Clinical trial NCT02495103
Conditions: Renal Cell Carcinoma Hereditary Leiomyomatosis Renal Cell Cancer
Keywords: Dose-Escalation Maximum Tolerated Dose Overall Response
Sponsor: National Cancer Institute (NCI)
Start date: 2015-08-26; Completion date: 2020-02-06
Enrollment: 7 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
Background:

\- There are no established treatments for people with certain advanced kidney cancers. These tumors often don't respond well to currently available treatments. Researchers believe that two drugs that treat other diseases metformin and vandetanib could help people with advanced kidney cancer.

Objective:

\- To test the combination of metformin and vandetanib in people with advanced kidney cancer. Phase I of the study will determine a safe dose for the drugs. Phase II will test this dose in people with certain kidney cancers.

Eligibility:

* For Phase I, people 18 and over with advanced kidney cancer
* For Phase II, people 18 and over with advanced hereditary leiomyomatosis and renal cell cancer (HLRCC), succinate dehydrogenase renal cell carcinoma (SDH-RCC), or advanced papillary renal cell carcinoma not related to a hereditary syndrome

Design:

* The study will last many months.
* Participants will be screened with medical history and physical exam.
* Participants will take the study drugs by mouth every day.
* Participants will measure and record their blood pressure every day.
* Participants will have many tests:
* Blood and urine tests
* Magnetic resonance imaging (MRI), computed tomography (CT), positron emission tomography (PET) scan, and other imaging tests: they will lie in machines that take pictures of their body.
* Electrocardiogram (ECG): soft electrodes will be stuck to the skin. A machine will record the hearts signals.
* Bone scan
* Some participants may have a gynecology evaluation or photos of skin tumors taken.
* Participants will have an optional tumor biopsy.
* After they stop taking the drugs, participants may have medical history, physical exam, and blood tests. They will be contacted once a year by phone to find out how they are doing.

Detailed description:
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 hypoxia-inducible factor 1 (HIF 1-) and its downstream targets that promote glucose delivery and uptake to fuel aerobic glycolysis, and c) downregulation of 5' AMP-activated protein kinase (AMPK), resulting in activation of the mammalian target of rapamycin (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 Vascular endothelial growth-factor receptor (VEGFR)/estimated glomerular filtration rate (EGFR) inhibitor that reverses the metabolic phenotype associated with fumarate hydratase (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 (Response Evaluation Criteria in Solid Tumors (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 every day (QD) and 250 mg twice a day (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 maximum tolerated dose (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.

Arms: arm 1: Phase I Component arm 2: Phase II Component
Interventions: intervention 1: Vandetanib intervention 2: Metformin intervention 3: Vandetanib/Metformin
Intervention descriptions: intervention 1: PHASE I: Vandetanib by mouth (PO) daily at 300mg in combination with escalating doses of metformin. intervention 2: Phase I: Metformin starting dose 250mg by mouth (PO) daily in combination with Vandetanib intervention 3: Phase II: Vandetanib and metformin by mouth (PO) daily at determined maximum tolerated dose (MTD).

Protocol documents:
ICF_002.pdf: 
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
INSTITUTE: 
National Cancer Institute 
STUDY NUMBER: 
15-C-0157 
PRINCIPAL INVESTIGATOR: 
Ramaprasad Srinivasan, M.D. 
STUDY TITLE:  
Phase I/II Trial of Vandetanib in Combination with Metformin in Subjects with 
HLRCC or SDH-Associated Kidney Cancer or Sporadic Papillary Renal Cell 
Carcinoma 
 
Continuing Review Approved by the IRB on 04/24/17 
Amendment Approved by the IRB on 09/30/16 (B) 
           Date posted to web: 05/18/17   
Phase II Standard 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent (2) 
 
 
INTRODUCTION 
We invite you to take part in a research study at the National Institutes of Health (NIH). 
First, we want you to know that: 
Taking part in NIH research is entirely voluntary.  
You may choose not to take part, or you may withdraw from the study at any time.  In 
either case, you will not lose any benefits to which you are otherwise entitled.  However, 
to receive care at the NIH, you must be taking part in a study or be under evaluation for 
study participation. 
You may receive no benefit from taking part.  The research may give us knowledge that 
may help people in the future. 
Second, some people have personal, religious or ethical beliefs that may limit the kinds of 
medical or research treatments they would want to receive (such as blood transfusions).  If you 
have such beliefs, please discuss them with your NIH doctors or research team before you agree 
to the study. 
Now we will describe this research study.  Before you decide to take part, please take as much 
time as you need to ask any questions and discuss this study with anyone at NIH, or with family, 
friends or your personal physician or other health professional.   


