Hormone Therapy and Ipilimumab in Treating Patients With Advanced Prostate Cancer

• Sponsor: Mayo Clinic (Other)
• Overall Status: Completed
• CT.gov ID: NCT00170157
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 112
• Location: 1
• Arms: 2
• Duration (Months): 108
• Patients Per Site Per Month: 1

Study Details

Study Description

Brief Summary

RATIONALE: Androgens can cause the growth of prostate cancer cells. Antihormone therapy, such as leuprolide acetate, goserelin, flutamide, or bicalutamide may lessen the amount of androgens made by the body. Monoclonal antibodies, such as ipilimumab, can block cancer growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry cancer-killing substances to them. Giving antihormone therapy together with ipilimumab may kill more tumor cells.

PURPOSE: This randomized phase II trial is study how well giving hormone therapy and ipilimumab together works in treating patients with advanced prostate cancer.

Condition or Disease	Intervention/Treatment	Phase
Prostate Adenocarcinoma; Prostate Carcinoma; Recurrent Prostate Carcinoma; Stage III Prostate Cancer; Stage IV Prostate Cancer	Drug: Bicalutamide; Drug: Flutamide; Drug: Goserelin Acetate; Drug: Ipilimumab; Drug: Leuprolide Acetate; Other: Pharmacological Study	Phase 2

Detailed Description

OBJECTIVES:

1. To generally test whether the addition of CTLA-4 blockade can enhance clinical treatment response in advance prostate cancer patients compared with treatment with AA therapy alone.

2. To specifically examine whether concomitant AA therapy + MDX-010 can be used to prolong the progression-free interval in advanced prostate cancer patients compared with inductive short-term AA therapy alone.

3. To specifically examine whether concomitant AA therapy + MDX-010 can be used to enhance initial PSA responses in advanced prostate cancer patients compared with inductive short-term AA therapy alone.

4. To specifically examine whether delayed MDX-010 can be used to induce PSA response in patients experiencing disease progression following cessation of short-term AA therapy.

5. To generally examine whether MDX-010 enhances host immune response that might be involved in conferring treatment advantages to patients receiving AA therapy.

6. To specifically examine whether MDX-010 potentiates T-cell responses in advanced prostate cancer patients initiating inductive short-term AA therapy.

7. To further examine whether treatment induced T-cell responses correlate with clinical response to treatment.

8. To examine whether short-term AA there (+/- MDX-010) induces the appearance of newly emigrated T or immature and/or B cells.

OUTLINE:

Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive either leuprolide acetate intramuscularly (IM) or goserelin subcutaneously (SC) on days 0, 28, and 56. Patients also receive oral flutamide three times daily or oral bicalutamide once daily. Treatment with antiandrogen (AA) therapy continues for 3 months (3-4 months for patients who initiated AA therapy <= 21 days prior to enrollment) in the absence of disease progression or unacceptable toxicity. Patients receive ipilimumab IV over 90 minutes on day 7 (within 7-28 days post-initiation of AA therapy for patients who initiated AA therapy <= 21 days prior to enrollment) of AA therapy.

Arm II: Patients receive AA therapy as in arm I. Patients may crossover to arm II in the case of disease progression.

After completion of study treatment, patients are followed periodically.

