AMG 386 and Abiraterone for Advanced Prostate Cancer
Condition: Prostatic Neoplasms; Prostate Cancer; Neoplasm, Prostate; Neoplasm,Prostatic
MeSH terms: Prostatic Neoplasms; Neoplasms
Intervention: AMG 386; Abiraterone; Prednisone
Intervention description: AMG 386 dose will be calculated using the subjects actual body weight (Kg). Supplied in 240 mg v will be administered as an intravenous (IV) infusion using an intravenous infusion pump given over a 60-minute period.; A 1,000 mg dose of abiraterone should be taken orally once daily; Prednisone should be taken orally either, at 5mg twice a day for each dose or 10 mg once a day a patients preference.
Intervention MeSH terms: Prednisone; Trebananib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 36.0
Sex: Male
Minimum age: 18 Years
Maximum age: 100 Years
Healthy volunteers: No
Keywords: Anti-Angiogenesis; Ang 1; Ang 2; Peptide-Fc fusion protein; Small Molecule

Summary:

      Background:

        -  Advanced prostate cancer is treated with surgery or drugs that lower the levels of
           androgens (male hormones) in the body. However, some cancers become resistant to this
           treatment. These types of cancers are known as castration-resistant prostate cancers.

        -  Interfering with the growth of blood vessels that feed tumors can slow prostate cancer
           growth. Trebananib (AMG 386), a new anticancer drug, targets the blood vessels that feed
           tumors. It has been tested for different types of cancer, but not for prostate cancer.
           Researchers want to see if AMG 386 can slow disease progression in men with
           castration-resistant prostate cancer. AMG 386 will be given with abiraterone and
           prednisone, two drugs that are also used to treat advanced prostate cancer.

      Objectives:

      - To test the safety and effectiveness of AMG 386 with abiraterone for castration-resistant
      prostate cancer.

      Eligibility:

      - Men at least 18 years of age with castration-resistant prostate cancer.

      Design:

        -  Participants will be screened with a physical exam, medical history, and imaging
           studies. Blood and urine samples will also be collected.

        -  Participants will be separated into two groups.

        -  The first group will have AMG 386 once per week for a total of four doses during a
           28-day cycle. They will also take abiraterone once a day and prednisone twice a day,
           every day of the cycle.

        -  The second group will not have AMG 386. They will take abiraterone once a day and
           prednisone twice a day, every day of the 28-day cycle.

        -  Treatment will be monitored with frequent blood tests and imaging studies.

        -  Participants will continue to take the study drugs as long as the disease does not
           progress and there are no severe side effects.
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

          -  Must have metastatic, progressive, castrate-resistant prostate cancer (CRPC) with
             radiographic evidence of disease that has continued to progress radiographically or
             biochemically (rising prostatic specific antigen (PSA) levels on successive
             measurements) despite adequate androgen-deprivation therapy. If patients had been on
             flutamide, disease progression is documented 4 weeks or more after withdrawal. For
             patients on bicalutamide or nilutamide disease progression is documented 6 or more
             weeks after withdrawal. Flutamide, nilutamide and bicalutamide disease progression
             requirements only apply to patients who have been on these drugs for at least the
             prior 6 months.

          -  Histopathological confirmation of prostate cancer by the Laboratory of Pathology of
             the National Cancer Institute (NCI) or Walter Reed National Military Medical Center
             prior to entering this study. Patients enrolled at participating sites may have
             histopathological confirmation at the enrolling center prior to entering the study.
             Patients whose pathology specimens are no longer available may be enrolled if the
             patient has a clinical course that is consistent with prostate cancer and available
             documentation from an outside pathology laboratory of the diagnosis. All efforts
             should be made to have the material forwarded to the research team for use in
             correlative studies in cases where original tissue blocks or archival biopsy material
             is available.

          -  Patients must have metastatic disease, defined as at least one lesion on bone scan or
             at least one lesion that can be accurately measured in at least one dimension (longest
             diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >20
             mm with conventional techniques or as >10 mm with spiral computed tomography (CT)
             scan, magnetic resonance imaging (MRI), or calipers by clinical exam.

          -  Patients participating in the study must have Metastatic Castration-Resistant Prostate
             Cancer (mCRPC).

          -  Patients who have received docetaxel plus androgen deprivation therapy (ADT) for
             metastatic castrate sensitive prostate cancer are eligible for the study. (Patients
             may enroll as long as they did not have progressive disease while on docetaxel and are
             6 months removed from treatment, with all treatment related toxicities resolving to at
             least grade 1.)

          -  Patients may not have had more than 7 days of treatment with ketoconazole by mouth in
             the past 6 months.

          -  Males greater than or equal to 18 years of age. Because no dosing or adverse event
             data are currently available on the use AMG 386 in combination with abiraterone in
             patients <18 years of age, children are excluded from this study, but will be eligible
             for future pediatric trials.

          -  Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2
             for run-in phase; ECOG less than or equal to 1 for randomized phase.

          -  Life expectancy of > 3 months for the run in phase and > 6 months for the randomized
             phase.

