Alternative Schedule Sunitinib in Metastatic Renal Cell Carcinoma: Cardiopulmonary Exercise Testing
Condition: Carcinoma, Renal Cell
MeSH terms: Carcinoma; Carcinoma, Renal Cell
Intervention: Sunitinib; Sunitinib
Intervention description: Patients randomized to sunitinib schedule 4/2 will receive sunitinib at 50 mg daily for 4 weeks on, followed by 2 weeks off, per standard of care. Cardiopulmonary Exercise Testing (CPET) will be performed at baseline, 4 weeks and 12 weeks.; Patients randomized to sunitinib schedule 2/1 will receive sunitinib 50 mg daily for 2 weeks on, followed by 1 week off. Cardiopulmonary Exercise Testing (CPET) will be performed at baseline, 5 weeks and 12 weeks.
Intervention MeSH terms: Sunitinib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 7.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: metastatic renal cell carcinoma; sunitinib; Sutent; cardiopulmonary function

Summary:

      The purpose of this study is to determine the effect of a sunitinib administration schedule
      2/1 (2 weeks of treatment followed by 1 week without) compared to a schedule 4/2 (4 weeks of
      treatment followed by 2 weeks without) on cardiopulmonary function in subjects with renal
      cell carcinoma. Subjects will be randomized 1:1 to one of two arms: 4/2 schedule of sunitinib
      administration or 2/1 schedule of sunitinib administration. Cardiopulmonary function will be
      assessed at baseline, week 4 (4/2 schedule only), week 5 (2/1 schedule only) and week 12. The
      investigators hypothesize that schedule 2/1 of sunitinib is not only better tolerated but
      will be associated with less fatigue and functional cardiovascular/muscular toxicity than the
      4/2 schedule.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Age ≥ 18 years.

          2. Histologically confirmed renal cell carcinoma (RCC)

          3. One of the two following populations:

               1. High risk for recurrence of RCC after nephrectomy, in the opinion of the
                  investigator, OR

               2. Locally advanced, unresectable or metastatic disease, in the opinion of the
                  investigator, and good or intermediate risk by IDMC Heng Criteria (see Appendix
                  I).

          4. Karnofsky Performance Status (KPS) ≥ 80 (see Appendix A)

          5. Good or intermediate risk by IDMC Heng Criteria (see Appendix I).4

          6. Appropriate for treatment with sunitinib in the opinion of the treating physician.

          7. Able to swallow sunitinib and comply with study requirements.

          8. Able to walk and jog on a treadmill, in the opinion of the treating physician.

          9. Must be able to complete an acceptable cardiopulmonary exercise test (CPET) at
             baseline (see Section 8.2), 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).

         10. Subjects must have normal organ and marrow function as defined below:

               -  Absolute neutrophil count ≥1,200/µL

               -  Hemoglobin ≥9 g/dL

               -  Platelets ≥75,000/µL

               -  Total bilirubin ≤1.5 x institutional upper limit of normal

               -  AST(SGOT)/ALT(SGPT) <2.5 x institutional upper limit of normal

               -  Urine protein creatinine (UPC) ratio of <1 (see Appendix G schedule of events
                  footnote)

               -  Creatinine ≤2.0 OR creatinine clearance >30 mL/min/1.73 m2 for subjects with
                  creatinine levels above institutional normal (see Appendix H).

               -  Left ventricular ejection fraction (LVEF) ≥lower limit of institutional normal as
                  assessed by echocardiography.

         11. For the sixteen patients who elect to participate in the optional technology portion
             involving electronic step counts and blood pressure monitoring, the patient must have
             a Bluetooth-enabled smart phone, which is compatible with the wireless health
             monitors.

         12. For women of childbearing potential (WOCBP) must have a negative serum pregnancy test
             prior to the start of the study. Women of childbearing potential (WOCBP) must agree to
             follow instructions for method(s) of contraception for the duration of the study.
             Medically acceptable contraceptives include: (1) surgical sterilization (such as a
             tubal ligation or hysterectomy), (2) approved hormonal contraceptives (such as birth
             control pills, patches, implants or injections), (3) barrier methods (such as a condom
             or diaphragm) used with a spermicide, or (4) an intrauterine device (IUD).
             Contraceptive measures such as Plan B (TM), sold for emergency use after unprotected
             sex, are not acceptable methods for routine use. If you do become pregnant during this
             study or if you have unprotected sex, you must inform your study physician
             immediately.