Study Design

• Study Type: Interventional
• Actual Enrollment: 112 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Immunotherapeutic Trial: Combination Androgen Ablative Therapy and CTLA-4 Blockade as a Treatment for Advanced Prostate Cancer
• Study Start Date: Jun 1, 2004
• Actual Primary Completion Date: Apr 1, 2011
• Actual Study Completion Date: Jun 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm I Patients receive either leuprolide acetate intramuscularly (IM) or goserelin subcutaneously (SC) on days 0, 28, and 56. Patients also receive oral flutamide three times daily or oral bicalutamide once daily. Treatment with antiandrogen (AA) therapy continues for 3 months (3-4 months for patients who initiated AA therapy <= 21 days prior to enrollment) in the absence of disease progression or unacceptable toxicity. Patients receive ipilimumab IV over 90 minutes on day 7 (within 7-28 days post-initiation of AA therapy for patients who initiated AA therapy <= 21 days prior to enrollment) of AA therapy.	Drug: Bicalutamide; Given orally; Other Names: Casodex Cosudex ICI 176,334 ICI 176334 ; Drug: Flutamide; Given orally; Other Names: 4'-Nitro-3'-trifluoromethylisobutyranilide Apimid Chimax Drogenil Euflex Eulexin Eulexine Flucinom Flucinome Flugerel Fluken Flulem FLUT Fluta-Gry Flutabene Flutacan Flutamex Flutamin Flutan Flutaplex Fugerel Grisetin Niftolid Oncosal Profamid Prostacur Prostadirex Prostica Prostogenat SCH 13521 Tafenil Tecnoflut Testotard ; Drug: Goserelin Acetate; Given SC; Other Names: ZDX Zoladex ; Drug: Ipilimumab; Given IV; Other Names: Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody BMS-734016 MDX-010 MDX-CTLA4 Yervoy ; Drug: Leuprolide Acetate; Given IM; Other Names: A-43818 Abbott 43818 Abbott-43818 Carcinil Depo-Eligard Eligard Enanton Enantone Enantone-Gyn Ginecrin LEUP Leuplin Leuprorelin Acetate Lucrin Lucrin Depot Lupron Lupron Depot Lupron Depot-3 Month Lupron Depot-4 Month Lupron Depot-Ped Procren Procrin Prostap TAP-144 Trenantone Uno-Enantone Viadur ; Other: Pharmacological Study; Correlative study
Active Comparator: Arm II Patients receive AA therapy as in arm I. Patients may crossover to arm II in the case of disease progression.	Drug: Bicalutamide; Given orally; Other Names: Casodex Cosudex ICI 176,334 ICI 176334 ; Drug: Flutamide; Given orally; Other Names: 4'-Nitro-3'-trifluoromethylisobutyranilide Apimid Chimax Drogenil Euflex Eulexin Eulexine Flucinom Flucinome Flugerel Fluken Flulem FLUT Fluta-Gry Flutabene Flutacan Flutamex Flutamin Flutan Flutaplex Fugerel Grisetin Niftolid Oncosal Profamid Prostacur Prostadirex Prostica Prostogenat SCH 13521 Tafenil Tecnoflut Testotard ; Drug: Leuprolide Acetate; Given IM; Other Names: A-43818 Abbott 43818 Abbott-43818 Carcinil Depo-Eligard Eligard Enanton Enantone Enantone-Gyn Ginecrin LEUP Leuplin Leuprorelin Acetate Lucrin Lucrin Depot Lupron Lupron Depot Lupron Depot-3 Month Lupron Depot-4 Month Lupron Depot-Ped Procren Procrin Prostap TAP-144 Trenantone Uno-Enantone Viadur ; Other: Pharmacological Study; Correlative study

Outcome Measures

Primary Outcome Measures

1. Number of Participants Progression-free at 18 Months [18 months from the start of AA therapy]

   PSA progression is defined as a rise in PSA to >4.0 ng/mL demonstrated twice in measurements taken two weeks apart.

Secondary Outcome Measures

1. Percent of Participants With Undetectable Prostate-specific Antigen (PSA) Response [3 months]

   Percent of participants who had undetectable PSA at 3 months on the initially assigned treatment arm (prior to crossing over).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• NOTE: All values must be obtained =< 14 prior to study entry

• Histologically confirmed adenocarcinoma of the prostate staged within 180 days of study enrollment, >cT2cN0/M0 stage with or without metastatic disease, with the exclusion of central nervous system (CNS) metastases; includes post radical prostatectomy patients with a rising PSA

• An initial PSA >= 4.0 ng/mL (Hybritech Assay)

• For those patients who have received hormone therapy =< 21 days, a documented PSA of

= 4.0 prior to initiation of hormone therapy is acceptable.

• For patients who are post radical prostatectomy, a rising PSA is acceptable.

• Adequate organ function defined as: WBC >= 3,000/uL; platelets >= 75,000/uL; total bilirubin =< 1.5 mg/dL; transaminases =< 2.5 x upper limit of normal (ULN); serum creatine =< 2.0 mg/dL or calculated creatinine clearance >= 60 mL/min

• ECOG performance status of 0-2

• Able to understand and sign informed consent

Exclusion Criteria:

• Underlying other serious medical condition which, in the opinion of the investigator precludes study participation; this includes immune-suppressive disease such as AIDS or autoimmune disorders such as multiple sclerosis, lupus, or myasthenia gravis

• Patients not recovered from major infections and/or surgical procedures

• Prior hormonal therapy > 21 days prior to enrollment, including estrogens, LH/RH agonists, or antiandrogens

• Recent (=< 3 months of informed consent) usage of immune-suppressive medication including steroids, Immuran, Cyclosporin; topical or inhalational steroid use is permissible

• Prior systemic chemotherapy

• Prior radiation therapy to the prostate

• Prior malignancy, unless the patient has been cancer-free for five years or more

• Uncontrolled underlying medical or psychiatric illness, or serious active infections