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:  15-C-0157 
CONTINUATION: page 2 of 17 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
Why is this study being done?  
There are no established treatments for patients with advanced non-hereditary papillary kidney 
cancers or kidney cancers associated with Hereditary Leiomyomatosis and Renal Cell Cancer 
(HLRCC) or Succinate Dehydrogenase Renal Carcinoma (SDH-RCC) and these tumors do not 
usually respond well to the treatments that are currently available and approved by the FDA for 
treatment of kidney cancer.    
Although several treatments are FDA-approved for treatment of the more common, clear cell 
form of kidney cancer, these treatments generally work for relatively short periods of time and 
are not curative.  Vandetanib is an FDA approved agent for the treatment of advanced medullary 
thyroid cancer. It has been shown to have activity against a variety of tumors and has been 
shown to inhibit some forms of papillary renal cancer cells and to cause tumor shrinkage in mice 
with human papillary kidney cancer.  Metformin, an FDA approved agent for treatment of 
diabetes, has been shown in laboratory experiments to enhance the effect of vandetanib in some 
forms of papillary kidney cancer. Neither metformin nor vandetanib are approved for use in 
papillary kidney cancer. 
In this study, we will test the combination of metformin and vandetanib. The dose you will be 
receiving was determined in the first part of the study, called phase 1.  
Why are you being asked to take part in this study? 
You are being asked to participate in this study because you have been diagnosed with advanced 
hereditary leiomyomatosis and renal cell cancer (HLRCC), succinate dehydrogenase renal cell 
carcinoma (SDH-RCC) or advanced papillary renal cell carcinoma not related to a hereditary 
syndrome. 
How many people will take part in this study?  
Up to 73 subjects will take part in the study. This includes up to 27 subjects in the dose finding 
phase portion (phase 1) of the study and up to 46 subjects in the phase 2 portion of the study. 
You will be taking part in the phase 2 portion of the study. 
Description of Research Study 
The highest safe dose level for this phase of the study (phase 2) was found enrolling patients in 
phase 1 portion of the study. You will be receiving vandetanib in combination with metformin at 
doses that were determined to be safe for further study in the phase 1 portion. This is an open 
label study, meaning that you will know the doses of the agents you will receive. You will not 
receive a ‘placebo’ on this trial. 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:  15-C-0157 
CONTINUATION: page 3 of 17 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
What will happen if you take part in this research study?   
Before you begin the study 
You will need to have the following exams, tests and procedures if you can be in the study.  
These exams, tests and procedures are part of regular cancer care and may be done even if you 
do not join the study.  If you have had some of them done recently, they may not need to be 
repeated.  This will be up to the study team. 
• A complete medical history, including your cancer history and prior cancer treatments, all 
drugs that you may be taking, including over the counter drugs, vitamins and herbal 
supplements. 
• A complete physical examination, including assessing your ability to do physical 
activities and measuring your blood pressure, heart rate and breathing. 
• Standard blood and urine tests to evaluate your organs’ functioning (such as liver, 
kidneys, blood sugar and blood electrolytes). 
• Evaluation of your cancer, which will include an MRI and CT and other imaging tests as 
if clinically indicated.   
• ECG (electrocardiogram) to assess your heart. 
• A pregnancy test will be performed in women who are able to have children.  Women 
who are pregnant or breast-feeding will not be allowed to participate, as the effects of 
vaccine on a developing fetus or infant are not known. 
• Confirmation of diagnosis by NCI Laboratory of Pathology (a review of the slides 
showing your tumor will be sent to NIH and looked at here by our pathologist).  
During the study 
If you are determined to be eligible for this study and agree to take part, you take vandetanib and 
metformin at the dose level determined in the phase 1 portion of the study.  Your time in this 
study will be divided into cycles, with each cycle lasting 28 days.  You will take vandetanib once 
per day and metformin twice every day. 
With the exception of the first day you are on the trial, you will be taking both medications every 
day. Take the medications together with a full glass of water after eating a light breakfast. 
Record the date and time you take the medications on your diary. If you are taking the metformin 
in the AM and PM, take the evening dose of Metformin 12 hours after your AM dose. 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:  15-C-0157 
CONTINUATION: page 4 of 17 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
If you have any procedure that require the use of IV contrast such as a CT scan, you should not 
take metformin on the morning that the procedure is planned and should only resume when 
instructed to do so by your physician/medical team.  
You will continue to take metformin and vandetanib until your disease worsens, until you have 
intolerable side effects that require us to immediately stop your vandetanib.  If your side effects 
require us to permanently discontinue metformin, you may be able to continue on the study, 
taking vandetanib alone. 
We will provide you with equipment and a diary to measure and record your blood 
pressure every day while you are on vandetanib. If you experience any worrisome side 
effects (e.g., headaches, chest pain, dizziness), or if your systolic blood pressure (upper or 
higher number) is above 140, or if your diastolic (lower number) is above 90 or above, you 
should call your doctors at the NIH or seek medical attention from your local doctors as 
soon as possible. 
We will also obtain/test the items below while you are on study medication. Some of these tests 
will be done more frequently during your first cycle. You will receive a calendar outlining what 
is to be done each cycle from your study nurse. 
• History and physical examination  
• Routine blood tests  
• Routine urine tests  
• Pregnancy test (if you are a woman who could become pregnant) 
• Electrocardiogram (ECG)  
• CT scans or MRI  
• Bone scan  
• PET scan  
• Photographs of skin tumors in patients with HLRCC associated skin tumors  
• 1 – 2 teaspoons of blood for research will be collected before you have taken any study 
medication, then at the end of each cycle through cycle 8. We will also collect blood for 
research if your disease worsens during the study. 
• An optional CT- or ultrasound-guided tumor biopsy may be done before you begin 
treatment and approximately 8 weeks following start of treatment.  We will only collect 
the biopsy if the tumor can be easily reached. The tumor samples we obtain will be used 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:  15-C-0157 
CONTINUATION: page 5 of 17 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
to look for special markers that may be helpful in the study of kidney cancer and in 
understanding the effect of the study drugs on the tumor.  We may also use the samples to 
grow tumor cell lines (cells which keep dividing and growing in the laboratory, 
sometimes for years allowing us to continually study those cells).  Results of research 
done on your specimens and data will not be available to you or your doctor.  A separate 
consent form will be provided to you at the time of the biopsy for you to grant permission 
to that procedure if you agree to the biopsies. 
During this study you will not be able to receive any other cancer treatments. You will be asked 
not to participate in any other clinical trials involving another experimental treatment while you 
are being treated in this study. 
Several medications (both prescription and non-prescription), ‘alternative/complementary’ or 
herbal preparations, dietary supplements, and foods such as grapefruit juice, can have 
undesirable interactions with the medications provided as part of this study. You will not be 
allowed to take certain medications, supplements, and grapefruit juice during your participation 
in this study.  Your doctor or the study staff will review the list of drugs that you are currently 
taking, as well as those that you took prior to participating in this study. Once you are on study, 
please talk to your NIH doctors prior to starting any new drugs, dietary supplements or 
herbal or complementary medications. 
Drugs that affect the normal growth of blood vessels can delay or complicate wound healing 
following injury or surgical procedures. You should not schedule any elective surgeries while 
you are being treated in this study.  If you have an unplanned surgery, inform you doctor 
immediately, as you may not be able to continue study drug treatment. 
You will be asked not to wear contact lenses while on this study since vandetanib can lead to 
changes in your eye that may be worsened by wearing contact lenses. 
Pharmacogenetic Testing 
For this study approximately 1 teaspoon of blood will be drawn (4 mL) before you start the 
treatment.  The purpose of this additional research study is to use the blood sample from you for 
research on genes, to see how genes and genetic variations are related to how the drug works 
and/or to learn more about your disease and the response to treatment.  To do this, we will 
analyze your blood sample.  
Pharmacogenetic research is an important way to try to understand the role of genetics in human 
disease and how genes impact the effectiveness of drugs. There are many differences, or 
variations, in genes from one person to another, which may affect a person’s chances of suffering 
from a particular disease. These differences in genes can also change the way a person responds 
to a particular drug.  


