INTENSE: A Study of a Supervised or Semi-Supervised Exercise InterveNtion or Usual Care With Functional Capacity and Quality of Life Evaluations in Subjects Receiving Ipilimumab and Nivolumab for Advanced or Metastatic Renal Cell Carcinoma

Exercise interventions also have been shown to improve both cancer- and treatment-related
fatigue and quality of life across multiple tumor types. Thus, an exercise intervention could
improve the tolerability of combination immunotherapy. Furthermore, functional capacity
and/or amount of physical activity are associated with survival in several cancers. Finally,
there is emerging evidence that exercise training may augment beneficial cancer-specific
immune function. This study will examine parallel groups of supervised or semi-supervised
exercise training or usual care in patients with mRCC treated with nivolumab and ipilimumab
combination therapy. Fitness level will be evaluated by cardiopulmonary exercise testing
(CPET), wearable exercise tracking devices and questionnaires after 12 weeks of
semi-supervised, home-based exercise.

Inclusion Criteria:

- Age ≥18 years.

- Histologically confirmed renal cell carcinoma (RCC).

- Locally advanced, unresectable or metastatic disease, in the opinion of the
investigator.

- Scheduled to receive ipilimumab and nivolumab per standard of care.

- No prior checkpoint inhibitor therapy for RCC.

- Subjects with brain metastases are allowed if they are asymptomatic, without edema,
and not on systemic corticosteroids or receiving radiation therapy for at least 14
days prior to beginning protocol therapy.

- Karnofsky Performance Status (KPS) of at least 70%

- Able to walk on a treadmill, in the opinion of the treating physician.

- Must be able to complete an acceptable cardiopulmonary exercise test (CPET) at
baseline (see Section 5.5) defined as at least one of the following:

- Achieving a plateau in oxygen consumption concurrent with an increase in power
output, or

- A respiratory exchange ratio ≥ 1.1 (RER), or

- Volitional exhaustion with a rating of perceived exertion ≥17 (RPE).

- To participate in the optional fitness tracker cohort, the patient must either have a
Bluetooth-enabled smart phone that is compatible with the wireless fitness tracker or
be willing and able to upload data weekly via an internet-connected computer.

- Ability to understand English and the willingness to sign a written informed consent
document.

Exclusion Criteria:

- Major surgery (e.g. nephrectomy) less than 28 days prior to the first dose of study
drug.

- Palliative, focal radiation therapy less than 14 days prior to the first dose of study
drug.

- History of cerebrovascular accident including transient ischemic attack (TIA) within
the past 6 months.

- Osseous metastatic disease with unacceptable risk of impending fracture due to study
assessments, in the opinion of the investigator. Note: This criterion must be met
prior to CPET.

- Absolute contraindications to cardiopulmonary exercise testing and/or aerobic
training, as determined by the attending oncologist:

- 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.

- Poorly controlled hypertension [defined as systolic blood pressure (SBP) of >150 mmHg
or diastolic blood pressure (DBP) of >90 mmHg].