Ipilimumab + Androgen Depravation Therapy in Prostate Cancer

Study Overview
=================
Brief Summary
-----------------
The goal of this clinical research study is to learn if ipilimumab in combination with either Lupron® (leuprolide), Zoladex® (goserelin), or Firmagon® (degarelix) can affect prostate-specific antigen (PSA) levels in patients with prostate cancer. Researchers also want to learn if these drug combinations affect the body's immune system. The safety of these drug combinations will also be studied.

Detailed Description
-----------------
The Study Drugs: Ipilimumab is designed to block the activity of cells that decrease the immune system's ability to fight cancer. Leuprolide, goserelin, and degarelix are designed to help stop the body from making testosterone (a male sex hormone that prostate cancer cells need to survive), which may slow the growth of cancer cells. Study Drug Administration: If you are found to be eligible to take part in this study, you will receive either leuprolide, goserelin or degarelix . The drug you receive will depend on what the doctor thinks is in your best interest and/or which drug your insurance provider will help to cover. Leuprolide is given through a needle in the muscle. Goserelin and degarelix are given through a needle under the skin in the abdomen. Beginning at Week 1, you will receive the drug 1 time every month or every 3 months for up to 8 months. Your doctor will tell you more about which dosing schedule you will use. You will also receive ipilimumab by vein over about 90 minutes at Weeks 5, 9, 13, and 17. Your blood pressure will be measured every 30 minutes during the infusion, as well as an hour after you are finished receiving the drug. Study Visits: Before each dose of ipilimumab, and every 4 weeks for 6 months after the last dose of ipilimumab, and every 12 weeks after that, the following tests and procedures will be performed: You will have a physical exam. You will be asked about any other drugs and/or treatments you may be receiving. You will be asked about any side effects you may have experienced. Your performance status will be recorded. Blood (about 3 teaspoons) will be drawn for routine tests and to measure your protein, PSA, and testosterone levels, and to check the function of your pancreas, thyroid, and adrenal glands. Urine will be collected for routine tests. This blood will also be tested for other hormone levels to check the function of your thyroid and adrenal glands (before each dose of ipilimumab and 4 weeks after the last dose only). Every 12 weeks, you will have the same imaging scans that you had at screening. Length of Study: You may receive the study drugs for up to 8 months. You will remain on study for as long as the disease remains stable. You will be taken off study treatment if you have intolerable side effects or if the disease gets worse. End-of-Study Treatment/Observation Visit: Within 14 days after your disease gets worse, the following tests and procedures will be performed: You will have a physical exam. You will be asked about any drugs and/or treatments you may be receiving. You will be asked about any side effects you may have experienced. Blood (about 3 teaspoons) will be drawn for routine tests. This blood will also be tested to measure your protein, PSA, and testosterone levels, and to check the function of your pancreas, thyroid, and adrenal glands. You will have the same imaging scans that you had at screening. Long-Term Follow-Up: A member of the study staff will check up on you about every 6 months after your End-of-Study Treatment/Observation Visit. This will consist of a phone call, an e-mail, or a review of your medical and/or other records. If you are contacted by phone, the call will only last a few minutes. This is an investigational study. Leuprolide, goserelin, and degarelix are FDA approved and commercially available for the treatment of prostate cancer. Ipilimumab is FDA approved and commercially available for melanoma. Its use to treat prostate cancer is investigational. Up to 48 patients will take part in this study. All will be enrolled at MD Anderson.

Official Title
-----------------
A Phase II Study of Ipilimumab PLUS Androgen Depravation Therapy in Castrate Sensitive Prostate Carcinoma

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

Intervention / Treatment
-----------------
* Drug: Ipilimumab
* Drug: Leuprolide
* Drug: Goserelin
* Drug: Degarelix


