Bicalutamide and Goserelin or Leuprolide Acetate With or Without Cixutumumab in Treating Patients With Newly Diagnosed Metastatic Prostate Cancer
Bicalutamide and Goserelin or Leuprolide Acetate With or Without Cixutumumab in Treating Patients With Newly Diagnosed Metastatic Prostate Cancer
This randomized phase II trial is studying bicalutamide, goserelin, or leuprolide acetate to
 see how well they work when given with or without cixutumumab in treating patients with newly
 diagnosed metastatic prostate cancer. Androgens can cause the growth of prostate cancer
 cells. Antihormone therapy, such as bicalutamide, goserelin, or leuprolide acetate, may
 lessen the amount of androgens made by the body. Monoclonal antibodies, such as cixutumumab,
 can block tumor 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 tumor-killing substances to them.
 It is not yet known whether bicalutamide, goserelin, or leuprolide acetate are more effective
 when given with or without cixutumumab in treating prostate cancer.
PRIMARY OBJECTIVES:

 I. To compare the undetectable prostate-specific antigen (PSA) rate (PSA < 0.2 ng/mL) after
 seven cycles (28 weeks) of protocol treatment between those randomized to a luteinizing
 hormone-releasing hormone (LHRH) agonist and bicalutamide and those randomized to a LHRH
 agonist, bicalutamide and IMC-A12 (cixutumumab).

 SECONDARY OBJECTIVES:

 I. To assess the safety and tolerability of the combination of IMC-A12 with a LHRH agonist
 and bicalutamide.

 II. To compare the proportion of men who do not achieve a PSA of < 4 ng/mL between the two
 groups.

 III. To assess the accuracy of the prognostic model of undetectable PSA that was developed
 from Southwest Oncology Group (SWOG)-9346 using current trial data from each arm.

 IV. To assess serum samples and peripheral blood mononuclear cells (PBMNC) for
 pharmacodynamic activity with potential biomarkers for IMC-A12 (including, but not limited
 to: insulin-like growth factor [IGF]-I, free IGF-I, IGF-II, IGF binding protein [IGFBP]2,
 IGFBP3, growth hormone, insulin and C-peptide) obtained from optional blood specimens both
 before initiation of androgen deprivation therapy and twelve weeks after initiation of
 combined therapy.

 V. To determine baseline pre-treatment circulating tumor cell (CTC) quantities and response
 to therapy (for those patients with detectable CTC levels >= 1) twelve weeks later.

 VI. In the same subset of patients where CTC levels are obtained, determine baseline serum
 levels of micro-ribonucleic acids (RNAs) to include but not limited to microRNA (mi)-141 both
 before initiation of androgen deprivation therapy and twelve weeks after combined therapy.

 OUTLINE: Patients are randomized to 1 of 2 treatment arms.

 ARM I: Patients receive androgen deprivation therapy comprising bicalutamide orally (PO) once
 daily (QD) on days 1-28 and either goserelin acetate subcutaneously (SC) or leuprolide
 acetate intramuscularly (IM) every 1, 3, 4, 6, or 12 months. Patients also receive
 cixutumumab intravenously (IV) over 1 hour on days 1 and 15. Treatment repeats every 28 days
 for 7 courses in the absence of disease progression or unacceptable toxicity.

 ARM II: Patients receive androgen deprivation therapy comprising bicalutamide and either
 goserelin acetate or leuprolide acetate as in arm I.

 After completion of study treatment, patients are followed up every 6 months for 2 years and
 then annually for 3 years.
Inclusion Criteria:

 -  All patients must have a histologically or cytologically proven diagnosis of
 adenocarcinoma of the prostate; note: If there is no formal biopsy report documenting
 the diagnosis of prostate cancer, the patient can be allowed on trial if the PSA level
 is at least 20, and there are at least three definitive metastatic lesions seen on
 scan; all patients must have had metastatic (M1) disease as evidenced by soft tissue
 and/or bony metastases prior to androgen deprivation therapy initiation; patients must
 have at least one of the following at the time they started androgen deprivation
 therapy:

 -  Visceral disease (liver, lung, or other viscera)

 -  Bone metastases to sites in either the axial (spine, pelvis, ribs, or skull)
 and/or the appendicular (clavicle, humerus, or femur) skeleton

 -  Lymph node disease not considered to be encompassed within a single radiotherapy
 port (e.g., above the aortic bifurcation, etc.)

 -  Patients who have measurable disease must have radiographic assessment (at least an
 abdominal/pelvic computed tomography [CT]) within 28 days prior to registration;
 non-measurable disease must also be assessed (e.g., bone scan) in all patients within
 56 days prior to registration; all disease must be assessed and documented on the
 Baseline Tumor Assessment Form

 -  Patients must have a PSA >= 5 ng/mL obtained within 90 days prior to initiation of
 androgen deprivation therapy

 -  Patients with known brain metastases are not eligible; brain imaging studies are not
 required for eligibility if the patient has no neurologic signs or symptoms, but if
 brain imaging studies are performed, they must be negative for disease

