Hormone Therapy and Ipilimumab in Treating Patients With Advanced Prostate Cancer

A Phase II Immunotherapeutic Trial: Combination Androgen Ablative Therapy and CTLA-4 Blockade as a Treatment for Advanced Prostate Cancer

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.

Study Overview

• Status: Completed
• Conditions: Prostate Adenocarcinoma; Prostate Carcinoma; Recurrent Prostate Carcinoma; Stage III Prostate Cancer; Stage IV Prostate Cancer
• Intervention / Treatment: Drug: Goserelin Acetate; Drug: Leuprolide Acetate; Drug: Bicalutamide; Drug: Ipilimumab; Drug: Flutamide; Other: Pharmacological Study

Detailed Description

OBJECTIVES:

I. 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.

II. 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.

III. 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.

IV. 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.

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

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

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

VIII. 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 Type: Interventional
• Enrollment (Actual): 112
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / 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: Goserelin Acetate; Given SC; Other Names: ZDX; Zoladex; Drug: Leuprolide Acetate; Given IM; Other Names: Enantone; LEUP; Lupron; Lupron Depot; Leuprorelin Acetate; A-43818; Abbott 43818; Abbott-43818; Carcinil; Depo-Eligard; Eligard; Enanton; Enantone-Gyn; Ginecrin; Leuplin; Lucrin; Lucrin Depot; Lupron Depot-3 Month; Lupron Depot-4 Month; Lupron Depot-Ped; Procren; Procrin; Prostap; TAP-144; Trenantone; Uno-Enantone; Viadur; Drug: Bicalutamide; Given orally; Other Names: Casodex; Cosudex; ICI 176,334; ICI 176334; Drug: Ipilimumab; Given IV; Other Names: Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody; BMS-734016; MDX-010; MDX-CTLA4; Yervoy; Drug: Flutamide; Given orally; Other Names: Apimid; Chimax; Drogenil; Euflex; Eulexine; Flucinom; Flucinome; Flugerel; Fluken; Flulem; FLUT; Fluta-Gry; Flutabene; Flutacan; Flutamex; Flutamin; Flutan; Flutaplex; Fugerel; Grisetin; Oncosal; Profamid; Prostacur; Prostadirex; Prostica; Prostogenat; Tafenil; Tecnoflut; Testotard; 4'-Nitro-3'-trifluoromethylisobutyranilide; Eulexin; SCH 13521; Niftolid; 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: Leuprolide Acetate; Given IM; Other Names: Enantone; LEUP; Lupron; Lupron Depot; Leuprorelin Acetate; A-43818; Abbott 43818; Abbott-43818; Carcinil; Depo-Eligard; Eligard; Enanton; Enantone-Gyn; Ginecrin; Leuplin; Lucrin; Lucrin Depot; Lupron Depot-3 Month; Lupron Depot-4 Month; Lupron Depot-Ped; Procren; Procrin; Prostap; TAP-144; Trenantone; Uno-Enantone; Viadur; Drug: Bicalutamide; Given orally; Other Names: Casodex; Cosudex; ICI 176,334; ICI 176334; Drug: Flutamide; Given orally; Other Names: Apimid; Chimax; Drogenil; Euflex; Eulexine; Flucinom; Flucinome; Flugerel; Fluken; Flulem; FLUT; Fluta-Gry; Flutabene; Flutacan; Flutamex; Flutamin; Flutan; Flutaplex; Fugerel; Grisetin; Oncosal; Profamid; Prostacur; Prostadirex; Prostica; Prostogenat; Tafenil; Tecnoflut; Testotard; 4'-Nitro-3'-trifluoromethylisobutyranilide; Eulexin; SCH 13521; Niftolid; Other: Pharmacological Study; Correlative study

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Mayo Clinic
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Eugene Kwon, Mayo Clinic

Study record dates

Study Major Dates

• Study Start: June 1, 2004
• Primary Completion (ACTUAL): April 1, 2011
• Study Completion (ACTUAL): June 1, 2013

Study Registration Dates

• First Submitted: September 13, 2005
• First Submitted That Met QC Criteria: September 13, 2005
• First Posted (ESTIMATE): September 15, 2005

Study Record Updates

• Last Update Posted (ACTUAL): May 15, 2017
• Last Update Submitted That Met QC Criteria: April 6, 2017
• Last Verified: January 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Genital Neoplasms, Male; Prostatic Diseases; Prostatic Neoplasms; Carcinoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Immunological; Hormone Antagonists; Immune Checkpoint Inhibitors; Reproductive Control Agents; Fertility Agents, Female; Fertility Agents; Androgen Antagonists; Leuprolide; Goserelin; Bicalutamide; Ipilimumab; Flutamide
• Other Study ID Numbers: MC0253 (OTHER: Mayo Clinic); P30CA015083 (U.S. NIH Grant/Contract); NCI-2009-01214 (REGISTRY: CTRP (Clinical Trial Reporting Program))