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:  15-C-0157 
CONTINUATION: page 6 of 17 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
We would like to learn more about your type of tumor by measuring certain characteristics, so 
called “biological markers” in your blood sample.   “Markers” refer to different types of genetic 
material (DNA or RNA) found in your blood that is associated with disease and/or your response 
to treatment. The aim is to find out if there are markers, which may help in predicting how well 
the treatment works.  
This is voluntary and you are not required to participate in this blood study in order to be on this 
study.  You will be given the opportunity to decide whether you want to participate in the 
pharmacogenetic study.  The decision to participate in this part of the research is optional, and no 
matter what you decide to do, it will not affect your care. 
When you are finished taking the drugs (treatment) 
If you stop taking the study drug, we would like to perform the following tests if possible within 
approximately 60 days after your last dose. The tests may be done at NCI or by your local 
physician: 
• History and physical exam 
• Routine blood tests 
If the tests cannot be performed, we would like to contact you by telephone to find out how you 
are doing. 
In addition, after the 60 day follow up visit/contact, when possible we would like to contact you 
one a year by phone to find out how you are doing. 
Birth Control 
If you are a woman who is breast feeding or pregnant, you may not take part in the study because 
we don’t know how this medicine would affect your baby or your unborn child. If you are a 
woman who can become pregnant, or are the partner of a woman who can become pregnant, you 
will need to practice an effective form of birth control before starting study treatment, during 
study treatment, and for 6 months after you finish study treatment.  If you think that you or your 
partner is pregnant, you should tell your study doctor or nurse at once.   
Effective forms of birth control include:  
• abstinence  
• intrauterine device (IUD) 
• hormonal [birth control pills, injections, or implants] 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:  15-C-0157 
CONTINUATION: page 7 of 17 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
• tubal ligation 
• vasectomy 
Risks or Discomforts of Participation 
If you choose to take part in this study, there is a risk that: 
• You may lose time at work or home and spend more time in the hospital or doctor’s 
office than usual 
• You may be asked sensitive or private questions which you normally do not discuss 
The drugs used in this study may affect how different parts of your body work such as your liver, 
kidneys, heart, and blood. The study doctor will be testing your blood and will let you know if 
changes occur that may affect your health. 
There is also a risk that you could have side effects from the study drugs. 
Here are important points about side effects: 
• The study doctors do not know who will or will not have side effects. 
• Some side effects may go away soon, some may last a long time, or some may never go 
away. 
• Some side effects may interfere with your ability to have children. 
• Some side effects may be serious and may even result in death. 
Here are important points about how you and the study doctor can make side effects less of a 
problem: 
• Tell the study doctor if you notice or feel anything different so they can see if you are 
having a side effect. 
• The study doctor may be able to treat some side effects. 
• The study doctor may adjust the study drugs to try to reduce side effects. 
The tables below show the most common and the most serious side effects that researchers know 
about. There might be other side effects that researchers do not yet know about. If important new 
side effects are found, the study doctor will discuss these with you. 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:  15-C-0157 
CONTINUATION: page 8 of 17 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
Possible Side Effects of Vandetanib  
COMMON, SOME MAY BE SERIOUS 
For every 100 people receiving Vandetanib, more than 20 and up to 100 may have: 
• Diarrhea, nausea, loss of appetite, constipation 
• Pain 
• Tiredness 
• Headache 
• Acne, rash 
• High blood pressure which may cause dizziness, blurred vision 
• Changes in the ECG 
• Weight loss 
• Depression or anxiety 
• Sleeplessness 
• Dizziness 
• Changes in measures of your kidney function, such as an increase in creatinine or 
increased protein in your urine 
• Delayed wound healing 
 
OCCASIONAL, SOME MAY BE SERIOUS 
For every 100 people receiving Vandetanib, from 4 to 20 may have: 
• Severe blood or other infection 
• Change in the heart rhythm, some of which may be life threatening 
• Dehydration 
• Changes in laboratory values of electrolytes and liver function tests 
• Low platelet counts, white blood counts or anemia 
• Itching 
• Pain, including pain associated with tumor 
• Brain damage which may cause headache, seizure, blindness (also known as Reversible 
Posterior Leukoencephalopathy Syndrome) 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:  15-C-0157 
CONTINUATION: page 9 of 17 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
OCCASIONAL, SOME MAY BE SERIOUS 
For every 100 people receiving Vandetanib, from 4 to 20 may have: 
• Damage to the lungs which may cause shortness of breath 
• Scarring of the lungs 
• Severe skin rash with blisters, ulcers can involve inside of mouth and other parts of the 
body 
• Bleeding 
• pain, redness, or peeling of the hands and feet 
• increased blood levels of calcium, a mineral normally found in blood 
• changes in levels of parathormone, a substance made in your body that regulates the levels 
of calcium and phosphorus 
• Inflammation of the pancreas 
• Inflammation/infection of the intestines 
• Abnormal accumulation of fluid in the brain 
• Development of an abnormal pathway between the esophagus (tube connecting the throat 
to the stomach) and trachea (windpipe) or surrounding structures 
• Development of an abnormal communication between the intestines and surrounding 
structures, including the urinary bladder 
• Decrease in thyroid function 
• Stroke 
• Mild nose bleeding 
• Abnormal taste in mouth 
• Dry or irritated eyes; vandetanib may also cause some visual changes or eye infections 
• Formation of clots, such as in the lung or in the legs 
• Lack of blood flow to heart (heart attack), brain (stroke), eye (blindness), legs, or bowel 
• Serious or life-threatening complications from rashes 
• Lung inflammation and stiffening, infections or fluid accumulation around the lungs 
• Blockage or penetration of the bowel or gall bladder duct 
 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:  15-C-0157 
CONTINUATION: page 10 of 17 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
RARE, AND SERIOUS 
For every 100 people receiving Vandetanib, 3 or fewer may have: 
• Heart failure which may cause shortness of breath, swelling of ankles, and tiredness 
• Stroke which may cause paralysis, weakness 
• Kidney stones 
• Life threatening problems resulting from abnormal heart rhythm 
• Detached retina 
 
Possible Side Effects of Metformin Hydrochloride  
 
COMMON, SOME MAY BE SERIOUS 
For every 100 people receiving Metformin Hydrochloride, more than 20 and up to 100 may 
have: 
• 
Diarrhea, nausea, vomiting 
 
OCCASIONAL, SOME MAY BE SERIOUS 
For every 100 people receiving Metformin Hydrochloride, from 4 to 20 may have: 
• 
Heartburn, passing gas 
• 
Headache 
• 
Tiredness 
 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:  15-C-0157 
CONTINUATION: page 11 of 17 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
RARE, AND SERIOUS 
In 100 people receiving Metformin Hydrochloride, 3 or fewer may have: 
• 
Lactic acid build up which may cause muscle aches, shortness of breath, or severe belly 
pain. If untreated this can lead to death 
 
