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
2. Phase I Component - Histologically confirmed advanced Renal Cell Carcinoma (RCC) of any subtype.
3. Phase II Component - Advanced RCC associated with 1) Hereditaryleiomyomatosis and renal cell carcinoma (HLRCC) or Succinate dehydrogenase (SDH) (Cohort 1); OR 2) advanced non HLRCC-related papillary RCC (Cohort 2).
4. Phase 1: Patients must have evaluable disease Phase 2: Patients must have measurable disease based on Response Evaluation Criteria inSolid Tumors (RECIST 1.1) criteria, defined as at least one lesion that can be accuratelymeasured in at least one dimension (longest diameter to be recorded for non-nodal lesionsand short axis for nodal lesions) as >20 mm with conventional techniques or as >10 mm withspiral computed tomography (CT) scan or magnetic resonance imaging (MRI) (except for lymphnodes, which must be >15 mm).
5. Prior Therapy
6. Phase 1- Patients with clear cell RCC must have either declined, be ineligible toreceive, have progressed on, or be intolerant to high dose Interleukin 2 (IL-2), orstandard first and second line Vascular endothelial growth factor (VEGF), or mammaliantarget of rapamycin (mTOR) targeted agents. As there is no standard therapy formetastatic non-clear cell RCC, no prior therapy is required.
7. Phase 2- No more than two prior VEGF-pathway targeted agents
8. No previous treatment with vandetanib. Previous or ongoing treatment with metformin isallowed.
9. Age greater than or equal to18 years.
10. Eastern Cooperative Oncology Group (ECOG) performance status <2 (Karnofsky >60%).
11. Negative pregnancy test (urine or serum) for female patients of childbearingpotential.
12. 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 upperlimit 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) lessthan or equal to 2.5 X institutional upper limit of normal Estimated glomerular filtration rate (eGFR) (Chronic Kidney Disease EpidemiologyCollaboration (CKD-EPI) greater than or equal to 50 mL/min/1.73 m^2
13. 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 studyparticipation and for at least 6 months after vandetanib/metformin therapy. Should awoman become pregnant (either a participant or the partner of a male participant) orsuspect she is pregnant while she is participating in this study, she should informher treating physician immediately.
14. Ability of subject to understand and the willingness to sign a written informedconsent document.

EXCLUSION CRITERIA:

1. Known serious allergic reaction to vandetanib or metformin.
2. Brain metastases or spinal cord compression that requires treatment, unless thetreatment ended at least 4 weeks before starting protocol therapy and thecondition 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 overnighthospital admission) within 28 days before starting treatment or inadequatelyhealed incision/scar from prior surgery.
4. Any unresolved chronic toxicity greater than Common Terminology Criteria forAdverse Event (CTCAE) Grade 2 or greater from previous anti-cancer therapy (thiscriterion does not apply to alopecia).
5. Unacceptable electrolyte values, including:

• Potassium <4.0 mmol/L despite supplementation, or elevated potassium abovethe CTCAE Grade 1 upper limit.
• Magnesium below the lower limit of normal range despite supplementation, orelevated magnesium above the CTCAE Grade 1 upper limit.
• Ionized calcium or corrected calcium values below the normal range orhypercalcemia 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 weeksbefore starting treatment, or presence of cardiac disease that in the opinion ofthe 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 despitetreatment, or asymptomatic sustained ventricular tachycardia. Patients withatrial fibrillation controlled by medication are permitted.
8. Hypertension not controlled by medical therapy (systolic blood pressure greaterthan 140 millimeter of mercury [mmHg] or diastolic blood pressure greater than 90mmHg).
9. Past medical history of interstitial lung disease, drug-induced interstitialdisease, radiation pneumonitis which required steroid treatment or any evidenceof clinically active interstitial lung disease.
10. Proteinuria > 1gram/24 hrs
11. Evidence of severe or uncontrolled systemic disease or any concurrent conditionwhich in the Investigators opinion makes it undesirable for the patient toparticipate in the trial or which would jeopardize compliance with the protocol.
12. Previous or current invasive malignancies of other histologies requiringtreatment within the last 2 years, with the exception of adequately treated basalcell 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 dePointes Drugs that in the investigators opinion cannot be discontinued, are allowedhowever, must be monitored closely 15 .Any concomitant potent inducers of cytochrome P450 3A4 (CYP3A4) function (seehttp://medicine.iupui.edu/clinpharm/ddis/table.aspx for a continually updated list ofCYP3A4 inducers). 16 History of QT prolongation associated with other medications that requireddiscontinuation of that medication. 17 Fridericia's (QTcF) correction unmeasurable or >450 ms on screeningelectrocardiogram (ECG) (Note: If a patient has a QTcF interval >450 ms on screeningECG, 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 beeligible for the study).
13. Women that are currently breast feeding.
14. Active treatment-refractory diarrhea that may affect the ability of the patient toabsorb the trial agents or tolerate further diarrhea.
15. Human immunodeficiency virus (HIV)-positive patients on combination antiretroviraltherapy are ineligible because of the potential for pharmacokinetic interactions withvandetanib/metformin.
16. Patients with active hemoptysis, clinically significant non hemorrhoidalgastrointestinal (GI) bleeding or those with bleeding diathesis