• Patient unwilling to complete all required follow-up visits

• History of motor neuropathy considered of the autoimmune origin (e.g. Guillian-Barre Syndrome)

• Concurrent malignancy, except for adequately treated basal cell or squamous cell skin cancer

• For patients who elect to undergo the baseline transrectal needle biopsy of the prostate, current usage of systemic anticoagulation therapy, i.e. heparin or Coumadin or inability to discontinue aspirin, aspirin-containing products or ibuprofen for seven days prior to the prostate biopsies required for this study

• No other investigational drugs will be allowed during the study

• Other chemotherapy, radiation therapy, immunotherapy, hormonal therapy, or biologic therapy may not be used while the patient is on study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic	Rochester	Minnesota	United States	55905

Sponsors and Collaborators

• Mayo Clinic
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Eugene Kwon, Mayo Clinic

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Mayo Clinic
• ClinicalTrials.gov Identifier: NCT00170157
• Other Study ID Numbers: MC0253; NCI-2009-01214; MC0253; P30CA015083
• First Posted: Sep 15, 2005
• Last Update Posted: May 15, 2017
• Last Verified: Jan 1, 2017

• Additional relevant MeSH terms: Carcinoma; Prostatic Neoplasms; Ipilimumab; Leuprolide; Goserelin; Bicalutamide; Flutamide

Study Results

Participant Flow

Recruitment Details	112 participants were recruited between June 2004 and June 2009 at Mayo Clinic.
Pre-assignment Detail	All participants were initially randomized to either arm.

Arm/Group Title	Androgen Ablative (AA) Therapy + MDX-010	Androgen Ablative (AA) Then AA Therapy + MDX-010
Arm/Group Description	3 months of concurrent androgen ablative (AA) therapy + MDX-010 Androgen ablative (AA) therapy is received a combined regimen of GnRH agonist and androgen receptor blocker. GnRH agonists must be in the form of a 1 month depot of either leuprolide acetate (Lupron) 7.5 mg intramuscular (IM), or goserelin acetate (Zoladex) 3.6 mg subcutaneous (SC) and will be administered on Day 0 (baseline), Day 28 and Day 56. Androgen receptor blockade may be provided by oral administration of either flutamide (Eulexin) 250 mg orally 3 times daily, or bicalutamide (Casodex) 50 mg orally once daily. MDX-010 is received as an infusion at a dose of 3.0 mg/kg on day 7.	3 months of initial AA therapy alone Androgen ablative (AA) therapy is received a combined regimen of GnRH agonist and androgen receptor blocker. GnRH agonists must be in the form of a 1 month depot of either leuprolide acetate (Lupron) 7.5 mg intramuscular (IM), or goserelin acetate (Zoladex) 3.6 mg subcutaneous (SC) and will be administered on Day 0 (baseline), Day 28 and Day 56. Androgen receptor blockade may be provided by oral administration of either flutamide (Eulexin) 250 mg orally 3 times daily, or bicalutamide (Casodex) 50 mg orally once daily.
Period Title: Treatment Period 1 Initial Randomization
STARTED	54	58
COMPLETED	54	58
NOT COMPLETED	0	0
Period Title: Treatment Period 1 Initial Randomization
STARTED	0	58
COMPLETED	0	41
NOT COMPLETED	0	17
Period Title: Treatment Period 1 Initial Randomization
STARTED	0	41
COMPLETED	0	41
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Entire Study Population
Arm/Group Description	All participants initially randomized.
Overall Participants	112
Age, Customized (participants) [Number]
<= 39	0 0%
40-49	5 4.5%
50-59	29 25.9%
60-69	48 42.9%
>= 70	30 26.8%
Sex: Female, Male (Count of Participants)
Female	0 0%
Male	112 100%
Region of Enrollment (participants) [Number]
United States	112 100%

Outcome Measures

1. Primary Outcome

Title	Number of Participants Progression-free at 18 Months
Description	PSA progression is defined as a rise in PSA to >4.0 ng/mL demonstrated twice in measurements taken two weeks apart.
Time Frame	18 months from the start of AA therapy

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Entire Study Population
Arm/Group Description	All participants (Androgen ablative (AA) therapy + MDX-010 and Androgen ablative (AA) therapy alone) initially randomized (i.e., before cross-over) were grouped together for this outcome. .
Measure Participants	112
Number [participants]	0 0%

2. Secondary Outcome

Title	Percent of Participants With Undetectable Prostate-specific Antigen (PSA) Response
Description	Percent of participants who had undetectable PSA at 3 months on the initially assigned treatment arm (prior to crossing over).
Time Frame	3 months

Outcome Measure Data

Analysis Population Description

105 participants had follow-up PSA information; those without a follow-up PSA were excluded from this analysis.