Tumor Biopsy Risks 
The biopsy procedure usually causes only brief discomfort at the site from which the biopsy is 
taken.  Rarely, infection or bleeding may occur at the needle site. 
Research Radiation Risks 
This research study involves exposure to radiation from 1 FDG PET/CT scan of 10mCi of FDG 
on cycle 1 day 15 and up to 2 CT scans for CT guided biopsy.  This radiation exposure is not 
required for your medical care and is for research purposes only. From participating in this, the 
total amount of radiation you will receive is 2.4 rem which is below the guideline of 5.0 rem per 
year allowed for research subjects by the NIH Radiation Safety Committee.  The average person 
in the United States receives a radiation exposure of 0.3 rem per year from natural sources, such 
as the sun, outer space, and the earth's air and soil.  If you would like more information about 
radiation, please ask the investigator for a copy of the pamphlet, An Introduction to Radiation for 
NIH Research Subjects. 
While there is no direct evidence that the amount of exposure received from participating in this 
study is harmful, there is indirect evidence it may not be completely safe.  There may be a very 
slight increase in the risk of cancer. 
 Please tell your doctor if you have had any radiation exposure in the past year, either from other 
research studies or from medical tests or care, so we can make sure that you will not receive too 
much radiation. Radiation exposure includes x-rays taken in radiology departments, cardiac 
catheterization, and fluoroscopy as well as nuclear medicine scans in which radioactive materials 
were injected into your body.  
If you are pregnant you will not be permitted to participate in this research study. If you are 
breast feeding and the protocol involves injection of radioactive material, you will not be 
permitted to participate.  It is best to avoid radiation exposure to unborn or nursing infants since 
they are more sensitive to radiation than adults.  
 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:  15-C-0157 
CONTINUATION: page 12 of 17 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
Potential Benefits of Participation 
Are there benefits to taking part in this study?  
The aim of this study is to establish a safe dose for the combination of vandetanib and metformin 
and also to determine whether this experimental combination will cause your tumors to shrink.  
We do not know if you will receive personal, medical benefit from taking part in this study.  
These potential benefits could include shrinking of your tumor or lessening of your symptoms, 
such as pain, that are caused by the cancer.  Because there is not much information about the 
drug’s effect on your cancer, we do not know if you will benefit from taking part in this study, 
although the knowledge gained from this study may help others in the future who have cancer.   
Alternative Approaches or Treatments 
What other choices do I have if I do not take part in this study?  
Instead of being in this study, you have these options: 
• Getting treatment or care for your cancer without being in a study 
• Taking part in another study 
• Getting comfort care, also called palliative care.  This type of care helps reduce pain, 
tiredness, appetite problems and other problems caused by the cancer.  It does not treat 
the cancer directly.  Instead, it tries to improve how you feel.  Comfort care tries to keep 
you as active and comfortable as possible. 
Please talk to your doctor about these and other options. 
Stopping Therapy 
Your doctor may decide to stop your therapy for the following reasons: 
• if he/she believes that it is in your best interest 
• if your disease comes back during treatment 
• if you have side effects from the treatment that your doctor thinks are too severe 
• if new information shows that another treatment would be better for you 
In this case, you will be informed of the reason therapy is being stopped. 
 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:  15-C-0157 
CONTINUATION: page 13 of 17 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
You can stop taking part in the study at any time. However, if you decide to stop taking part in 
the study, we would like you to talk to the study doctor and your regular doctor first. 
 
If you decide at any time to withdraw your consent to participate in the trial, we will not collect 
any additional medical information about you. However, according to FDA guidelines, 
information collected on you up to that point may still be provided to Sanofi Genzyme or 
designated representatives. If you withdraw your consent and leave the trial, any samples of 
yours that have been obtained for the study and stored at the NCI can be destroyed upon request. 
However, any samples and data generated from the samples that have already been distributed to 
other researchers or placed in the research databases cannot be recalled and destroyed. 
Research Subject’s Rights 
What are the costs of taking part in this study?  
If you choose to take part in the study, the following will apply, in keeping with the NIH policy: 
• 
You will receive study treatment at no charge to you. This may include 
surgery, medicines, laboratory testing, x-rays or scans done at the 
Clinical Center, National Institutes of Health (NIH), or arranged for you 
by the research team to be done outside the Clinical Center, NIH if the 
study related treatment is not available at the NIH.  
• 
There are limited funds available to cover the cost of some tests and 
procedures performed outside the Clinical Center, NIH.  You may have 
to pay for these costs if they are not covered by your insurance company. 
• 
Medicines that are not part of the study treatment will not be provided or  
• 
paid for by the Clinical Center, NIH. 
• 
Once you have completed taking part in the study, medical care will no 
longer be provided by the Clinical Center, NIH. 
Will your medical information be kept private?  
We will do our best to make sure that the personal information in your medical record will be 
kept private.  However, we cannot guarantee total privacy.  Organizations that may look at 
and/or copy your medical records for research, quality assurance, and data analysis include: 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:  15-C-0157 
CONTINUATION: page 14 of 17 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
• The National Cancer Institute (NCI) and other government agencies, like the Food and 
Drug Administration (FDA), which are involved in keeping research safe for people. 
• National Cancer Institute Institutional Review Board 
• Qualified representatives from Sanofi Genzyme, the pharmaceutical company that 
produces vandetanib. 
A description of this clinical trial will be available on http://www.Clinicaltrials.gov, as 
required by U.S. Law.  This Web site will not include information that can identify you.  At 
most the Web site will include a summary of the results.  You can search this Web site at any 
time. 
Certificate of Confidentiality  
To help us protect your privacy, we have obtained a Certificate of Confidentiality. The 
researchers can use this Certificate to legally refuse to disclose information that may identify you 
in any federal, state, or local civil, criminal, administrative, legislative, or other proceedings, for 
example, if there is a court subpoena. The researchers will use the Certificate to resist any 
demands for information that would identify you, except as explained below. 
You should also know that there are several circumstances in which the Certificate does not 
provide coverage. These include when information:  
• will be used for auditing or program evaluation internally by the NIH; or  
• must be disclosed to meet the legal requirements of the federal Food and Drug 
Administration (FDA).  
• is necessary for your medical treatment and you have consented to this disclosure;  
• is for other research.  
In addition, identifiable, sensitive information protected by this Certificate cannot be admissible 
as evidence or used for any purpose in any action, suit, or proceeding without your consent.  
You should understand that a Certificate of Confidentiality does not prevent you or a member of 
your family from voluntarily releasing information about yourself or your involvement in this 
research. If an insurer, employer, or other person obtains your written consent to receive research 
information, then the researchers will not use the Certificate to withhold that information. 
 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:  15-C-0157 
CONTINUATION: page 15 of 17 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
The Certificate of Confidentiality will not protect against the required reporting by hospital staff 
of information on suspected child abuse, reportable communicable diseases, and/or possible 
threat of harm to self or others. 
Conflict of Interest 
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts 
of interest.  This process is detailed in a Protocol Review Guide.  You may ask your research 
team for a copy of the Protocol Review Guide or for more information.  Members of the research 
team who do not work for NIH are expected to follow these guidelines but they do not need to 
report their personal finances to the NIH. 
 
