EXTEND Exercise Trial

EXTEND: Safety and Efficacy of EXercise Training in Men Receiving ENzalutamide in Combination With Conventional Androgen Deprivation Therapy for Hormone Naïve Prostate Cancer

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.

Study Overview

• Status: Completed
• Conditions: Non-metastatic, Hormone naïve Prostate Cancer
• Intervention / Treatment: Drug: Enzalutamide; Drug: Androgen deprivation therapy; Behavioral: Supervised exercise training

• Study Type: Interventional
• Enrollment (Actual): 26
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • New York
    • New York, New York, United States, 10017
      • Memorial Sloan Kettering Cancer Center
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center

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:

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ENZ+ADT+Usual care; The usual care arm will receive treatment with enzalutamide with androgen deprivation therapy, with no supervised exercise training.	Drug: Enzalutamide; Other Names: Xtandi; Drug: Androgen deprivation therapy
Experimental: ENZ+ADT+Exercise; The ENZ+ADT+Exercise arm will receive treatment with enzalutamide plus androgen deprivation therapy along with supervised exercise training.	Drug: Enzalutamide; Other Names: Xtandi; Drug: Androgen deprivation therapy; Behavioral: Supervised exercise training

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in VO2peak in Usual Care Versus Exercise Training Arms	Mean change in peak oxygen uptake (VO2peak) from week 1 to week 17 in the usual care and exercise training groups	From week 1 to week 17

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
17-week Change in Functional Capacity as Measured by Chair-stand Test	Mean change in number of seconds to perform the chair-stand test between baseline and week 17. This test measures the time taken to complete 5 repetitions of the sit-to-stand maneuver from a chair without an arm rest at 43 cm in height and 47.5 cm in depth. This test provides an indicator of functional performance of lower body strength; quicker times indicate greater strength	Baseline to 17 weeks
17-week Change in Upper and Lower Extremity Maximal Muscular Strength	Mean change in upper and lower extremity maximal muscular strength as measured by the voluntary one-repetition max (1-RM) and muscular endurance as measured by 70% of 1-RM between week 17 and baseline	Baseline to 17 weeks
Effects on Serum Glucose	Mean change in fasting serum glucose between week 17 and baseline.	Baseline to 17 weeks
Change in the Effect on Patient Reported Outcomes (PROs) of Interest Over Time	Mean change in PROs aggregate score between week 17 and baseline. PROs include the FACT-Prostate (FACT-P, range 0 to 104), FACIT-Fatigue (FACIT-F, range 0 to 52), and the Godin Leisure Questionnaire. Higher scores indicate better quality of life.	Baseline to 17 weeks
Eligibility Rate	Eligibility rate is defined as the number of subjects found to be eligible divided by the number approached for the study. Note that ineligible subjects are not randomized. This is reported as a percent.	29 months from study initiation
Acceptance Rate	Acceptance rate is defined as the number of patients agreeing to participate divided by total number randomized. This is reported as a percent.	29 months from study initiation
Adherence Rate	Adherence rate is defined as the percentage of days that each patient fulfilled the assigned exercise prescription of the 48 days. The median percentage is reported.	48 days
Attrition Rate	Attrition rate is defined as the percent of subjects who complete the 16 week exercise training program. This outcome applies only to the exercise arm.	16 weeks
17-week Change in Functional Capacity as Measured by Time Up and Go Test	Mean change in number of seconds to complete the timed up and go test between week 17 and baseline. This test requires patients to stand up from a chair with armrests, walk 3m, turn around, return to the chair, and sit down	Baseline to 17 weeks
17-week Change in Functional Capacity as Measured by Six Minute Walk Test	Mean change in distance covered during the six minute walk test between week 17 and baseline. This test requires patients to cover the longest distance possible in six minutes under the supervision of an exercise physiologist or designee.	Baseline to 17 weeks
17-week Change in Muscle Cross-sectional Area (CSA)	Mean change in muscle cross sectional area of the dominant quadricep, hamstring, and total mid-thigh between week 17 and baseline. Cross-sectional area was measured using magnetic resonance imaging with a 3.0T-scanner.	Baseline to 17 weeks
Effects on Serum Insulin	Mean change in fasting serum insulin between week 17 and baseline.	Baseline to 17 weeks
Effects on Blood Hemoglobin (Hgb)	Mean change in blood hemoglobin (Hgb) A1C between week 17 and baseline.	Baseline to 17 weeks
Effects on Body Composition	Mean change in lean body mass and fat body mass between week 17 and baseline as measured by a DEXA Scan.	Baseline to 17 weeks

Collaborators and Investigators

• Sponsor: Duke University

Publications and helpful links

General Publications

• Harrison MR, Davis PG, Khouri MG, Bartlett DB, Gupta RT, Armstrong AJ, McNamara MA, Zhang T, Anand M, Onyenwoke K, Edwardson S, Craig D, Michalski M, Wu Y, Oyekunle T, Coyne B, Coburn A, Jones LW, George DJ. A randomized controlled trial comparing changes in fitness with or without supervised exercise in patients initiated on enzalutamide and androgen deprivation therapy for non-metastatic castration-sensitive prostate cancer (EXTEND). Prostate Cancer Prostatic Dis. 2022 Mar;25(1):58-64. doi: 10.1038/s41391-022-00519-4. Epub 2022 Mar 10.

Study record dates

Study Major Dates

• Study Start (Actual): May 13, 2015
• Primary Completion (Actual): February 21, 2018
• Study Completion (Actual): July 17, 2018

Study Registration Dates

• First Submitted: August 22, 2014
• First Submitted That Met QC Criteria: October 1, 2014
• First Posted (Estimate): October 3, 2014

Study Record Updates

• Last Update Posted (Actual): April 18, 2019
• Last Update Submitted That Met QC Criteria: March 28, 2019
• Last Verified: March 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Male; Prostatic Diseases; Prostatic Neoplasms; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Androgens
• Other Study ID Numbers: Pro00053924