Ipilimumab and Nivolumab Combination Therapy With Supervised or Semi-supervised Exercise Intervention

• Patient-reported fatigue as measured by the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale[ Time Frame: 13 weeks ]
  The FACIT-F measures severity and impact of fatigue on functioning and health-related quality of life experienced in past seven days using 40 statements that patients are asked to rate as 0-4 with 0 being "Not at all" and 4 being "Very much".
• Patient-reported activity as measured by the Godin Leisure Time Exercise Questionnaire[ Time Frame: 13 weeks ]
• Patient-reported symptoms as measured by the Functional Assessment of Cancer Therapy-Kidney Symptom Index-19 (FKSI-19)[ Time Frame: 13 weeks ]
• Patient health outcome as measured by the EQ-5D health questionnaire[ Time Frame: 13 weeks ]
• Left ventricular ejection fraction (LVEF) at rest[ Time Frame: 13 weeks ]
• Left ventricular ejection fraction (LVEF) during exercise[ Time Frame: 13 weeks ]
• Cardiac function via 2D echocardiography[ Time Frame: 13 weeks ]
• Cardiac function via 3D echocardiography[ Time Frame: 13 weeks ]
• Upper extremity maximal muscular strength[ Time Frame: 13 weeks ]
  Measured by a calculated one-repetition maximum (1-RM)
• Lower extremity maximal muscular strength[ Time Frame: 13 weeks ]
  Measured by a calculated one-repetition maximum (1-RM)
• Cross-sectional area of the major muscles[ Time Frame: 13 weeks ]
• Muscle endurance[ Time Frame: 13 weeks ]
  Number of repetitions to fatigue at 70% of on-repetition maximum
• Evaluate co-existent depression using the Hospital Anxiety and Depression (HADS) scale[ Time Frame: 13 weeks ]
  The HADS scale consists of 14 statements that patients are asked to complete using statements that correlate to a score of 0 to 3, with high scores indicating higher levels of anxiety and/or depression
• Eligibility rate[ Time Frame: 13 weeks ]
  Eligibility rate is defined as the number of subjects eligible for the study divided by the number approached for the study (i.e., screen fail rate)
• Attrition[ Time Frame: 13 weeks ]
  The number of patients agreeing to participate divided by total number randomized
• Compliance as measured by the number of ipilimumab doses taken[ Time Frame: 13 weeks ]
• Compliance as measured by the number of nivolumab doses taken[ Time Frame: 13 weeks ]
• Compliance as measured by the percent of ipilimumab doses taken[ Time Frame: 13 weeks ]
• Compliance as measured by the percent of nivolumab doses taken[ Time Frame: 13 weeks ]
• Exercise-related adverse event rate[ Time Frame: 13 weeks ]
  Assessed using Common Terminology Criteria for Adverse Events (CTCAE) v5.0
• Dose intensity of nivolumab[ Time Frame: 13 weeks ]
  Will be determined by evaluating treatment logs
• Dose intensity of ipilimumab by evaluating treatment logs[ Time Frame: 13 weeks ]
  Will be determined by evaluating treatment logs

This study aims to report the effects of immediate or delayed exercise training on patients with advanced or metastatic renal cell carcinoma who are receiving nivolumab and ipilimumab.

• Behavioral: Exercise
  Patients will be asked to complete 3 x 30 minute exercise sessions each week.

• Experimental: 12 week supervised exercise program
  Patients will be asked to complete 3 30-minute supervised exercise sessions/week under the guidance of the study exercise physiologist. The preferred mode will be treadmill walking, however, alternatives such as cycling or stair climbing machines will be used. For these sessions, patients will be asked to wear a heart rate monitor. Following a 5 minute warm-up, the exercise physiologist will increase speed to correspond with an intensity of approximately 80% VO2peak for 1-minute before returning to a lower speed for 1-minute (50% VO2peak). Patients will complete up to 20 of each 1-minute interval, then cool-down for 5 minutes. At the end of each higher intensity interval patients will be asked to rate their perceived exertion (RPE). Additionally, patients will receive standard of care nivolumab (3 mg/kg i.v.) and ipilimumab (1 mg/kg i.v.) q3 weeks x 4 doses followed by nivolumab at 3 mg/kg q2 weeks.
• Experimental: 12 week semi-supervised exercise program
  This cohort will complete 12 weeks of a semi-supervised exercise program independently. Patients will be scheduled for an exercise session with a study exercise physiologist during clinical appointments to complete a sample intensity and time specific exercise session. The preferred mode will be walking, however cycling is also permitted. For each session the patient will wear a heart rate monitor. Following a 5 minute warm-up, patients will increase the intensity of exercise to reach a heart rate corresponding to approximately 60% VO2peak, and will continuously maintain this intensity for their individualized duration to elicit the desired energy expenditure. Each week, the exercise physiologist will call the patient and discuss how to approach the next set of exercise sessions. Additionally, patients will receive standard of care nivolumab (3 mg/kg i.v.) and ipilimumab (1 mg/kg i.v.) q3 weeks x 4 doses followed by nivolumab at 3 mg/kg q2 weeks.
• No Intervention: Control cohort
  Participants will have routine care for 12 weeks. This will consist of nivolumab (3 mg/kg i.v.) and ipilimumab (1 mg/kg i.v.) q3 weeks x 4 doses followed by nivolumab at 3 mg/kg q2 weeks.