Members of the research team working on this study may have up to $15,000 of stock in the 
companies that make products used in this study.  This is allowed under federal rules and is not a 
conflict of interest.  
The National Institutes of Health and the research team for this study are using vandetanib 
developed by Sanofi Genzyme, through a joint study with your researchers and the company.   
The company also provides financial support for this study. 
Use of Specimens and Data for Future Research 
To advance science, it is helpful for researchers to share information they get from studying 
human samples.  They do this by putting it into one or more scientific databases, where it is 
stored along with information from other studies. A researcher who wants to study the 
information must apply to the database and be approved.  Researchers use specimens and data 
stored in scientific databases to advance science and learn about health and disease.   
We plan to keep some of your specimens and data that we collect and use them for future 
research and share them with other researchers. We will not contact you to ask about each of 
these future uses.  These specimens and data will be stripped of identifiers such as name, address 
or account number, so that they may be used for future research on any topic and shared broadly 
for research purposes. Your specimens and data will be used for research purposes only and will 
not benefit you.  It is also possible that the stored specimens and data may never be used.  
Results of research done on your specimens and data will not be available to you or your doctor.  
It might help people who have cancer and other diseases in the future.   
If you do not want your stored specimens and data used for future research, please contact us in 
writing and let us know that you do not want us to use your specimens and/or data.  Then any 
specimens that have not already been used or shared will be destroyed and your data will not be 
used for future research. However, it may not be possible to withdraw or delete materials or data 
once they have been shared with other researchers. 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
STUDY NUMBER:  15-C-0157 
CONTINUATION: page 16 of 17 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH 
STUDY (Continuation Sheet) 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
OTHER PERTINENT INFORMATION 
1. 
Confidentiality.  When results of an NIH research study are reported in medical journals 
or at scientific meetings, the people who take part are not named and identified.  In most cases, 
the NIH will not release any information about your research involvement without your written 
permission.  However, if you sign a release of information form, for example, for an insurance 
company, the NIH will give the insurance company information from your medical record.  This 
information might affect (either favorably or unfavorably) the willingness of the insurance 
company to sell you insurance. 
The Federal Privacy Act protects the confidentiality of your NIH medical records.  However, you 
should know that the Act allows release of some information from your medical record without 
your permission, for example, if it is required by the Food and Drug Administration (FDA), 
members of Congress, law enforcement officials, or authorized hospital accreditation 
organizations. 
2. 
Policy Regarding Research-Related Injuries.  The Clinical Center will provide short-
term medical care for any injury resulting from your participation in research here.  In general, 
no long-term medical care or financial compensation for research-related injuries will be 
provided by the National Institutes of Health, the Clinical Center, or the Federal Government.  
However, you have the right to pursue legal remedy if you believe that your injury justifies such 
action. 
3. 
Payments.  The amount of payment to research volunteers is guided by the National 
Institutes of Health policies.  In general, patients are not paid for taking part in research studies at 
the National Institutes of Health.  Reimbursement of travel and subsistence will be offered 
consistent with NIH guidelines. 
4. 
Problems or Questions.  If you have any problems or questions about this study, or 
about your rights as a research participant, or about any research-related injury, contact the 
Principal Investigator, Ramaprasad Srinivasan, M.D., Building 10, Room 2-5950, Telephone:  
240-760-6251. You may also call the Clinical Center Patient Representative at 301-496-2626. If 
you have any questions about the use of your specimens or data for future research studies, you 
may also contact the Office of the Clinical Director, Telephone: 240-760-6070.  
5. 
Consent Document.  Please keep a copy of this document in case you want to read it 
again. 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
STUDY NUMBER:  15-C-0157 
CONTINUATION: page 17 of 17 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH 
STUDY (Continuation Sheet) 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
 
COMPLETE APPROPRIATE ITEM(S) BELOW: 
A. Adult Patient’s Consent 
B. Parent’s Permission for Minor Patient. 
I have read the explanation about this study 
and have been given the opportunity to discuss 
it and to ask questions.  I hereby consent to 
take part in this study. 
I have read the explanation about this study 
and have been given the opportunity to discuss 
it and to ask questions.  I hereby give 
permission for my child to take part in this 
study.   
(Attach NIH 2514-2, Minor’s Assent, if 
applicable.) 
 
  
  
 
 
 
Signature of Adult Patient/ 
Legal Representative 
Date 
Signature of Parent(s)/ Guardian Date 
 
 
Print Name 
 
 
Print Name 
C. Child’s Verbal Assent (If Applicable) 
The information in the above consent was described to my child and my child agrees to 
participate in the study. 
 
  
  
 
Signature of Parent(s)/Guardian 
Date 
Print Name 
THIS CONSENT DOCUMENT HAS BEEN APPROVED FOR USE  
FROM APRIL 24, 2017 THROUGH APRIL 23, 2018.  
 
 
 
 
 
 
 
 
Signature of Investigator 
Date 
Signature of Witness 
Date 
 
 
Print Name 
 
 
Print Name 
 

Prot_SAP_000.pdf: 
1 
Abbreviated Title: Vandetanib/Metformin in RCC 
Version Date: 05/01/2018 
 
Abbreviated Title: Vandetanib/Metformin in RCC 
CC Protocol Number: 15-C-0157 C 
NCT# NCT02495103 
Version Date: May 1, 2018 
 
Title: Phase I/II Trial of Vandetanib in Combination with Metformin in Subjects with HLRCC 
or SDH-Associated Kidney Cancer or Sporadic Papillary Renal Cell Carcinoma 
 
NCI Principal Investigator:   
Ramaprasad Srinivasan, M.D., Ph.D. 
Head, Molecular Cancer Section 
UOB, CCR, NCI 
10 Center Drive, Room 10/2-5950 
Tel: 240-760-6251 
 
 
 
 
 
Email: ramasrin@mail.nih.gov 
 
 
Investigational Agents:  
 
None 
 
 
Commercial Agents:   
x Vandetanib will be supplied by the manufacturer, 
Sanofi Genzyme 
x 
Metformin will be purchased from commercial sources 
by the NIH CC Pharmacy 


2 
Abbreviated Title: Vandetanib/Metformin in RCC 
Version Date: 05/01/2018 
 
PRÉCIS 
Background: 
x 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. 
x 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-D 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.   
x 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. 
x 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.  
x 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.   
Objectives: 
Phase I Component: 
x Establish the safety and maximum tolerated dose of the combination of vandetanib with 
metformin in patients with advanced RCC. 
Phase II Component: 
x Determine the overall response rate (RECIST 1.1) following treatment with combined 
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: 
x Diagnosis of advanced RCC 
x 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 
x No prior therapy is required in patients with non-clear cell RCC, but prior therapy is 
allowed 


