Clinical trial NCT01377389
Conditions: Prostate Cancer
Keywords: Prostate cancer Castrate sensitive prostate carcinoma Metastatic prostate carcinoma Androgen depravation therapy ADT Prostate-specific antigen PSA Ipilimumab Yervoy BMS-734016 MDX010 Leuprolide Lupron Depot Leuprolide Acetate Goserelin Zoladex Degarelix Firmagon
Sponsor: M.D. Anderson Cancer Center
Start date: 2011-06-17; Completion date: 2017-04-07
Enrollment: 30 participants; Allocation: NA; Intervention model: SINGLE_GROUP

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.

Arms: arm 1: 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.
Interventions: intervention 1: Ipilimumab intervention 2: Leuprolide intervention 3: Goserelin intervention 4: Degarelix
Intervention descriptions: intervention 1: 10 mg/kg by vein over 90 minutes once every 4 weeks, for 4 weeks. intervention 2: 7.5 mg intramuscular once a month for 8 months intervention 3: 3.6 mg subcutaneous once a month for 8 months intervention 4: 80 mg subcutaneous once a month for 8 months

Protocol documents:
Prot_SAP_000.pdf: 
2009-0378
February 15, 2013
Abstract - Page 1
Protocol Abstract Page
A Phase II Study of Ipilimumab PLUS Androgen Deprivation Therapy in 
Castrate Sensitive Prostate Carcinoma
2009-0378
Core Protocol Information
Study Chairman: 
Ana M. Aparicio
Department:
Genitourinary Medical Oncology
Full Title: 
A Phase II Study of Ipilimumab PLUS Androgen Deprivation Therapy in Castrate Sensitive 
Prostate Carcinoma
Protocol Phase:
Phase II
Version Status:
Activated -- Closed to new patient entry as of 10/11/2013
Version:
15
Document Status:
Final
Abstract
Objectives:
Primary Objectives:
To estimate the rate of PSA </= 0.2ng/mL at 7 months in patients treated with androgen 

deprivation therapy (ADT) plus Ipilimumab.
Secondary Objectives:
To profile immunological changes induced in patients with metastatic prostate carcinoma 

treated with intermittent ADT plus Ipilimumab.
To assess the time to testosterone recovery (> 50ng/mL) in patients treated with intermittent 

ADT plus Ipilimumab. 
To assess the time to PD off ADT, after treatment with intermittent ADT plus Ipilimumab.  

To characterize safety and drug-related adverse events of ipilimumab combined with 

complete androgen ablation.
To determine the overall survival of patients treated with intermittent ADT and ipilimumab.

 
Rationale: (Be as concise as possible)
Androgen ablation induces involution of prostate cancer at both primary and metastatic sites. Androgen 


2009-0378
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Abstract - Page 2
ablation also leads to an accumulation of mononuclear cells within the prostate, (which is associated with 
a better prognosis of the disease) and the development of new seroreactivities in patients with prostate 
cancer. These findings suggest that the induction of specific T cell responses might contribute to the 
anti-tumor effect of androgen ablation. Enhancing the host immune response against the tumor might 
lead to an improvement in the outcome of patients with metastatic prostate carcinoma. 
T cell activation is a complex process that is initiated when an antigen is presented to the T cell receptor 
(TCR) followed by the interaction of additional T cell surface molecules with their respective ligands on 
the antigen presenting cell (APC). This second interaction can result in a positive or a negative 
costimulatory signal depending on which specific molecules are involved. CTLA-4 is a T-cell surface 
molecule that, on interaction with the B7 molecule of the APC, leads to the termination of the T-cell 
response. Blockage of CTLA-4 with the monoclonal antibody Ipilimumab has led to a remarkable 
enhancement of the immune response in experimental models of cancer and infection.
Durable responses and SD after treatment with ipilimumab have been observed in several malignancies, 
including melanoma, prostate and renal cell carcinoma.
Eligibility: (List All Criteria)
Inclusion:
1)
Histologically or cytologically confirmed prostate carcinoma.
2)
Evidence of metastatic disease on previous bone scan and/or CT scan and/or MRI.
3)
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).
4)
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.
5)
ECOG performance status </= 1
6)
Patients must have normal organ and marrow function as defined below: a) WBC >/= 3000/uL; b) 
ANC >/= 1500/uL; c) Platelets >/= 100 x 10^3/uL; d) Hemoglobin >/= 9 g/dL; e) Creatinine </= 2mg/dL; f) 
ALT </= 2.5 x 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)
7)
Patients included in the study must be >/= 18 years old
8)
Ability to understand and willingness to sign a written informed consent document.
Exclusion:
1)
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., 