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically or cytologically confirmed prostate carcinoma. Evidence of metastatic disease on previous bone scan and/or CT scan and/or MRI. Castrate-sensitive disease. Patients already on ADT are eligible as long as the time from initiation of LHRH analog or antagonist is not greater than 1 month AND the total exposure time to the LHRH analog or antagonist will not exceed 8 months (i.e. the effectiveness of current depot LHRH analog or antagonist does not extend beyond 8 months since its initiation). Patients who have received prior hormonal therapy are allowed to participate as long as they have been off hormone ablation for 1.5 times as long as they were on it: e.g. 1) Patients who have received up to 4 months of hormonal ablation are eligible as long as they have been off hormonal ablation for >/= 6 months; 2) Patients who have received 1 year of hormonal ablation are eligible as long as they have been off hormone ablation for >/= 18 months; 3) Patients who have received up to 2 years of hormonal ablation are eligible as long as they have been off hormonal ablation for >/= 3 years have elapsed since its discontinuation. Eastern Cooperative Oncology Group (ECOG) performance status </= 1 Patients must have normal organ and marrow function as defined below: a) white blood cell count (WBC) >/= 3000/uL; b) Absolute neutrophil count (ANC) >/= 1500/uL; c) Platelets >/= 100 x 10^3/uL; d) Hemoglobin >/= 9 g/dL; e) Creatinine </= 2mg/dL; f) ALT </= 2.5 x upper limit of normal (ULN) for patients without liver metastases. For patients with liver metastasis ALT </= 5 x ULN is allowed; g) Bilirubin </= 3 x ULN (except for patients with Gilbert's Syndrome, who must have a total bilirubin </= 3mg/dL) Patients included in the study must be >/= 18 years old Ability to understand and willingness to sign a written informed consent document. Exclusion Criteria: Autoimmune disease: Patients with a history of inflammatory bowel disease (including Crohn's disease and ulcerative colitis) and autoimmune disorders such as rheumatoid arthritis, systemic progressive sclerosis [scleroderma], Systemic Lupus Erythematosus or autoimmune vasculitis [e.g., Wegener's Granulomatosis] are excluded from this study. Any underlying medical or psychiatric condition, which in the opinion of the Investigator, will make the administration of study drug hazardous or obscure the interpretation of AEs: e.g. a condition associated with frequent diarrhea or chronic skin conditions, recent surgery or colonic biopsy from which the patient has not recovered, or partial endocrine organ deficiencies. Patients with known brain metastases. Patients with small cell carcinoma of the prostate. History of other malignancies, other than nonmelanoma skin cancer or Ta or T1 (low grade) bladder carcinomas, unless in complete remission and off therapy for that disease for at least 5 years. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, history of congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. Known HIV, Hepatitis B, or Hepatitis C. Untreated symptomatic spinal cord compressions. Any non-oncology vaccine therapy used for prevention of infectious diseases (for up to one month prior to or after any dose of ipilimumab). Concomitant therapy with any of the following: IL-2, interferon or other non-study immunotherapy regimens; cytotoxic chemotherapy; immunosuppressive agents; other investigation therapies; or chronic use of systemic corticosteroids (used in the management of cancer or non-cancer-related illnesses). Previous participation in another ipilimumab clinical trial or prior treatment with a CD137 agonist or CTLA-4 inhibitor or agonist. History of acute diverticulitis, intra-abdominal abscess, GI obstruction, abdominal carcinomatosis or other known risk factors for bowel perforation. Patients who do not agree to practice appropriate birth control methods while on therapy. Concurrent use of 5-alpha reductase inhibitors (finasteride or dutasteride).

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

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

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

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

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ipilimumab + ADT<br>Ipilimumab 10 mg/kg intravenous (IV) Weeks 5, 9, 13, and 17 plus Androgen Depravation Therapy (ADT) of either Leuprolide 7.5 mg intramuscular (IM) , Goserelin 3.6 mg subcutaneous (SQ) or Degarelix 80 mg SQ once a month for 8 months beginning Week 1. | Drug: Ipilimumab<br>* 10 mg/kg by vein over 90 minutes once every 4 weeks, for 4 weeks.<br>* Other names: MDX010;Drug: Leuprolide<br>* 7.5 mg intramuscular once a month for 8 months<br>* Other names: Lupron Depot;Drug: Goserelin<br>* 3.6 mg subcutaneous once a month for 8 months<br>* Other names: Zoladex;Drug: Degarelix<br>* 80 mg subcutaneous once a month for 8 months<br>* Other names: Firmagon;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Progressed After 7 Months of Being on Treatment | Anti-tumor activity assessed through serial PSA measurements (blood tests) at 7 months on treatment. Progression defined as two consecutive PSA values increasing by at least 20% or more from the lowest PSA value for each patient. | at the end of 7 months on treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Number of Clonal Expansion of Cluster of Differentiation 8 (CD8) T-cells | CD8 T-cells are known as cytotoxic T-cells or killer T-cells. When the resting CD8 T-cells are activated, the activated CD8 T-cells multiple to fight a specific target so creating a group of specifically activated T-cells. This test measured the minimal number of clonal expansions of CD8 T-cells that always preceded an adverse response to treatment that was due to increased activity in the immune system itself. The minimal number of clonal expansion points to what this increased activity in the immune system might look like. | Each evaluable patient was followed from the time of their first dose until 30 days after their last dose of study drug | 
| Time to Testosterone Recovery (> 50ng/mL) in Patients Treated With Intermittent ADT Plus Ipilimumab. | The presence of testosterone was followed in each patient from the start of treatment until the testosterone lab test was found to be at a value greater than 50ng/mL. | 1 month up to 7 months. | 
| Time to Progression of Disease (PD) Off Androgen Depravation Therapy (ADT), After Treatment With Intermittent ADT Plus Ipilimumab. | The number of months after the last ADT dose until the PSA progression | 2 to 45 months | 
| The Total Number of Study Drug Related Events Indicated by the Participants | The total number of adverse events which were related to one of the study drugs. Grade 1- Mild, asymptomatic of mild symptoms; clinical or diagnostic observation only; intervention not indicated. Grade 2- Moderate, minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental (daily living activities). Grate 3- Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care of daily life activities. | From the first dose to the last follow-up, up to 60 months | 
| Overall Survival | Overall survival of patients treated with intermittent ADT and ipilimumab in months. | From the date of randomization until the date of first documented progression or date of death from any case, whichever came first, assessed up to 70 months. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Firmagon, Leuprolide, Lupron Depot, Leuprolide Acetate, Goserelin, Zoladex, Degarelix, Prostate cancer, Castrate sensitive prostate carcinoma, Metastatic prostate carcinoma, Androgen depravation therapy, ADT, Prostate-specific antigen, PSA, Ipilimumab, Yervoy, BMS-734016, MDX010