Enzalutamide in Combination With PSA-TRICOM in Patients With Non-Metastatic Castration Sensitive Prostate Cancer

Study Overview
=================
Brief Summary
-----------------
Background: - Enzalutamide is a well tolerated hormone therapy that is used to treat advanced prostate cancer. It is given to help kill cancer cells and limit cancer cell growth. A new possible way of treating prostate cancer is using a therapeutic cancer vaccine (immune stimulating therapy) that may help activate the immune system against the cancer. The immune stimulating vaccine will help white blood cells recognize and kill the cancer cells throughout the body. This vaccine therapy has been tested in hundreds of patients and is very well tolerated. Researchers want to see whether this vaccine, given with enzalutamide, is more effective at treating advanced prostate cancer than enzalutamide alone. Objectives: - To compare the safety and effectiveness of enzalutamide with and without vaccine therapy for advanced prostate cancer. Key Eligibility: Men at least 18 years of age who have advanced castration sensitive prostate cancer. Patients must have testosterone within the normal range No evidence of metastatic prostate cancer on computed tomography (CT) or Bone scan No history of autoimmune diseases No previous immunotherapy within 3 years Design: Participants will be screened with a physical exam and medical history. Blood and urine samples will be collected. Imaging studies will be used to monitor the cancer before treatment. Participants will be separated into two groups. One group will have enzalutamide and the study vaccine. The other group will have enzalutamide alone. All participants will take enzalutamide once a day. They will take the drug for 3 months. This form of intermittent therapy is common in this population of patients. The vaccine group of participants will receive the new study vaccine. They will have a single injection on the first day of the first study cycle. There will be regular booster injections afterward. There will be one injection during the third week of treatment, and one in the fifth week. The vaccine will then be given every 4 weeks until 21 weeks have passed. Treatment will be monitored with frequent blood tests and imaging studies.

Detailed Description
-----------------
Background: Androgen deprivation therapy (ADT) and surveillance are standard therapy options for prostate cancer patients with biochemical progression after localized therapy (or nonmetastatic castration sensitive prostate cancer; nmCSPC also known as D0 Prostate Cancer). These patients cannot be cured of prostate cancer and the primary therapeutic goal is to contain the disease with anti-androgen therapy. ADT can be administered intermittently consisting of multiple short courses or continuously with similar long-term clinical outcomes. Previous studies with high dose bicalutamide (androgen receptor antagonist, ARA) have shown significant biochemical control in nmCSPC. Enzalutamide is a modern ARA with greater androgen receptor affinity than bicalutamide and further impairs downstream effects of androgen receptor activation. This agent is FDA approved for the treatment of chemotherapy refractory metastatic castration resistant prostate cancer. Given its favorable side effect profile, there is strong interest in using enzalutamide to treat patients with earlier stages of prostate cancer including nmCSPC. PSA-TRICOM (Prostvac; developed by the National Cancer Institute [NCI] and licensed to Bavarian Nordic, Mountain View, California (CA)) is a novel candidate prostate cancer immunotherapy for the treatment of prostate cancer. It is a viral vector based therapeutic cancer vaccine that is administered via subcutaneous injections. In a randomized controlled Phase 2 trial, PSA-TRICOM therapy was associated with a prolongation of survival in men with metastatic castrate-resistant prostate cancer. A phase III trial is currently enrolling patients in this same population. There is also rationale to use therapeutic cancer vaccines such as PSA-TRICOM in earlier stage prostate cancer patients to maximize the potential therapeutic effect of immune stimulating therapy. An ongoing NCI clinical trial that combined PSA-TRICOM with flutamide (an older Food and Drug Administration (FDA) approved ARA) in nonmetastatic castration resistant prostate cancer has demonstrated safety and suggested the potential to improve time to progression. Analysis of previous trials using therapeutic cancer vaccines alone and in combination suggests that such therapies may alter tumor growth rate. If this hypothesis is correct, a therapeutic cancer vaccine may alter tumor regrowth rate/recovery after a cytoreductive therapy such as enzalutamide is discontinued. If PSA-TRICOM with enzalutamide can result in a reduced tumor regrowth rate as measured by PSA after a short course of enzalutamide therapy, it would provide an important proof of concept and potentially define it more clear role for therapeutic cancer vaccines in prostate cancer and potentially other cancers. To prospectively evaluate this hypothesis, all patients will be treated with enzalutamide in a manner similar to how short course ADT is used in common clinical practice. Half the patients will also be given PSA-TRICOM and PSA recovery after enzalutamide therapy will be compared between patients who received vaccine and those who did not. Preliminary data from the first cohort of randomized patients suggests that enzalutamide alone can induce an immunologic response. A second cohort of 15 patients will explore a lower dose of enzalutamide at 80 mg to determine if similar immunologic responses can also be seen at a lower dose, where toxicity is less likely. Objectives: Primary Endpoint: -Determine if PSA-TRICOM combined with the novel androgen receptor antagonist enzalutamide will result in a decrease in PSA growth kinetics (tumor re-growth rate) after enzalutamide discontinuation in patients with non-metastatic, castration sensitive prostate cancer (i.e. patients with normal testosterone). Eligibility: Patients with nonmetastatic castration sensitive prostate cancer and a PSA over 2.0 ng/ml Patients with normal testosterone levels. Histologically confirmed adenocarcinoma. Patients with a PSA doubling time of 12 months or less. Eastern Cooperative Oncology Group (ECOG) 0-1. Design: Randomized pilot study Cohort 1: Thirty-four patients to be enrolled and randomized 1:1 to Arm A: Enzalutamide for 3 months. Arm B: Enzalutamide 3 months + PSA-TRICOM on weeks 1, 3,5,9,13,17 and 21. Cohort 1: Arm A: Enzalutamide (n=17) Arm B: Enzalutamide + PSA-TRICOM (n=17) Enzalutamide will be given at the standard dose of 160 mg daily for 3 months. PSATRICOM (Prostvac-V/F) will consist of a single subcutaneous (sc) immunization of Prostvac-V in Week 1, followed by 6 Prostvac-F immunizations administered in Weeks 3, 5, 9, 13, 17, and 21. Patients will be retreated with a 3-month course of enzalutamide after PSA has returned to baseline values at study entry or higher. Patients will have had to be on study for at least 7 months or longer in order to be retreated with an additional course of enzalutamide therapy. Patients will be followed for PSA recovery after enzalutamide has been discontinued. Patients who do not develop a 25% decline in PSA after 3 months will not be evaluated for tumor re-growth and additional patients will be enrolled to evaluate for that endpoint. Patients will be stratified based on a doubling time of greater than or less than 6 months.

