Vandetanib in Combination With Metformin in People With HLRCC or SDH-Associated Kidney Cancer or Sporadic Papillary Renal Cell Carcinoma

* INCLUSION CRITERIA:

  1. Diagnosis/Histology

     1. Phase I Component - Histologically confirmed advanced Renal Cell Carcinoma (RCC) of any subtype.
     2. Phase II Component - Advanced RCC associated with 1) Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) or Succinate dehydrogenase (SDH) (Cohort 1); OR 2) advanced non HLRCC-related papillary RCC (Cohort 2).
  2. Phase 1: Patients must have evaluable disease

Phase 2: Patients must have measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST 1.1) criteria, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as \>20 mm with conventional techniques or as \>10 mm with spiral computed tomography (CT) scan or magnetic resonance imaging (MRI) (except for lymph nodes, which must be \>15 mm).

3\. Prior Therapy

1. Phase 1- Patients with clear cell RCC must have either declined, be ineligible to receive, have progressed on, or be intolerant to high dose Interleukin 2 (IL-2), or standard first and second line Vascular endothelial growth factor (VEGF), or mammalian target of rapamycin (mTOR) targeted agents. As there is no standard therapy for metastatic non-clear cell RCC, no prior therapy is required.
2. Phase 2- No more than two prior VEGF-pathway targeted agents
3. No previous treatment with vandetanib. Previous or ongoing treatment with metformin is allowed.

   4\. Age greater than or equal to18 years.

   5\. Eastern Cooperative Oncology Group (ECOG) performance status \<2 (Karnofsky \>60%).

   6\. Negative pregnancy test (urine or serum) for female patients of childbearing potential.

   7\. Patients must have normal organ and marrow function as defined below:

   absolute neutrophil count greater than or equal to 1,500/mcL

   platelets greater than or equal to 100,000/mcL

   total bilirubin less than or equal to 1.5x upper limit of reference range ( \< 3x upper limit of reference range in patients with Gilbert's disease)

   aspartate aminotransferase (AST)(serum glutamic-oxaloacetic transaminase (SGOT)/alanine aminotransferase (ALT)(Serum glutamic pyruvic transaminase (SGPT) less than or equal to 2.5 X institutional upper limit of normal

   Estimated glomerular filtration rate (eGFR) (Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) greater than or equal to 50 mL/min/1.73 m\^2

   8\. Men and women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) for the duration of study participation and for at least 6 months after vandetanib/metformin therapy. Should a woman become pregnant (either a participant or the partner of a male participant) or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately.

   9\. Ability of subject to understand and the willingness to sign a written informed consent document.

   EXCLUSION CRITERIA:
   1. Known serious allergic reaction to vandetanib or metformin.
   2. Brain metastases or spinal cord compression that requires treatment, unless the treatment ended at least 4 weeks before starting protocol therapy and the condition has been stable without steroid treatment for at least 10 days.
   3. Major surgery (includes any surgery that carries significant risk of blood loss, extended periods of general anesthesia, or requires at least an overnight hospital admission) within 28 days before starting treatment or inadequately healed incision/scar from prior surgery.
   4. Any unresolved chronic toxicity greater than Common Terminology Criteria for Adverse Event (CTCAE) Grade 2 or greater from previous anti-cancer therapy (this criterion does not apply to alopecia).
   5. Unacceptable electrolyte values, including:

      * Potassium \<4.0 mmol/L despite supplementation, or elevated potassium above the CTCAE Grade 1 upper limit.
      * Magnesium below the lower limit of normal range despite supplementation, or elevated magnesium above the CTCAE Grade 1 upper limit.
      * Ionized calcium or corrected calcium values below the normal range or hypercalcemia above the CTCAE Grade 1 upper limit.
   6. Significant cardiac event (eg, myocardial infarction), New York Heart Association (NYHA) classification of heart disease greater than or equal to 2 within 12 weeks before starting treatment, or presence of cardiac disease that in the opinion of the Investigator increases the risk of ventricular arrhythmia.
   7. History of arrhythmia (multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia), which is symptomatic or requires treatment (CTCAE Grade 3), symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia. Patients with atrial fibrillation controlled by medication are permitted.
   8. Hypertension not controlled by medical therapy (systolic blood pressure greater than 140 millimeter of mercury \[mmHg\] or diastolic blood pressure greater than 90 mmHg).
   9. Past medical history of interstitial lung disease, drug-induced interstitial disease, radiation pneumonitis which required steroid treatment or any evidence of clinically active interstitial lung disease.
   10. Proteinuria \> 1gram/24 hrs
   11. Evidence of severe or uncontrolled systemic disease or any concurrent condition which in the Investigators opinion makes it undesirable for the patient to participate in the trial or which would jeopardize compliance with the protocol.
   12. Previous or current invasive malignancies of other histologies requiring treatment within the last 2 years, with the exception of adequately treated basal cell or squamous cell carcinoma of the skin (phase 2 only).

   13 Congenital long Q wave T wave (QT) syndrome.

   14 Any concomitant medications that are known to be associated with Torsades de Pointes Drugs that in the investigators opinion cannot be discontinued, are allowed however, must be monitored closely

   15 .Any concomitant potent inducers of cytochrome P450 3A4 (CYP3A4) function (see http://medicine.iupui.edu/clinpharm/ddis/table.aspx for a continually updated list of CYP3A4 inducers).

   16 History of QT prolongation associated with other medications that required discontinuation of that medication.

   17 Fridericia's (QTcF) correction unmeasurable or \>450 ms on screening electrocardiogram (ECG) (Note: If a patient has a QTcF interval \>450 ms on screening ECG, the screening ECG may be repeated twice \[at least 24 hours apart\] for a total of 3 ECGs. The average QTcF from the three

   screening ECGs must be less than or equal to 450 ms in order for the patient to be eligible for the study).

   18\. Women that are currently breast feeding.

   19\. Active treatment-refractory diarrhea that may affect the ability of the patient to absorb the trial agents or tolerate further diarrhea.

   20\. Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with vandetanib/metformin.

   21\. Patients with active hemoptysis, clinically significant non hemorrhoidal gastrointestinal (GI) bleeding or those with bleeding diathesis