3 
Abbreviated Title: Vandetanib/Metformin in RCC 
Version Date: 05/01/2018 
 
Phase II Component: 
x Diagnosis of advanced RCC associated with HLRCC or SDH-RCC (cohort 1) or 
sporadic/non-HLRCC papillary RCC (cohort 2) 
x No more than 2 prior regimens with VEGF-pathway antagonists 
 
General requirements for both Phase I and II: 
x Age ≥18 
x 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 
x No major surgery within four weeks or inadequately healed wounds prior to study 
enrollment 
x Adequate organ function 
Design: 
Phase I Component: 
x Combination vandetanib and metformin will be administered at starting doses of 300 mg 
QD and 250 mg BID, respectively. 
x The study design is based on a single arm, fixed order dose-escalation Phase 1 study using 
a modified Fibonacci schema.   
x 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: 
x Once the MTD is determined, the appropriate combination dose will be evaluated in the 
phase 2 component.   
x Patients will be accrued into one of two independent, parallel cohorts: 
o Cohort 1 – Patients with advanced HLRCC or SDH associated RCC. 
o Cohort 2 – Patients with advanced sporadic/non-HLRCC papillary kidney cancer. 
x Patients will be evaluated for response every 8-12 weeks using RECIST 1.1. 
x The study is based on open label two-stage optimal phase II design. 
x The accrual ceiling for this portion of the study will be 21 patients for each cohort.  
 
 
 


4 
Abbreviated Title: Vandetanib/Metformin in RCC 
Version Date: 05/01/2018 
 
TABLE OF CONTENTS  
PRÉCIS ............................................................................................................................................2 
TABLE OF CONTENTS .................................................................................................................4 
1 INTRODUCTION .....................................................................................................................7 
1.1 
Study Objectives ...............................................................................................................7 
1.2 
Background and Rationale ................................................................................................7 
2 ELIGIBILITY ASSESSMENT AND ENROLLMENT ..........................................................30 
2.1 
Eligibility Criteria ...........................................................................................................30 
2.2 
Screening Evaluation ......................................................................................................32 
2.3 
Recruitment Strategies ....................................................................................................33 
2.4 
Registration Procedures ..................................................................................................33 
2.5 
Treatment Assignment Procedures .................................................................................33 
3 STUDY IMPLEMENTATION ...............................................................................................33 
3.1 
Study Design ...................................................................................................................33 
3.2 
Drug Administration .......................................................................................................38 
3.3 
Treatment Modifications.................................................................................................39 
3.4 
Study Evaluation .............................................................................................................46 
3.5 
Study Calendar ................................................................................................................49 
3.6 
Follow up evaluations .....................................................................................................54 
3.7 
Criteria for Removal from Protocol Therapy and Off Study Criteria.............................54 
4 CONCOMITTANT MEDICATION .......................................................................................55 
4.1 
Concurrent and Excluded Therapies ...............................................................................55 
4.2 
Supportive Care ..............................................................................................................56 
5 BIOSPECIMEN COLLECTION .............................................................................................56 
5.1 
Correlative Studies for Research ....................................................................................56 
5.2 
Pharmacokinetic/Pharmacogenetic Studies ....................................................................58 
6 DATA COLLECTION AND EVALUATION ........................................................................61 
6.1 
Data Collection ...............................................................................................................61 
6.2 
Response Criteria ............................................................................................................62 
6.3 
Toxicity Criteria ..............................................................................................................68 
7 SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN
..................................................................................................................................................68 
7.1 
Definitions ......................................................................................................................68 
7.2 
Relatedness of Adverse Event to an Intervention ...........................................................70 


5 
Abbreviated Title: Vandetanib/Metformin in RCC 
Version Date: 05/01/2018 
 
7.3 
NCI IRB and Clinical Director (CD) Reporting .............................................................71 
7.4 
Safety Reporting Criteria to the Pharmaceutical Collaborators......................................71 
7.5 
Data and Safety Monitoring Plan....................................................................................72 
8 STATISTICAL CONSIDERATIONS.....................................................................................72 
8.1 
Phase I Component .........................................................................................................72 
8.2 
Phase II Component ........................................................................................................73 
8.3 
Accrual Ceiling ...............................................................................................................74 
9 COLLABORATIVE AGREEMENTS ....................................................................................74 
9.1 
Cooperative Research and Development Agreement (CRADA) ...................................74 
10 HUMAN SUBJECTS PROTECTIONS ..................................................................................75 
10.1 Rationale For Subject Selection ......................................................................................75 
10.2 Participation of Subjects Unable to Give Consent..........................................................75 
10.3 Evaluation of Benefits and Risks/Discomforts ...............................................................76 
10.4 Alternative Treatments ...................................................................................................76 
10.5 Consent Processes and Documentation ..........................................................................76 
11 PHARMACEUTICAL INFORMATION ................................................................................77 
11.1 Vandetanib ......................................................................................................................77 
11.2 Metformin .......................................................................................................................78 
12 REFERENCES ........................................................................................................................80 
13 APPENDIX A: PERFORMANCE STATUS CRITERIA .......................................................84 
14 APPENDIX B: NEW YORK HEART ASSOCIATION (NYHA) CARDIAC 
CLASSIFICATION .................................................................................................................85 
15 APPENDIX C: MEDICATIONS KNOWN TO PROLONG THE QT INTERVAL 
AND/OR INDUCE TORSADES DE POINTES (TDP) .........................................................86 
15.1 Group 1: Drugs that are generally accepted by authorities to have a risk of causing 
Torsades de Pointes ........................................................................................................86 
15.2 Group 2: Drugs that in some reports may be associated with Torsades de Pointes but 
at this time lack substantial evidence of causing Torsades de Pointes. ..........................88 
16 APPENDIX D: PATIENT DRUG AND SIDE EFFECTS DIARY ........................................91 
16.1 Lead in Cycle ..................................................................................................................91 
16.2 All Other Cycles .............................................................................................................92 
17 APPENDIX E: PATIENT INSTRUCTIONS FOR METFORMIN / VANDETANIB...........96 
18 APPENDIX F: BLOOD PRESSURE MONITORING FORM ...............................................97 
18.1 Lead in Cycle ..................................................................................................................97 


6 
Abbreviated Title: Vandetanib/Metformin in RCC 
Version Date: 05/01/2018 
 
18.2 All Other Cycles .............................................................................................................98 
 
 