Official Title
-----------------
A Phase II Trial of Enzalutamide in Combination With PSA-TRICOM in Patients With Non-Metastatic Castration Sensitive Prostate Cancer

Conditions
-----------------
Prostate Cancer

Intervention / Treatment
-----------------
* Biological: PROSTVAC-F (Fowlpox)/TRICOM
* Biological: PROSTVAC-V (Vaccinia)/TRICOM
* Drug: Enzalutamide (Xtandi)


Participation Criteria
=================
Eligibility Criteria
-----------------
INCLUSION CRITERIA: A. Histopathological documentation of prostate cancer confirmed in the Laboratory of Pathology at the National Institutes of Health (NIH) Clinical Center, or Walter Reed National Military Medical Center prior to enrollment. If no pathologic specimen is available, patients may enroll with a pathologists report showing a histologic diagnosis of prostate cancer and a clinical course consistent with the disease. B. Biochemical progression defined as follows: For patients following definitive radiation therapy: a rise in prostate-specific antigen (PSA) of greater than or equal to 2 ng/mL above the nadir (per Radiation Therapy Oncology Group (RTOG)-American Society for Therapeutic Radiology and Oncology (ASTRO) consensus criteria). For patients following radical prostatectomy: rising PSA after surgical procedure. (Patients must have a PSA greater than or equal to 2ng/ml) C. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 (Karnofsky greater than or equal to 80%). D. Patients must have a PSA doubling time of 12 months or less. E. Patients must have a rising PSA as confirmed by 3 values done at least 1 week apart and over no less than 1 month. F. Recovery from acute toxicity related to prior therapy, including surgery and radiation, or no toxicity greater than or equal to grade 2. G. Negative computed tomography (CT) scan/magnetic resonance imaging (MRI) and bone scan for metastatic prostate cancer. H. Hematological eligibility parameters (within 16 days before starting therapy): Granulocyte count greater than or equal to 1000/mm(3) Platelet count greater than or equal to 100,000/mm(3) Hemoglobin (Hgb) greater than or equal to 10 g/dL I. Biochemical eligibility parameters (within 16 days before starting therapy): Hepatic function: bilirubin less than or equal to 1.5 mg/dL (OR in patients with Gilbert's syndrome, a total bilirubin less than or equal to 3.0), aspartate transaminase (AST) and alanine transaminase (ALT) less than or equal to 2.5 times upper limit of normal. J. No other active malignancies within the past 36 months (with the exception of nonmelanoma skin cancers or carcinoma in situ of the bladder) or life-threatening illnesses K. Willing to travel to the National Institutes of Health (NIH) for follow-up visits. L. 18 years of age or older. M. Able to understand and sign informed consent. N. Baseline testosterone greater than or equal to lower limit of normal. O. PSA less than or equal to 20 ng/mL. P. The effects of enzalutamide, PSA-TRICOM or the combination on the developing human fetus are unknown. For this reason, men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while her partner is participating in this study, she should inform her treating physician immediately. EXCLUSION CRITERIA: A. Immunocompromised status due to: Human immunodeficiency virus (HIV) positivity. Active autoimmune diseases such as Addison's disease, Hashimoto s thyroiditis, systemic lupus erythematosus, Sjogren syndrome, scleroderma, myasthenia gravis, Goodpasture syndrome or active Graves disease. Patients with a history of autoimmunity that has not required systemic immunosuppressive therapy or does not threaten vital organ function including central nervous system (CNS), heart, lungs, kidneys, skin, and gastrointestinal (GI) tract will be allowed. Other immunodeficiency diseases B. Chronic administration (defined as daily or every other day for continued use greater than 14 days) of corticosteroids deemed systemic by investigator within 28 days before the first planned dose of PSA-TRICOM. Use of inhaled steroids, nasal sprays, and topical creams for small body areas is allowed. C. Serious intercurrent medical illness that, in the judgment of the investigator, would interfere with patient's ability to carry out the treatment program. D. History of seizure, including any febrile seizure, loss of consciousness, or transient ischemic attack, or any condition that may pre-dispose to seizure (e.g., prior stroke, brain arteriovenous