EXTEND Exercise Trial
Condition: Non-metastatic, Hormone naïve Prostate Cancer
MeSH terms: Prostatic Neoplasms
Intervention: Enzalutamide; Androgen deprivation therapy; Supervised exercise training
Intervention MeSH terms: Androgens
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 26.0
Sex: Male
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This study will examine the effect of supervised exercise training on cardiopulmonary
      function in men receiving the combination of enzalutamide (ENZ) and androgen deprivation
      therapy (ADT) for treatment of non-metastatic, hormone-naïve prostate cancer. No study to
      date has examined the efficacy, tolerability, and safety of exercise training to prevent
      and/or mitigate common adverse toxicities in men receiving combination androgen suppression
      therapy for hormone-naïve prostate cancer.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Male age ≥ 18 years.

          2. Histologically-confirmed adenocarcinoma of the prostate.

          3. Completion of appropriate prior treatment with local therapy (i.e., prostatectomy,
             radiation therapy or equivalent), per NCCN Guidelines.

          4. Detectable PSA, defined as PSA ≥0.01 ng/ml

          5. Appropriate for treatment with ADT in the opinion of the treating physician.

          6. Serum total testosterone ≥150 ng/dL (5.2 nmol/L).

          7. ECOG performance status of ≤ 1 (Appendix A)

          8. Planned treatment with castration therapy (GnRH agonist/antagonist) for ≥8 months.

          9. Must not have any of the following absolute contraindications to cardiopulmonary
             exercise testing and/or aerobic training as determined by the attending oncologist:

             Absolute Contraindications

               -  Acute myocardial Infarction (within 3-5 days of any planned study procedures)

               -  Unstable angina

               -  Uncontrolled arrhythmia causing symptoms or hemodynamic compromise

               -  Recurrent syncope

               -  Active endocarditis

               -  Acute myocarditis or pericarditis

               -  Symptomatic severe aortic stenosis

               -  Uncontrolled heart failure

               -  Acute (within 3 months) pulmonary embolus or pulmonary infarction

               -  Thrombosis of lower extremities

               -  Suspected dissecting aneurysm

               -  Uncontrolled asthma

               -  Pulmonary edema

               -  Room air desaturation at rest <85%

               -  Respiratory failure

               -  Acute non-cardiopulmonary disorders that may affect exercise performance or be
                  aggravated by exercise (i.e. infection, renal failure, thyrotoxicosis)

               -  Mental impairment leading to inability to cooperate.

         10. Able to swallow enzalutamide and comply with study requirements.

         11. Must be able to complete an acceptable cardiopulmonary exercise test (CPET) at
             baseline (see Section 9), defined as at least one of the following:

               -  Achieving a plateau in oxygen consumption concurrent with an increase in power
                  output;

               -  Respiratory exchange ratio ≥ 1.1 (RER);

               -  Volitional exhaustion with a rating of perceived exertion ≥ 17 (RPE)

         12. Must be able to complete an acceptable muscular strength test (assessed using
             calculated one-repetition maximum (1-RM)) at baseline (see Section 9), in the opinion
             of the fitness specialist, exercise physiologist, or trained designee administering
             the test.

         13. Life expectancy of ≥ 12 months.

         14. Must use a condom if having sex with a pregnant woman.

         15. Male subject and his female partner who is of childbearing potential must use 2
             acceptable methods of birth control (one of which must include a condom as a barrier
             method of contraception) starting at screening and continuing throughout the study
             period and for 3 months after final study drug administration. Two acceptable methods
             of birth control thus include the following:

               -  Condom (barrier method of contraception); AND

             One of the following is required:

               -  Established use of oral, or injected or implanted hormonal method of
                  contraception by the female partner;

               -  Placement of an intrauterine device (IUD) or intrauterine system (IUS) by the
                  female partner;

               -  Additional barrier method: Occlusive cap (diaphragm or cervical/vault caps) with
                  spermicidal foam/gel/film/cream/suppository by the female partner;

               -  Tubal ligation in the female partner;

               -  Vasectomy or other procedure resulting in infertility (e.g., bilateral
                  orchiectomy), for more than 6 months

         16. Subjects must have normal organ and marrow function as defined below:

               -  absolute neutrophil count >1,500/µL

               -  platelets >100,000/µL

               -  total bilirubin <2.5 X institutional upper limit of normal

               -  AST(SGOT)/ALT(SGPT) <2.5 X institutional upper limit of normal

               -  Creatinine ≤ 2.0 OR creatinine clearance >30 mL/min/1.73 m2 for subjects with
                  creatinine levels above institutional normal.

        Exclusion Criteria:

          1. Definite evidence of metastatic prostate cancer, in the opinion of the treating
             physician. Pelvic and retroperitoneal lymph nodes < 2.0 cm in short axis are allowed.

          2. Subjects who have had treatments with GnRH agonists/antagonists and/or anti-androgens
             within 1 year of randomization.

          3. Use of herbal products that may have hormonal anti-prostate cancer activity and/or are
             known to decrease PSA values (e.g., saw palmetto) or systemic corticosteroids for
             prostate cancer within 4 weeks of day 29 visit (start of Enzalutamide and ADT).

          4. Subjects who have had radiotherapy within 12 weeks prior to entering the study or
             those who have not recovered from adverse events due to agents or therapies
             administered for treatment of prostate cancer more than 4 weeks earlier (except
             urinary, rectal, and sexual side effects related to prostatectomy or radiotherapy are
             permitted)

          5. Subjects who have had any surgical procedure (i.e. TURP, etc.) within 4 weeks prior to
             entering the study.

          6. Subjects who are receiving any other investigational agents.

          7. Significant cardiovascular disease, including:

               -  Symptomatic left ventricular dysfunction or known baseline left ventricular
                  ejection fraction (LVEF) by multigated acquisition scan (MUGA) or echocardiogram
                  (ECHO) of < lower limit of institutional normal (LLN). "Symptomatic" is defined
                  as New York Heart Association (NYHA) Class II or greater. Note: MUGA and ECHCO do
                  NOT need to be measured to establish eligibility for this study.

               -  Uncontrolled hypertension (in the opinion of the treating provider).

               -  Myocardial infarction, severe angina, or unstable angina within 6 months prior to
                  administration of first dose of study drug.

               -  History of serious ventricular arrhythmia (i.e., ventricular tachycardia or
                  ventricular fibrillation) within 12 months of first dose of study drug.

               -  Uncontrolled cardiac arrhythmias.

               -  Coronary or peripheral artery bypass graft within 6 months of first dose of study
                  drug.

               -  History of CVA, TIA, or rest claudication within 6 months of first dose of study
                  drug.

          8. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
             arrhythmia, or psychiatric illness/social situations that would limit compliance with
             study requirements (in the opinion of the treating provider).

          9. Subjects with any condition (e.g., gastrointestinal tract disease resulting in an
             inability to take oral medication or a requirement for IV alimentation, prior surgical
             procedures affecting absorption, or active peptic ulcer disease) that impairs the
             ability to swallow and retain enzalutamide are excluded.

         10. History of another invasive cancer within 5 years of randomization with the exceptions
             of (a) non-melanoma skin cancers and (b) American Joint Committee on Cancer (AJCC)
             Stage 0 or 1 cancers that have a remote probability of recurrence, in the opinion of
             the treating physician, in consultation with the principal investigator.

         11. Known or suspected brain metastasis or leptomeningeal disease.

         12. History of seizure or any condition that may predispose to seizure (e.g., prior
             cortical stroke, significant brain trauma) at any time in the past. Also, history of
             loss of consciousness or transient ischemic attack within 12 months of the Day 1
             visit.