          -  Adequate bone marrow, hepatic, and renal function with:

               -  Leukocytes greater than or equal to 3000/mu L

               -  Absolute neutrophil count (ANC) greater than or equal to 1500/mu L

               -  Platelets greater than or equal to 100000/mu L

               -  Total bilirubin less than or equal to 1.5 times institutional upper limits of
                  normal

               -  Aspartate aminotransferase (AST) serum glutamic oxaloacetic
                  transaminase(SGOT)/alanine aminotransferase (ALT) serum glutamic pyruvic
                  transaminase(SGPT) less than or equal to 2.5 times institutional upper limits of
                  normal

               -  Partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT)
                  less than or equal to 1.5 times upper limits of normal (ULN) per institutional
                  laboratory range and international normalized ratio (INR) less than or equal to 5

               -  Creatinine less than or equal to 1.5 times institutional upper limits of normal

        OR

          -  Creatinine clearance of >40 mL/min per 24 h urine collection or calculated according
             to the Cockcroft-Gault formula

             ---Creatinine clearance (CrCl) (mL/min) = (((140-age) times actual body weight
             (kg))/(72 x serum creatinine (mg/dL)))*(x 0.85 for females)

          -  Urinary protein less than or equal to 30 mg/dL in urinalysis or less than or equal
             to1+ on dipstick, unless quantitative protein is <1000 mg in a 24h urine sample

               -  Generally well-controlled blood pressure with systolic blood pressure less than
                  or equal to 140 mmHg AND diastolic blood pressure less than or equal to 90 mmHg
                  prior to enrollment. The use of antihypertensive medications to control
                  hypertension is permitted.

               -  Must have recovered from any acute toxicity related to prior therapy, including
                  surgery. Toxicity should be less than or equal to grade 1 Common Terminology
                  Criteria in Adverse Events (CTCAE) version 4 or has returned to baseline.
                  Alopecia >grade 1 is permitted.

               -  The effects of AMG 386 on the developing human fetus are unknown. For this reason
                  and because inhibitors of angiogenesis as well as other therapeutic agents used
                  in this trial are known to be teratogenic, men must agree to use adequate
                  contraception

        (hormonal or barrier method of birth control; abstinence) prior to study entry and for the
        duration of study participation. Should a woman become pregnant or suspect she is pregnant
        while her partner is participating in this study, she should inform her treating

        physician immediately. Men treated or enrolled on this protocol must agree to use adequate
        contraception prior to the study, for the duration of study participation, and 6 months
        after completion of AMG 386 administration.

        -Must have the ability to understand and the willingness to sign a written informed consent
        document.

        EXCLUSION CRITERIA:

          -  Patients who have had chemotherapy for metastatic castration-resistant prostate
             cancer.

          -  History or presence of known central nervous system metastases.

          -  History of venous or arterial thromboembolism within 12 months prior to
             enrollment/randomization.

          -  History of clinically significant bleeding within 6 months of
             enrollment/randomization.

          -  Currently or previously treated with AMG 386, or other molecules that primarily
             inhibit the angiopoietins or Tie2 receptor.

          -  Clinically significant cardiovascular disease within 12 months prior to
             enrollment/randomization, including myocardial infarction, unstable angina, grade 2 or
             greater peripheral vascular disease, cerebrovascular accident, transient ischemic
             attack, congestive heart failure, or arrhythmias not controlled by outpatient
             medication or placement of percutaneous transluminal coronary angioplasty/stent.

          -  Major surgery within 28 days prior to enrollment or still recovering from prior
             surgery.

          -  Minor surgical procedures, placement of tunneled central venous access device within 3
             days prior to randomization/enrollment.

          -  Treatment within 30 days prior to enrollment with the following: cyclosporine,
             tacrolimus, sirolimus, mycophenolate mofetil, methotrexate, azathioprine, rapamycin,
             and targeted immune modulators such as abatacept (CTLA-4-Ig), adalimumab,

        alefacept, anakinra, belatacept (LEA29Y), efalizumab, etanercept, infliximab, or rituximab.

          -  Patients who have had large field radiotherapy must wait 2 weeks prior to entering the
             study.

          -  Non-healing wound, ulcer (including gastrointestinal), or fracture.

          -  Contraindication to steroid use or history of allergic reactions attributable to the
             study compounds.

          -  History of allergic reactions to bacterially-produced proteins.

          -  Previously diagnosed with another malignancy, within the past two years with the
             exception of non-melanoma skin cancers or non-invasive bladder cancer.

          -  Patients who have not yet completed at least 28 days (30 days for prior monoclonal
             antibody therapy) since receiving other investigational drugs.

          -  Inability to absorb abiraterone after oral administration (i.e., previous major
             gastrointestinal surgery or gastrointestinal disease resulting in malabsorption).

          -  Use of ketoconazole, itraconazole, ritonavir, cyclosporine, carbamazepine, phenytoin,
             phenobarbital within 2 weeks prior to and while on study therapy.

          -  Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
             therapy are ineligible because of the potential for pharmacokinetic interactions with
             the study agents. In addition, these patients are at increased risk of lethal
             infections when treated with marrow-suppressive

        therapy. Appropriate studies will be undertaken in patients receiving combination
        antiretroviral therapy when indicated.

          -  Uncontrolled intercurrent illness or infections, unstable angina pectoris, cardiac
             arrythmias, renal dysfunction, or psychiatric illness/social situations that would
             limit compliance with study requirements.

          -  Have had treatment with docetaxel for the treatment of metastatic castrate-sensitive
             prostate cancer within 6 months before the first dose of study enrollment.

          -  Have had progression of prostate cancer on prior docetaxel treatment for castrate
             sensitive disease.