malformation, head trauma with loss of consciousness requiring hospitalization). E. Other medications used for urinary symptoms including 5-alpha reductase inhibitors (finasteride and dutasteride) and alternative medications known to alter PSA (eg phytoestrogens and saw palmetto) F. History of prior chemotherapy G. History of prior immunotherapy within the last 3 years H. Major surgery within 4 weeks prior to enrollment (Day 1 visit). I. History of allergic reactions attributed to compounds of similar chemical or biologic composition to enzalutamide or poxviral vaccines (e.g., vaccinia vaccine) J. Known allergy to eggs, egg products, aminoglycoside antibiotics (for example, gentamicin or tobramycin). K. History of atopic dermatitis or active skin condition (acute, chronic, exfoliative) that disrupts the epidermis L. Previous serious adverse reactions to smallpox vaccination M. Unable to avoid close contact or household contact with the following highrisk individuals for three weeks after the Day 1 vaccination: (a) children 3 years of age, (b) pregnant or nursing women, (c) individuals with prior or concurrent extensive eczema or other eczematoid skin disorders, or (d) immunocompromised individuals, such as those with human immunodeficiency virus (HIV). N. Receipt of an investigational agent within 30 days (or 60 days for an antibody based therapy) before the first planned dose of study drugs. O. Patients who test positive for Hepatitis B virus (HBV) or hepatitis C virus (HCV) P. Use of herbal products that may decrease PSA levels (e.g. saw palmetto) Q. Any gastrointestinal disease that could hinder the absorption of enzalutamide R. Uncontrolled hypertension (Systolic Blood Pressure (SBP)>170/ Diastolic Blood Pressure (DBP)>105)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 100 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A - Enzalutamide for 3 months<br>Enzalutamide for 3 months | Drug: Enzalutamide (Xtandi)<br>* An androgen receptor inhibitor.<br>* Other names: Xtandi;|
| Experimental: Arm B - Enzalutamide for 3 months + PSA-TRICOM<br>Enzalutamide 3 months + PSA-TRICOM (Prostvac-V/F) on weeks 1, 3, 5, 9,13,17 and 21 | Biological: PROSTVAC-F (Fowlpox)/TRICOM<br>* A recombinant fowlpox virus vector vaccine containing the genes for human prostate specific antigen (PSA) and three co-stimulatory molecules.<br>* Other names: PROSTVAC-F/TRICOM;Biological: PROSTVAC-V (Vaccinia)/TRICOM<br>* A recombinant vaccinia virus vector vaccine containing the genes for human prostate specific antigen (PSA) and three co-stimulatory molecules.<br>* Other names: PROSTVAC-V/TRICOM;Drug: Enzalutamide (Xtandi)<br>* An androgen receptor inhibitor.<br>* Other names: Xtandi;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tumor Growth Rate | Growth rate was measured using the growth rate equation -f(t) = exp (-d*t) + exp (g*t) -1 where exp is the base of the natural algorithm, e = 2.7182 and t is days since treatment started. The tumor growth rate equation measures Prostate Specific Antigen (PSA) rise over time. The UOM is unitless because this is a way to measure PSA kinetics. | 7 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Pretreatment Plasma Vascular Endothelial Growth Factor (VEGF) Concentration 30 Days After the Start of Course 1 and Course 2 of Enzalutamide | VEGF was measured by the enzyme-linked immunosorbent assay (ELISA) assay. The lower limit of quantitation of assay was 9.0 pg/ml. | 30 Days After the Start of Course 1 and Course 2 of Enzalutamide | 
| Median Testosterone After 84 Days of Enzalutamide | Normal testosterone is 270-1070 nd/dL. | 84 days | 
| Percent Change in Prostate Specific Antigen (PSA) After 84 Days of Enzalutamide in Course 1 | Median PSA change would be considered optimal. | 84 days | 
| Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0) | Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned. | Date treatment consent signed to date off study, approximately 43 months and 13 days for Arm A, and 78 months and 6 days for Arm B. | 
| Median Time Until Prostate Specific Antigen (PSA) Recovery From Baseline Following Course 1 and Course 2 of Enzalutamide | PSA recovery is defined as the return above baseline PSA in participants with normal testosterone and non-metastatic, castration sensitive prostate cancer. | up to 41 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Immunotherapy, Gene Transfer, Androgen Receptor Antagonist, PSA, Immune Response