Arm/Group Title	Androgen Ablative (AA) Therapy + MDX-010	Androgen Ablative (AA) Then AA Therapy + MDX-010
Arm/Group Description	3 months of concurrent androgen ablative (AA) therapy + MDX-010 Androgen ablative (AA) therapy is received a combined regimen of GnRH agonist and androgen receptor blocker. GnRH agonists must be in the form of a 1 month depot of either leuprolide acetate (Lupron) 7.5 mg intramuscular (IM), or goserelin acetate (Zoladex) 3.6 mg subcutaneous (SC) and will be administered on Day 0 (baseline), Day 28 and Day 56. Androgen receptor blockade may be provided by oral administration of either flutamide (Eulexin) 250 mg orally 3 times daily, or bicalutamide (Casodex) 50 mg orally once daily. MDX-010 is received as an infusion at a dose of 3.0 mg/kg on day 7.	3 months of initial AA therapy alone Androgen ablative (AA) therapy is received a combined regimen of GnRH agonist and androgen receptor blocker. GnRH agonists must be in the form of a 1 month depot of either leuprolide acetate (Lupron) 7.5 mg intramuscular (IM), or goserelin acetate (Zoladex) 3.6 mg subcutaneous (SC) and will be administered on Day 0 (baseline), Day 28 and Day 56. Androgen receptor blockade may be provided by oral administration of either flutamide (Eulexin) 250 mg orally 3 times daily, or bicalutamide (Casodex) 50 mg orally once daily
Measure Participants	53	52
Number [percentage of participants]	55 49.1%	39 NaN