2009-0378
February 15, 2013
Abstract - Page 3
Wegener’s Granulomatosis] are excluded from this study.
2)
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.
3)
Patients with known brain metastases.
4)
Patients with small cell carcinoma of the prostate.
5)
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.
6)
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.
7)
Known HIV, Hepatitis B, or Hepatitis C.
8)
Untreated symptomatic spinal cord compressions.
9)
Any non-oncology vaccine therapy used for prevention of infectious diseases (for up to one month 
prior to or after any dose of ipilimumab).
10)
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).
11)
Previous participation in another ipilimumab clinical trial or prior treatment with a CD137 agonist or 
CTLA-4 inhibitor or agonist.
12)
History of acute diverticulitis, intra-abdominal abscess, GI obstruction, abdominal carcinomatosis or 
other known risk factors for bowel perforation.
13)
Patients who do not agree to practice appropriate birth control methods while on therapy.
14)
Concurrent use of 5-alpha reductase inhibitors (finasteride or dutasteride).
Is there an age limit?  Yes
Why?  Provide scientific justification:
Prostate cancer does not occur in patients under the age of 18.
Disease Group:
Prostate
Treatment Agents/Devices/Interventions:
Degarelix, Goserelin Acetate, Ipilimumab, Leuprolide Acetate
Proposed Treatment/Study Plan:


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Abstract - Page 4
 


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Abstract - Page 5


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Abstract - Page 6


2009-0378
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Statistical Considerations:
This is a single arm phase II trial to evaluate the rate of PSA < 0.2ng/mL in patients treated with ADT 
plus Ipilimumab. The primary endpoint is the proportion of patients achieving a PSA < 0.2ng/mL at 
month 7.
The trial was originally designed to use a Simon’s optimal two-stage design to stop the trial if 7 or less 
among the first 16 patients achieved a PSA < 0.2ng/mL at month 7. However, since then ipilimumab 
has been approved by the FDA for use in melanoma patients and there are data showing that the full 
effect of immunotherapies can take many months (possibly longer than 7) to become evident.  On the 
other hand, the accrual rate for this trial has been faster than we originally expected. Since its 
activation on 06/17/2011, we have already enrolled 9 patients. Given the fast accrual rate and the 
desirability of a longer wait time and of data from the secondary endpoints to reliably assess efficacy, 
we now propose to change the study to a single-stage design for efficacy endpoint.  Based on new 
safety data obtained since the trial was first designed, the safety monitoring plan has also been 
changed as described below.  We will perform a final analysis on the primary and secondary efficacy 
endpoints when the study is complete. 
Let S be the event of achieving PSA < 0.2ng/mL at month 7. It is assumed that ADT plus Ipilimumab 
will have a target rate of 60% for S.  A rate of 40% or lower is considered a failure and the 
combination therapy will be rejected under this circumstance.  With a sample size of 48 patients, we 
will have an 80% power to detect such a 20% difference using a Chi-squared test and with a 
two-sided type I error rate of 0.05. The sample size was computed using nQuery Advisor 7.0.
Safety Monitoring and Rules:
The PI will meet with the research nurse and data coordinator regularly to monitor toxicity events. 
Toxicity reports will be generated monthly and reviewed by the PI and the statistician.  If at any time 
during the study,one of the following criteria is met, then accrual will be suspended until the PI has 
reviewed the events and determined the appropriate course of action, which could include a protocol 
amendment to decrease the dose of ipilimumab.
> 40% of subjects treated on the ipilimumab arm develop a > Grade 3 toxicity thought to be related to 

the ipilimumab.
> 10% of subjects experience an ipilimumab related > Grade 3 toxicity that cannot be alleviated or 

controlled by appropriate care and/or steroid and/or infliximab therapy within 14 days of the initiation 
of such therapy


2009-0378
February 15, 2013
Abstract - Page 8
Any 2 ipilimumab related deaths unless also attributed to progression have occurred