         13. For men who are sexually active, must agree to use a two medically acceptable forms of
             birth control (one of which must include a condom as a barrier method of
             contraception) in order to be in this study. Medically acceptable contraceptives
             include: (1) surgical sterilization (such as a vasectomy), or (2) a condom used with a
             spermicide. Contraceptive measures such as Plan B (TM), sold for emergency use after
             unprotected sex, are not acceptable methods for routine use. Men must also agree to
             inform their partner of the potential for harm to an unborn child. She should know
             that if pregnancy occurs, the subject will need to report it to the study doctor, and
             she should promptly notify her doctor. The study doctor will ask if the subject's
             partner is willing to provide updates on the progress of the pregnancy and its
             outcome. If the subject's partner agrees, this information will be provided to Pfizer,
             Inc. for safety monitoring follow-up.

        Exclusion Criteria:

          1. Any prior anti-VEGF therapies (i.e., sunitinib, sorafenib, pazopanib, axitinib,
             cabozantinib, bevacizumab, etc.), including in the adjuvant or neoadjuvant setting.

          2. Prior systemic therapy for advanced RCC; however, treatment with immunotherapy (i.e.,
             high-dose bolus IL-2, ipilimumab + nivolumab, etc.) is allowed.

          3. Subjects who are receiving any other investigational agents.

          4. Subjects who are receiving strong CYP3A4 inhibitors or CYP3A4 inducers (see Section
             5.3.2.2).

          5. Radiotherapy within 2 weeks prior to taking the first dose of study drug, or those who
             have not recovered from adverse events due to agents administered more than 2 weeks
             earlier.

          6. Central nervous system (CNS) metastases at baseline, with the exception of those
             subjects who have previously treated CNS metastases (surgery ± radiotherapy,
             radiosurgery, or gamma knife) and who meet both of the following criteria: a) are
             asymptomatic, and b) have no requirement for steroids or enzyme-inducing
             anticonvulsants in the prior 28 days.

          7. Clinically significant gastrointestinal abnormalities that may increase the risk for
             gastrointestinal bleeding including, but not limited to:

               -  Active peptic ulcer disease

               -  Known intraluminal metastatic lesion(s) with risk of bleeding

               -  Inflammatory bowel disease (e.g., ulcerative colitis, Crohn's disease) or other
                  gastrointestinal conditions with increased risk of perforation

               -  History of abdominal fistula, gastrointestinal perforation, or intra-abdominal
                  abscess within 28 days prior to beginning study treatment

          8. History of any one or more of the following cardiovascular conditions within the past
             6 months:

               -  Cardiac angioplasty or stenting

               -  Myocardial infarction

               -  Unstable angina

               -  Coronary artery bypass graft surgery

               -  Symptomatic peripheral vascular disease

               -  Class III or IV congestive heart failure, as defined by the New York Heart
                  Association (NYHA) (see Appendix J)

          9. Absolute contraindications to cardiopulmonary exercise testing and/or aerobic
             training, as determined by the attending oncologist:

             Absolute Contraindications

               -  Uncontrolled arrhythmia causing symptoms or hemodynamic compromise

               -  Recurrent syncope

               -  Active endocarditis

               -  Acute myocarditis or pericarditis

               -  Symptomatic severe aortic stenosis

               -  Uncontrolled heart failure

               -  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. Poorly controlled hypertension [defined as systolic blood pressure (SBP) of >150 mmHg
             or diastolic blood pressure (DBP) of >90 mmHg].

         11. History of cerebrovascular accident including transient ischemic attack (TIA),
             pulmonary embolism, or untreated deep venous thrombosis (DVT) within the past 6
             months.

         12. Major surgery or trauma within 28 days prior to first dose of investigational product
             and/or presence of any non-healing wound, fracture, or ulcer (procedures such as
             catheter placement are not considered to be major surgery).

         13. Osseous metastatic disease with unacceptable risk of impending fracture due to study
             assessments, in the opinion of the investigator

         14. Evidence of active bleeding or bleeding diathesis.

         15. Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels that
             increase the risk of pulmonary hemorrhage.