7 
Abbreviated Title: Vandetanib/Metformin in RCC 
Version Date: 05/01/2018 
 
1 
INTRODUCTION 
1.1 
STUDY OBJECTIVES 
1.1.1 Primary Objective 
x Phase 1 Component: To establish the safety and maximum tolerated dose (MTD) of 
vandetanib and metformin when used in combination in patients with metastatic RCC. 
x Phase 2 Component: To determine the overall response rate (RECIST 1.1) following 
treatment with the combination of vandetanib and metformin in patients with 1) advanced 
RCC associated with HLRCC or SDH, and 2) advanced sporadic/non-HLRCC papillary 
RCC. 
1.1.2 Secondary Objectives 
x Phase 1 Component 
x To evaluate the clinical activity of the combination of vandetanib and metformin. 
x To evaluate modulation of the biochemical and metabolic phenotype following 
therapy using paired pre- and on-treatment tumor biopsies (when available). 
x To identify drug interaction between metformin and vandetanib at clinically-
relevant doses. 
x Phase 2 Component 
x To assess duration of response, progression-free survival and overall survival with 
this combination. 
x To investigate the effect of vandetanib/metformin on potential biomarkers of 
angiogenesis in plasma such as VEGF and soluble VEGFR2. 
x To evaluate modulation of the biochemical and metabolic phenotype following 
therapy using paired pre- and on-treatment tumor biopsies (when available). 
x To evaluate the prevalence of somatic fumarate hydratase (FH) and succinate 
dehydrogenase (SDH) mutations/inactivation as well as activation of/mutations in 
the NRF2/KEAP1/CUL3 pathway in patients with sporadic papillary RCC and to 
determine if there is a correlation between the presence of a mutation and response. 
 
1.2 
BACKGROUND AND RATIONALE 
In 2013, kidney cancer was ranked the sixth and eight most common malignancy among American 
men and women, respectively, with an estimated 65,150 new cases and 13,680 deaths (1).  While 
surgical treatment for localized disease can be curative, the outlook for patients with metastatic 
disease remains poor.  With increased understanding of the molecular pathways involved in the 
pathogenesis of RCC, several new systemic agents are available for use in metastatic disease, 
largely for patients with clear cell RCC.  Unfortunately, with the exception of high dose 
interleukin-2, these therapies are not curative and seldom lead to long-term durable responses. 
Several subtypes of RCC have been defined according to their histologic appearance, including 
clear-cell (the most common histologic subtype), papillary, chromophobe, and other less 
frequently encountered subtypes.  Individual subtypes of RCC are characterized by distinct genetic 
alterations and metabolic properties, which can potentially predict targets for therapeutic 


8 
Abbreviated Title: Vandetanib/Metformin in RCC 
Version Date: 05/01/2018 
 
intervention.  Recent work has shown that alterations in the critical metabolic pathways of a cell, 
including those involved in oxygen, nutrient, and energy sensing/utilization are a common theme 
in most subtypes of RCC.   
Glycolysis is a multistep process whereby glucose is converted to pyruvate, a key substrate for the 
mitochondrial Krebs cycle.  Through a multi-enzymatic process, the Krebs cycle produces ATP 
and NADPH.  When oxygen availability is limited, ATP is produced (albeit less efficiently) by the 
conversion of pyruvate into lactate.  In the early 20th century, Dr. Otto Warburg noted that in 
comparison to normal cells, cancer cells consumed large amounts of glucose and produced lactate 
even in the presence of oxygen.  This phenomenon is referred to as the “Warburg effect” and is 
thought to result from dysfunctional mitochondria and impaired oxidative phosphorylation, 
leaving affected cells dependent on ATP generated during the conversion of pyruvate to lactate.  
The term “aerobic glycolysis” was coined because this process occurred in an oxygen-rich 
environment.  The role of aerobic glycolysis as the exclusive source of ATP in cancer remains a 
source of debate.  Most cancers appear to have a functioning oxidative phosphorylation pathway, 
while also utilizing aerobic glycolysis to some extent.  Our group and others have characterized 
RCC variants with defects in the Krebs cycle that render these cells reliant on glycolysis for their 
energy requirements (2).   
1.2.1 HLRCC and Papillary RCC 
Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) is a familial syndrome in which 
affected individuals are at increased risk for the development of papillary renal cell cancer, as well 
as cutaneous and uterine leiomyomas.  Linkage analysis studies have led to the identification of 
germline mutations in the Krebs’ cycle enzyme fumarate hydratase (FH) as the genetic event 
underlying this inherited syndrome (3, 4). 
Although kidney cancer occurs less frequently than leiomyomas (approximately one third of 
patients with HLRCC seen at the National Cancer Institute had kidney cancer), it is usually 
associated with an aggressive clinical course and poor outcome. Unlike other well described 
hereditary renal cancer syndromes where multiple bilateral renal tumors are the norm (i.e. von 
Hippel Lindau disease), most HLRCC patients tend to have solitary renal lesions; however, 
bilateral, multifocal lesions have been described in some patients.  
Renal cell cancer associated with HLRCC is characterized by distinct histopathologic features and 
clinical course.  The tumors tend to metastasize early with a predilection for regional and distant 
lymph nodes, liver, and bone.  There are currently no standard treatment options available for 
patients with advanced or unresectable disease, with the majority of these patients dying due to 
metastatic disease.  In the past, HLRCC-associated renal tumors have been histologically described 
as resembling papillary type II or collecting duct tumors.  In a recent report, Merino et al. have 
described the distinctive histopathologic features of HLRCC-associated renal tumors based on a 
review of forty tumors (5).  These tumors have characteristic large orangiophilic nuclei and a clear 
perinuclear halo, with a variety of architectural patterns such as papillary, tubulo-papillary, tubular, 
solid or mixed.   
There is currently no well described sporadic counterpart to HLRCC-associated kidney cancer and 
no conclusive evidence that somatic FH mutations play a significant role in sporadic kidney cancer 
tumorigenesis.  However, we (investigators in the UOB/NCI) have evaluated several patients with 
papillary histology whose tumors histologically resemble that of HLRCC-associated renal cancer, 


