/Low-volume Bone 0.01 (0.01 to 0.2); High Volume/no Prior tx 1.4 (0.1 to 34.4)
• Efficacy as Measured by Number Who PSA Progressed (Secondary), Count of participants, Participants: Definitive Local Therapy 0; Nodal Only/Low-volume Bone 0; High Volume/no Prior tx 1
• Quality of Life Measure by FACT-P Scale (Secondary), Median, units on a scale: Definitive Local Therapy 97 (62 to 135); Nodal Only/Low-volume Bone 99 (87 to 123); High Volume/no Prior tx 105 (58 to 115)
• Quality of Life Measure by FACT-P Scale (Secondary), Median, units on a scale: Definitive Local Therapy 94 (62 to 114); Nodal Only/Low-volume Bone 97 (85 to 124); High Volume/no Prior tx 102 (58 to 121)
• Quality of Life Measure by FACT-P Scale (Secondary), Median, units on a scale: Definitive Local Therapy 79 (79 to 79); Nodal Only/Low-volume Bone 94 (89 to 123); High Volume/no Prior tx 114 (101 to 121)
• Quality of Life Measure by FACT-P Scale (Secondary), Median, units on a scale: Definitive Local Therapy ; Nodal Only/Low-volume Bone 96 (93 to 126); High Volume/no Prior tx 113 (99 to 121)
• Quality of Life Measure by FACT-P Scale (Secondary), Median, units on a scale: Definitive Local Therapy ; Nodal Only/Low-volume Bone ; High Volume/no Prior tx 107 (89 to 117)
• Quality of Life Measure by FACT-P Scale (Secondary), Median, units on a scale: Definitive Local Therapy 94 (83 to 115); Nodal Only/Low-volume Bone 118 (92 to 142); High Volume/no Prior tx 99 (93 to 105)
• Safety of Drug Regimen as Measured by Number of Adverse Events (Secondary), Number, adverse event: Definitive Local Therapy 115; Nodal Only/Low-volume Bone 270; High Volume/no Prior tx 166

Adverse events

Time frame: 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.

Serious adverse events by term

Other adverse events by term

77 more terms not shown.

Limitations and caveats: Early termination of study leading to small number of subjects analyzed

• Study Protocol and Statistical Analysis Plan (PDF, 2016-01-26)

• Robert J Amato, DO, Principal investigator, The University of Texas Health Science Center, Houston