Adverse Events

Adverse Event Reporting Description	Two participants cancelled prior to beginning study treatment, thus did not experience any adverse events.
Arm/Group Title	Entire Study Population
Arm/Group Description	All participants (Androgen ablative (AA) therapy + MDX-010 and Androgen ablative (AA) therapy alone the AA Therapy + MDX-010) were grouped together for this outcome.
All Cause Mortality
	Entire Study Population
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Entire Study Population
	Affected / at Risk (%)	# Events
Total	10/110 (9.1%)
Cardiac disorders
Ischemia/Infarction	2/110 (1.8%)	2
Eye disorders
Vision-Blurred	1/110 (0.9%)	1
Gastrointestinal disorders
Diarrhea-No Colostom	1/110 (0.9%)	1
Ileus	1/110 (0.9%)	1
Pain-Abdominal	1/110 (0.9%)	1
Hepatobiliary disorders
Hepatic	1/110 (0.9%)	1
Immune system disorders
Hypersensitivity	1/110 (0.9%)	1
Infections and infestations
Urinary tract infection	1/110 (0.9%)	1
Investigations
Alanine aminotransferase increased	1/110 (0.9%)	1
Alkaline phosphatase	1/110 (0.9%)	1
Amylase	1/110 (0.9%)	1
Aspartate aminotransferase increased	1/110 (0.9%)	1
Creatinine	1/110 (0.9%)	1
Lipase increased	1/110 (0.9%)	1
Metabolism and nutrition disorders
Hypercalcemia	1/110 (0.9%)	1
Hyperuricemia	2/110 (1.8%)	2
Nervous system disorders
Peripheral motor neuropathy	1/110 (0.9%)	1
Respiratory, thoracic and mediastinal disorders
Pneumonitis	1/110 (0.9%)	1
Skin and subcutaneous tissue disorders
Pruritus	1/110 (0.9%)	1
Rash/Desquamation	1/110 (0.9%)	1
Vascular disorders
Hypertension	1/110 (0.9%)	1
Thrombosis	1/110 (0.9%)	1
Other (Not Including Serious) Adverse Events
	Entire Study Population
	Affected / at Risk (%)	# Events
Total	107/110 (97.3%)
Blood and lymphatic system disorders
Anemia	21/110 (19.1%)	34
Lymph node pain	1/110 (0.9%)	2
Cardiac disorders
Cardiovascular	1/110 (0.9%)	1
Ventricular tachycardia	1/110 (0.9%)	1
Endocrine disorders
Endocrine	4/110 (3.6%)	5
Eye disorders
Vision	1/110 (0.9%)	1
Vision-Blurred	24/110 (21.8%)	44
Gastrointestinal disorders
Anal hemorrhage	1/110 (0.9%)	1
Colitis	2/110 (1.8%)	2
Colonic hemorrhage	2/110 (1.8%)	2
Diarrhea-No Colostom	8/110 (7.3%)	8
Duodenal ulcer	1/110 (0.9%)	1
Dyspepsia	7/110 (6.4%)	7
Pain-Abdominal	1/110 (0.9%)	1
General disorders
Constitutional Symptoms	5/110 (4.5%)	5
Edema: Limb	3/110 (2.7%)	4
Facial pain	1/110 (0.9%)	1
Fatigue	79/110 (71.8%)	160
Pain-Chest	1/110 (0.9%)	1
Rigors	2/110 (1.8%)	2
Hepatobiliary disorders
Hepatic	1/110 (0.9%)	1
Immune system disorders
Hypersensitivity	3/110 (2.7%)	3
Infections and infestations
Abdominal infection	1/110 (0.9%)	1
Colon infection	1/110 (0.9%)	1
Lung (pneumonia) infection	2/110 (1.8%)	2
Penis infection	1/110 (0.9%)	1
Pneumonia	1/110 (0.9%)	1
Skin (cellulites) infection	1/110 (0.9%)	2
Wound infection	1/110 (0.9%)	1
Injury, poisoning and procedural complications
Bruising (in absence of grade 3 or 4 thrombocytopenia)	1/110 (0.9%)	1
Investigations
Alanine aminotransferase increased	32/110 (29.1%)	65
Alkaline phosphatase	28/110 (25.5%)	69
Amylase	1/110 (0.9%)	1
Aspartate aminotransferase increased	31/110 (28.2%)	55
Blood bilirubin increased	22/110 (20%)	36
Coagulation	1/110 (0.9%)	1
Creatinine	14/110 (12.7%)	29
Lipase increased	1/110 (0.9%)	1
Metabolic/Lab	10/110 (9.1%)	12
Platelet count decreased	1/110 (0.9%)	3
Weight loss	10/110 (9.1%)	10
Metabolism and nutrition disorders
Bicarbonate	2/110 (1.8%)	2
Dehydration	1/110 (0.9%)	1
Hypercalcemia	24/110 (21.8%)	37
Hyperglycemia	87/110 (79.1%)	279
Hyperkalemia	22/110 (20%)	31
Hyperuricemia	18/110 (16.4%)	34
Hypoalbuminemia	2/110 (1.8%)	2
Hypocalcemia	4/110 (3.6%)	4
Hypoglycemia	2/110 (1.8%)	2
Hypokalemia	6/110 (5.5%)	10
Hyponatremia	1/110 (0.9%)	1
Hypophosphatemia	8/110 (7.3%)	11
Musculoskeletal and connective tissue disorders
Arthritis	1/110 (0.9%)	1
Back pain	1/110 (0.9%)	1
Bone pain	28/110 (25.5%)	61
Extremity-lower necrosis	1/110 (0.9%)	1
Musculoskeletal	3/110 (2.7%)	3
Myalgia	3/110 (2.7%)	3
Nervous system disorders
Cognitive disorder	1/110 (0.9%)	3
Headache	1/110 (0.9%)	2
Ischemia-Cerebral	1/110 (0.9%)	1
Neuro	1/110 (0.9%)	2
Peripheral motor neuropathy	33/110 (30%)	74
Peripheral sensory neuropathy	1/110 (0.9%)	1
Psychiatric disorders
Depression	1/110 (0.9%)	2
Insomnia	2/110 (1.8%)	3
Renal and urinary disorders
Pollakiuria	75/110 (68.2%)	171
Ureteral Obstruction	1/110 (0.9%)	1
Urinary bladder hemorrhage	10/110 (9.1%)	11
Urinary retention	24/110 (21.8%)	42
Reproductive system and breast disorders
Breast pain	2/110 (1.8%)	2
Prostatic pain	1/110 (0.9%)	1
Respiratory, thoracic and mediastinal disorders
Atelectasis	1/110 (0.9%)	1
Cough	1/110 (0.9%)	1
Dyspnea	1/110 (0.9%)	1
Pharyngolaryngeal pain	1/110 (0.9%)	1
Pulmonary	1/110 (0.9%)	1
Sinus Reactions	1/110 (0.9%)	1
Skin and subcutaneous tissue disorders
Acne	2/110 (1.8%)	2
Alopecia	1/110 (0.9%)	1
Decubitus Ulcer	1/110 (0.9%)	1
Dry skin	2/110 (1.8%)	3
Nail Changes	1/110 (0.9%)	2
Pruritus	3/110 (2.7%)	5
Rash/Desquamation	21/110 (19.1%)	29
Urticaria	1/110 (0.9%)	1
Vascular disorders
Flushing	1/110 (0.9%)	1
Hot flashes	88/110 (80%)	207
Hypertension	1/110 (0.9%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.