 -  Patient must have had no more than 30 days of prior medical castration for metastatic
 prostate cancer (prior androgen deprivation therapy is allowed if it was received with
 curative intent in the neoadjuvant, concurrent, and/or adjuvant fashion and at least 2
 years have elapsed since completion of androgen deprivation therapy); the start date
 of medical castration is considered the day the patient first received an injection of
 a LHRH agonist, not an oral antiandrogen; if the method of castration is luteinizing
 hormone releasing hormone (LHRH) agonists (i.e., leuprolide or goserelin), the patient
 must be willing to continue the use of LHRH agonists and add bicalutamide for combined
 androgen deprivation therapy (ADT) during protocol treatment; the 30 day window begins
 from the date of receiving the LHRH agonist, not the oral antiandrogen; if the patient
 was on a different antiandrogen (e.g. flutamide), the patient must be willing to
 switch over to bicalutamide; patients must not have received bilateral orchiectomy;
 patients must not have received or be planning to receive LHRH antagonists (i.e.,
 Degarelix); however, if the patient was initiated on a LHRH antagonist within the 30
 day window and is willing to switch to a LHRH agonist with bicalutamide, he may enroll
 on the late induction group

 -  Patients who have not already started androgen deprivation therapy must be offered the
 opportunity to participate in the translational medicine studies; once a patient has
 started any form of antiandrogen (i.e., either bicalutamide or LHRH agonist), he is
 not eligible for any translational medicine studies

 -  Patients must not have received any prior cytotoxic chemotherapy for metastatic
 prostate cancer; prior cytotoxic chemotherapy with curative intent in the neoadjuvant
 or adjuvant setting is allowed; patients must not have received any prior treatment
 with agents that directly inhibit IGF or IGFRs

 -  Patients must not have received prior strontium-89, rhenium-186, rhenium-188, or
 samarium-153 radionuclide therapy within 28 days prior to registration

 -  Patients may have received prior radiation therapy or biologic therapy (e.g. vaccines,
 immunotherapy, anti-sense, small molecules, monoclonal antibodies); however, at least
 28 days must have elapsed since completion of therapy and patient must have recovered
 from all side effects

 -  Patients may have received prior surgery; for all major surgeries, at least 28 days
 must have elapsed since completion and patient must have recovered from all side
 effects

 -  Leukocytes >= 3,000 mcL

 -  Absolute neutrophil count (ANC) >= 1,500 mcL

 -  Hemoglobin >= 9 g/dL

 -  Platelets >= 100,000/mcL

 -  Bilirubin =< 1.5 times the institutional upper limit of normal (ULN) (unless
 documented Gilbert's disease)

 -  Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) and
 serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 3
 times the institutional ULN, or =< 5 times the institutional ULN if liver metastases
 are present

 -  Creatinine =< 2.0 x the institutional ULN or calculated creatinine clearance >= 40
 mL/min

 -  International normalized ratio (INR) =< 1.5

 -  Partial thromboplastin time (PTT) no more than 5 seconds above the institutional ULN

 -  Patients receiving prophylactic low dose coumadin or low molecular weight heparin are
 eligible as long as they meet these coagulation criteria; patients requiring full-dose
 (therapeutic) anticoagulation are eligible provided that they have been on a stable
 dose of anticoagulation and the coagulation parameters are stable within the
 therapeutic range (e.g., INR 2-3 for patients on therapeutic warfarin)

 -  Patients must have a hemoglobin A1c (HgA1c) =< 7% AND fasting glucose of < 160 mg/dL
 or below the institutional ULN within 14 days prior to registration; patients with
 diabetes mellitus who meet this criterion must be on a stable dietary or therapeutic
 regimen for this condition

 -  Patients must not have a history of symptomatic congestive heart failure or a known
 ejection fraction (left ventricular ejection fraction [LVEF]) that is >= 10% below the
 lower limit of normal (LLN); if left ventricular (LV) dysfunction is suspected, but
 not confirmed by review of past medical history, a multi gated acquisition scan (MUGA)
 or echocardiogram must be obtained within 90 days prior to registration

 -  Patient must not have a history of allergic reaction attributed to compounds of
 similar chemical or biologic composition to IMC-A12; patients must not have received
 prior chimerized or murine monoclonal antibody therapy

 -  Patients must have a Zubrod performance status of 0 - 2; Zubrod performance status 3
 will be allowed if from bone pain only

 -  Patients with human immunodeficiency virus (HIV) positivity requiring antiretroviral
 therapy are not eligible for this study

 -  Patients must have no plans to receive concurrent chemotherapy, hormonal therapy
 (other than the LHRH agonist and oral anti-androgen), radiotherapy, immunotherapy or
 any other type of therapy for treatment of cancer while on this protocol treatment;
 concurrent bone targeting agents that do not have effect on PSA (i.e. denosumab or
 zoledronic acid) are allowed

 -  Patients must have no plans to receive concurrent five-alpha reductase inhibitors
 (e.g. finasteride and dutasteride), ketoconazole, diethylstilbestrol/DES, or other
 estrogen-based therapy while on this protocol treatment

 -  No other prior malignancy is allowed except for the following: adequately treated
 basal cell or squamous cell skin cancer, adequately treated stage I or II cancer from
 which the patient is currently in complete remission, or any other cancer from which
 the patient has been disease-free for 5 years

 -  Men of reproductive potential must have agreed to use an effective contraceptive
 method while receiving treatment on this study and for at least three months after
 protocol treatment ends

 -  All patients must be informed of the investigational nature of this study and must
 sign and give written informed consent in accordance with institutional and federal
 guidelines

 -  As part of the OPEN registration process, the treating institution's identity is
 provided in order to ensure that the current (within 365 days) date of institutional
 review board approval for this study has been entered in the system