A Study of Docetaxel + ARN-509 in Castration-Resistant Prostate Cancer
Condition: Prostate Cancer
MeSH terms: Prostatic Neoplasms
Intervention: Leuprolide Acetate; Prednisone; Docetaxel; Apalutamide
Intervention description: a GnRH agonist; Prednisone is a corticosteroid; Docetaxel is an antineoplastic agent that acts by disrupting the microtubular network in cells that is essential for mitotic and interphase cellular functions. Docetaxel binds to free tubulin and promotes the assembly of tubulin into stable microtubules while simultaneously inhibiting their disassembly.; The apalutamide drug substance is an almost white to slightly brown powder. The tablet formulation of apalutamide is an immediate release oral tablet containing 60-mg of drug substance, with a non-functional green film coat
Intervention MeSH terms: Prednisone; Docetaxel; Leuprolide
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 9.0
Sex: Male
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Prostate Cancer

Summary:

      This research study is studying a combination of drugs as a possible treatment for
      castration-resistant prostate cancer.

      The interventions involved in this study are:

        -  Docetaxel (a type of chemotherapy)

        -  Apalutamide (the study medication, also known as ARN-509)

        -  Prednisone (a corticosteroid given to prevent reactions to docetaxel).

        -  Leuprolide acetate (also known as Lupron, a GnRH agonist or similar drug which is
           standard of care, causes chemical castration which greatly lowers the level of
           testosterone in the body)
    

Eligibility criteria:

        Inclusion Criteria:

          -  Histologically confirmed adenocarcinoma of the prostate

          -  Castration-resistant prostate cancer requires the following criteria:

               -  A castrate level of testosterone (< 50ng/dL)

               -  Prostate cancer progression on or since last treatment as documented by PSA rise
                  or bone progression according to PCWG2 or soft tissue radiographic progression
                  according to RECIST criteria Version 1.1

               -  If on anti-androgen, will need to show no PSA decline after at least a 6 week
                  withdrawal period from the last dose of bicalutamide or nilutamide or 4 weeks
                  from last flutamide dose

               -  Will require a 2 week washout period from last dose of ketoconazole, abiraterone
                  acetate or radiation

          -  Treatment with abiraterone acetate for CRPC in the past is required. Does not need to
             be the last treatment prior to enrollment.

          -  There is no limit to number of prior therapies

          -  Metastatic disease by bone scan or other nodal or visceral lesions on CT or MRI

          -  Age ≥ 18 years

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (See Appendix
             A)

          -  Adequate organ function as evaluated by the following laboratory criteria:

               -  Hemoglobin ≥ 9g/dL; no transfusions and erythropoietin supplementation permitted
                  within the last 3 months

               -  Absolute neutrophil count (ANC) ≥ 1500/µL

               -  Platelet count ≥ 100 x 10^9/L

               -  Total bilirubin ≤ upper limit of normal (ULN, Note: In subjects with Gilbert's
                  syndrome, if total bilirubin is ≥ 1.5 × ULN, measure direct and indirect
                  bilirubin and if direct bilirubin is ≤ ULN, subject may be eligible)

               -  AST and ALT < 2.5 x ULN or < 5x the ULN if liver metastasis

               -  Serum creatinine < 2.0 × ULN or creatinine clearance > 30cc/min

               -  Serum albumin ≥ 3.0 g/dL

               -  Serum potassium ≥ 3.5 mmol/L (if < 3.5, can be repleted and reassess for
                  eligibility as long as stable off potassium supplementation for > 48 hrs)

          -  Ability to swallow the study drug as a whole tablet

          -  The effects of apalutamide and docetaxel on the developing human fetus are unknown.
             For this reason and because chemotherapeutic agents are known to be teratogenic, men
             must agree to use adequate contraception. Specifically, they must agree to use a
             condom (even men with vasectomies) and another effective method of birth control if he
             is having sex with a woman of childbearing potential or agree to use a condom if he is
             having sex with a woman who is pregnant while on study drug and for 3 months following
             the last dose of study drug. They must also agree not to donate sperm during the study
             and for 3 months after receiving the last dose of study drug.

          -  Ability to understand and the willingness to sign a written informed consent document.

        Exclusion Criteria:

          -  Pathology consistent with majority of specimen having small cell carcinoma of the
             prostate (prostate cancer with neuroendocrine features is acceptable).

          -  Prior treatment with enzalutamide for CPRC; non-CRPC use allowed (e.g., neoadjuvant,
             combined with radiation for localized disease and didn't progress while on it in those
             settings)

          -  Prior treatment with docetaxel chemotherapy except if > 12 months since it was given
             in either the neoadjuvant or adjuvant setting or for hormone sensitive disease (e.g.,
             CHAARTED population)

          -  Presence of untreated brain metastasis

          -  Seizure or known condition that may pre-dispose to seizure (including but not limited
             to prior stroke, transient ischemic attack within 1 year prior to randomization, brain
             arteriovenous malformation; or intracranial masses such as schwannomas and meningiomas
             that are causing edema or mass effect). Loss of consciousness within 12 months may be
             permitted upon discussion with study PI.

          -  Medications known to lower the seizure threshold must be discontinued or substituted
             at least 4 weeks prior to study entry.

          -  Current, recent (within 4 weeks of the first dose of this study), or planned
             participation in an experimental drug study

          -  Persistent grade > 1 (NCI CTCAE v4.0) AEs due to investigational drugs that were
             administered more than 14 days before study enrollment.

          -  Radiation within 2 weeks prior to entering the study

          -  Peripheral neuropathy ≥ Grade 2.

          -  Current evidence of any of the following:

               -  Uncontrolled hypertension

               -  Gastrointestinal disorder affecting absorption

               -  Active infection (e.g., human immunodeficiency virus [HIV] or viral hepatitis) or
                  other medical condition that would make prednisone/prednisolone (corticosteroid)
                  use contraindicated

          -  Uncontrolled intercurrent illness including, but not limited to, severe or unstable
             angina, myocardial infarction, symptomatic congestive heart failure (defined as New
             York Heart Association Grade II or greater), arterial or venous thromboembolic events
             (e.g., pulmonary embolism), or clinically significant ventricular arrhythmias,
             significant vascular disease (e.g. aortic aneurysm, aortic dissection), or symptomatic
             peripheral vascular disease within 6 months prior to randomization.

          -  Psychiatric illness/social situations that would limit compliance with study
             requirements.

          -  Any condition that in the opinion of the investigator, would preclude participation in
             this study

          -  History of allergic reactions or severe hypersensitivity reactions to drugs formulated
             with polysorbate 80 or antisense oligonucleotides.

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to apalutamide or docetaxel

          -  Participants receiving any medications or substances that are strong inhibitors or
             inducers of CYP3A4 are ineligible. Because the lists of these agents are constantly
             changing, it is important to regularly consult a frequently-updated list such as
             http://medicine.iupui.edu/clinpharm/ddis/table.aspx; medical reference texts such as
             the Physicians' Desk Reference may also provide this information. As part of the
             enrollment/informed consent procedures, the patient will be counseled on the risk of
             interactions with other agents, and what to do if new medications need to be
             prescribed or if the patient is considering a new over-the-counter medicine or herbal
             product.

          -  Inability to comply with study and/or follow-up procedures