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

BACKGROUND:

- The management of advanced renal cell carcinoma (RCC) continues to remain a challenge,
particularly for patients with papillary and non-clear cell variants of RCC, for whom
there is no standard therapy of proven benefit.

- Inactivation of the Krebs cycle enzyme Fumarate Hydratase (FH) in tumors associated with
hereditary leiomyomatosis and renal cell cancer (HLRCC) results in a metabolic shift
characterized by a) reliance on aerobic glycolysis for energy production, b)
upregulation of HIF 1- and its downstream targets that promote glucose delivery and
uptake to fuel aerobic glycolysis, and c) downregulation of AMPK, resulting in
activation of the mTOR pathway and increased macromolecule synthesis.

- Inactivation of another Krebs cycle enzyme, Succinate Dehydrogenase (SDH), is also
associated with a familial form of kidney cancer which shares some of the above
metabolic features.

- Vandetanib is a dual VEGFR/EGFR inhibitor that reverses the metabolic phenotype
associated with FH (and SDH) inactivation and has potent preclinical activity in FH-/-
and SDH -/- tumors. Metformin activates AMPK and has demonstrated potent synergy when
combined with vandetanib, in preclinical models of FH -/- tumors.

- In this phase 1/2 trial, we first propose to establish the safety and dosing parameters
of combined vandetanib and metformin therapy. We then propose to test the activity of
vandetanib in combination with metformin in patients with HLRCC or SDH-associated RCC,
as well as those with sporadic forms of papillary RCC.

OBJECTIVE:

Phase I Component:

-Establish the safety and maximum tolerated dose of the combination of vandetanib with
metformin in patients with advanced RCC.

Phase II Component:

-Determine the overall response rate (RECIST 1.1) following treatment with combine
vandetanib/metformin in patients with 1) advanced RCC associated with hereditary
leiomyomatosis and renal cell carcinoma (HLRCC) or succinate dehydrogenase renal cell
carcinoma (SDH-RCC), and 2) advanced sporadic papillary renal cell carcinoma.

ELIGIBILITY:

Phase I Component:

- Diagnosis of advanced RCC

- Patients with clear cell RCC must have either declined, be unable to receive, progressed
on, or be intolerant of high-dose IL-2 or established first and second line VEGF and/or
mTOR targeted agents

- No prior therapy is required in patients with non-clear cell RCC, but prior therapy is
allowed

Phase II Component:

- Diagnosis of advanced RCC associated with HLRCC or SDH-RCC (cohort 1) or
sporadic/non-HLRCC papillary RCC (cohort 2)

- No more than 2 prior regimens with VEGF-pathway antagonists

General requirements for both Phase I and II:

- Age greater than or equal to18

- 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

- No major surgery within four weeks or inadequately healed wounds prior to study
enrollment

- Adequate organ function

DESIGN:

Phase I Component:

- Combination vandetanib and metformin will be administered at starting doses of 300 mg QD
and 250 mg BID, respectively.

- The study design is based on a single arm, fixed order dose-escalation Phase 1 study
using a modified Fibronacci schema.

- Up to 6 patients may be enrolled in a specific dose combination cohort. Based on the
assumption that 3 dose levels will be evaluated, the total number of evaluable patients
will be 18. To allow for a few patients who may be inevaluable, the accrual ceiling for
this portion of the study will be set at 21. Based on how dose escalation proceeds and
the adverse events seen, the total number of patients to be accrued may be changed via a
protocol amendment.

Phase II Component:

- Once the MTD is determined, the appropriate combination dose will be evaluated in the
phase 2 component.

- Patients will be accrued into one of two independent, parallel cohorts:

- Cohort 1 Patients with advanced HLRCC or SDH associated RCC.

- Cohort 2 Patients with advanced sporadic/non-HLRCC papillary kidney cancer.

- Patients will be evaluated for response every 8-12 weeks using RECIST 1.1.

- The study is based on open label two-stage optimal phase II design.

- The accrual ceiling for this portion of the study will be 21 patients for each cohort.

- INCLUSION CRITERIA:

1. Diagnosis/Histology

1. Phase I Component Histologically confirmed advanced RCC of any subtype.

2. Phase II Component Advanced RCC associated with 1) HLRCC or 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 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 CT scan or 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 IL-2, or standard first and
second line VEGF, or 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. 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)

AST(SGOT)/ALT(SGPT) less than or equal to 2.5 X institutional upper limit of normal

eGFR (CKD-EPI) greater than or equal to 50 mL/min/1.73 m2

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 Investigator s 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 QT syndrome.

14 Any concomitant medications that are known to be associated with Torsades de
Pointes Drugs that in the investigator s 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 QTcF correction unmeasurable or >450 ms on screening 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. 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 GI
bleeding or those with bleeding diathesis