Endpoint Definitions and Analysis Plan
For the primary analysis, the proportion of patients achieving PSA < 0.2ng/mL at 7 months will be 
estimated in the ITT population, along with the exact 95% confidence interval. Kaplan-Meier methods 
will be used to analyze the time-to-event outcomes, including:
1.  Time to testosterone recovery: Defined as the time between day 224 of the protocol and the date at 
which serum testosterone returns to > 50ng/mL. As per Section 5.1, the effect of ADT should not last 
beyond 8 months, i.e. beyond day 224. Patients who have not achieved testosterone recovery (ie, 
returns to > 50ng/mL) at the last follow-up time will be treated as censoring. 
2.  Time to PD off ADT: defined as the time between day 224 of the protocol and the date of the first PSA 
measurement that is >20% above the nadir, as long as the rise is confirmed by a two additional PSA 
measurements separated by at least one week as described in Section 7.2. Patients who have not 
experienced PSA progression at the last follow-up time will be treated as censoring. 
3.  Overall survival: defined as the time between the date of registration and the date of death. Patients 
who have not died at the last follow-up time will be treated as censoring.
Where Will Participants Be Enrolled:
Only at MDACC
Is this an NCI-Cancer Therapy Evaluation Protocol (CTEP)?
No
Is this an NCI-Division of Cancer Prevention Protocol (DCP)?
No
Estimated Accrual:
Total Accrual at MDACC:
48
Estimated monthly accrual at MDACC:
1-2
Accrual Comments:
Do you expect your target population to include non-english 
speaking participants?
No
Location of Treatment:
This protocol is performed on an Outpatient basis.
Length of Stay: What is the length & frequency of hospitalization?
n/a
Return Visits: How often must participants come to MDACC?


2009-0378
February 15, 2013
Abstract - Page 9
Patients will return every 4 weeks for follow-up and treatment with ipilimumab for the first 32 
weeks on study.  Patients will return every 4 weeks for 6 months after last dose of Ipilimumab and 
every 12 weeks thereafter.
Home Care: Specify what, if any, treatment may be given at home.
n/a
Name of Person at MDACC Responsible for Data Management:  Mary Storms
Prior protocol at M. D. Anderson:
Has the Principal Investigator ever had a clinical or behavioral protocol at MDACC that accrued patients?
Yes
Data Monitoring Committee:
Is treatment assignment randomized? No
Is this a blinded or double-blinded study? No
Does this protocol have a schedule for interim and final analysis?
No
Radiation Safety:
Does this study involve the administration of radioisotopes or a radioisotope 
labeled agent?
No
Is the radioactive compound (or drug) FDA approved and/or commercially 
available?
No
Investigational New Drugs:
Does this protocol require an IND?
Yes
Please list the IND holder and provide the IND number:
IND Holder:
MDACC
IND Number:
106,207
Investigational Device:
Is the Investigational Device approved by the FDA?
N/A
Is the Investigational Device being used in the manner approved by 
the FDA?
N/A
Has the Investigational Device been modified in a manner not 
approved by the FDA?
N/A
Name of Device:
Manufacturer:


2009-0378
February 15, 2013
Abstract - Page 10
What is the FDA Status of the Investigational Device?
Is the study being conducted under an Investigational Device Exemption (IDE)?
IDE Holder:
IDE Number:
Risk Assessment:
Please answer the following questions regarding the Investigational Device.
Intended as an implant?
No
Purported or represented to be for use supporting or sustaining human life?
No
For use of substantial importance in diagnosing, curing, mitigating, or treating 
disease, or otherwise preventing impairment of human health?
No
You may attach sponsor documentation of the risk assessment:
Will participant be charged for the Investigational Device? No
Sponsorship and Support Information:
Does the Study have a Sponsor or Supporter?
Yes
Sponsor or Supporter:
Bristol-Myers Squibb
Type(s) of Support:
Funds
Agent
Monitored by Sponsor or Sponsor Represenative (CRO)?
No
Is this Protocol listed on any Federal Grant or Foundation Funding Application?No
Biosafety:
Does this study involve the use of Recombinant DNA Technology? 
No
Does this study involve the use of organisms that are infectious to humans? 
No
Does this study involve stem cells?
No
Technology Commercialization:
Does this study include any agents or devices manufactured or produced at 
MD Anderson Cancer Center?
No
Laboratory Tests:
Where will laboratory tests be performed on patient materials?  (Please select all that apply)
Division of Pathology & Laboratory Medicine CLIA Certified Laboratory


2009-0378
February 15, 2013
Abstract - Page 11
Manufacturing:
Will you manufacture in full or in part (split manufacturing) a drug or biological 
product at the M. D. Anderson Cancer Center for the proposed clinical study?
No