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with no accompanying family history, germline FH mutation, or other sequelae of this syndrome.  
Most pathologists currently offer vague descriptions of these tumors, often characterizing them as 
papillary type 2 RCC or collecting duct tumors.  Evaluation of these non-familial cases of papillary 
RCC variants for evidence of somatic inactivation of FH is ongoing. 
1.2.2 Genetic and Biochemical Basis of Renal Oncogenesis in HLRCC 
Patients with HLRCC have a germline mutation in FH, localized to the long arm of chromosome 
1 (1q42.3-q43).  The gene responsible for HLRCC was identified through linkage analysis, and 
encodes FH, a Krebs cycle enzyme.  In addition to the germline loss/mutation of one FH allele, 
functional inactivation of the remaining copy of FH has also been found in most HLRCC 
associated renal tumors, cutaneous leiomyomas, and uterine leiomyomas. Correspondingly, 
tumors in HLRCC patients have been found to have extremely low or absent FH enzymatic 
activity. Thus, the FH gene appears to act as a tumor suppressor gene, following Knudson’s “two 
hit” model of carcinogenesis.  Germline mutations are generally due to missense, frameshift, 
nonsense, or splice site mutations, and are distributed throughout the gene. 
Our group has developed the first cell line from an HLRCC-associated kidney cancer (UOK262) 
and has demonstrated that there is a three-step process involved in renal oncogenesis in FH -/- 
kidney cancer. 
Step 1: Metabolic Shift to Aerobic Glycolysis 
When FH is inactivated, the respiratory capacity of the Krebs cycle/electron transport chain is 
severely compromised.  The cell is unable to generate ATP by oxidative phosphorylation, resulting 
in a dramatic increase in glucose transport and glycolysis to sustain ATP production.  The main 
source of ATP for the FH -/- deficient kidney cancer cell is glycolysis (Figure 1); almost all of the 
glucose that enters the cell is used to generate ATP via glycolysis and very little goes to the Krebs 
cycle (6).   
 
OCR pMoles/min/1.5x104 cells)
Time (min)
UOK262EV
UOK262WT
HK-2
Oxygen Consumption Rate (OCR)
 
ECAR (mpH/min/1.5x104 cells)
Time (min)
UOK262EV
UOK262WT
HK-2
Extra-Cellular Acidification Rate (ECAR)
 
Figure 1:  Oxygen consumption is very low in UOK262 versus UOK262WT or control cells (left 
panel).  Extra-cellular acidification (a surrogate for lactate production, i.e., glycolosis) is significantly 
increased in the HLRCC FH-deficient UOK262 kidney cancer cell line (right panel). 
 
HLRCC-associated fumarate hydratase deficient kidney cancer is the prototypic example of the 
Warburg effect in cancer; i.e., a cancer that has undergone a metabolic shift to aerobic glycolysis.   


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Step 2: Inhibition of prolyl hydroxylase leads to an increase in hypoxia inducible factor 1α 
(HIF1α) 
One consequence of FH inactivation is an increase in cellular levels of its substrate, fumarate (7).  
Increased fumarate inhibits prolyl hydroxylase, which leads to an increase in HIF1α (
 
Figure 2).  Increased intracellular levels of HIF1α result in transcriptional upregulation of VEGF 
levels (promoting tumor vasculature/neoangiogenesis) and GLUT1 and GLUT4, which increase 
glucose uptake for this glucose-dependent tumor. This fact is supported by the demonstration by 
Pollard et al. (by immunochemistry and immunoblotting) that there was strong hypoxia inducible 
factor-1 (HIF-1) expression in kidney tumors from HLRCC patients (8).  Similarly, Isaacs et al. 
demonstrated increased expression of both HIF-1  and HIF-2  in renal tumors from patients with 
HLRCC compared to normal, matched renal tissue from the same patient (9).  In addition, there is 
also evidence of increased expression of downstream tumorigenic and pro-angiogenic 
transcriptional targets of HIF.  For instance, the observed increase in microvessel density 
correlated with an increase in expression of VEGF mRNA.  Furthermore, increased microvessel 
density is seen in leiomyomas from HLRCC patients, when compared to matched normal 
myometrium (8). 
 
Figure 2. In HLRCC FH-deficient kidney cancer, fumarate is increased and the increased fumarate inhibits prolyl 


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hydroxylase, which results in HIF accumulation and increased VEGF and GLUT1 and GLUT4 in the tumor. (2010 
Nature Rev Urol) 
Step 3: Increased ATP production by glycolysis decreases AMPK, which, in turn, increases fatty 
acid synthesis and stimulates mTOR. 
We have recently shown that the increased ATP production by glycolysis in fumarate hydratase-
deficient kidney cancer causes a decrease in the both the levels of and phosphorylation of the 
primary energy sensing complex in the cell, AMPK.  Decreased AMPK, in turn, activates the 
mTOR pathway and fatty acid synthesis (Figure 3) (10).  This metabolic shift in FH -/- kidney 
cancer results in an extremely aggressive kidney cancer phenotype. 
 
 
Figure 3.The increased ATP production by increase glycolysis in the glucose-dependent HLRCC FH-/- kidney cancer 
cells decreases AMPK, activates mTOR, increases fatty acid production and further stabilizes increased levels of 
HIF1α. 
Succinate Dehydrogenase Renal Carcinoma (SDH-RCC) 
Succinate Dehydrogenase Renal Carcinoma (SDH-RCC) is a syndrome related to hereditary 
paraganglioma (PGL) in which patients are at risk for the development of pheochromocytoma, 
paraganglioma, and kidney cancer. SHD-RCC is characterized by germline mutation of the Krebs 
cycle enzyme succinate dehydrogenase.  The SDH enzyme is an inner mitochondrial membrane 
enzyme critical to the Krebs cycle and the electron transport chain.  This enzyme is made up of 
four subunits (SDHA, SDHB, SDHC, and SDHD) and catalyzes the oxidation of succinate to 
fumarate.  Germline mutations of SHDB, SDHC and SDHD have been found in SDH-RCC 
families (11, 12). The SDH complex catalyzes the oxidation of succinate to fumarate in the Krebs 
cycle and serves as complex II in the electron transport chain. We have found that renal tumors 
associated with this syndrome demonstrate impaired oxidative phosphorylation with reliance on 
aerobic glycolysis, and are clinically aggressive, as is the case with HLRCC-associated tumors. 
Tumors associated with SDHB have a distinct morphology with cuboidal cells having “bubbly, 
eosinophilic cytoplasm” with indistinct cell borders. Our experience is that the biologic basis for 
The Glycolytic Shift in FH-Deficient Kidney Cancer
Lowers AMPK and Increases Anapleurotic Growth
TCA Cycle
AMPK Activity
ACC Activity
S6 Activity
p53
Glycolys is
DMT1
Cytosolic Fe
IRP1 Activity
Repression of
HIF-2α Translation
HIF2- α
IRP
HIF1- α
Accumulation
HIF1- α
PHD
Fumarate
FH
Stabilization of HIF-1α Protein
HIF-1α Protein
HIF-2α Protein
Cancer Cell 20:2011


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genesis of RCC in these patients is similar to that seen with HLRCC.  We have shown that SDH-
deficient kidney cancer is characterized by aerobic glycolysis; i.e., the UOK269 SDH-deficient 
kidney cancer cell line is characterized by very low respiration and significantly increased 
glycolysis (Rouault et al., personal communication, manuscript in preparation).  We hypothesize 
that both types of kidney cancer might be susceptible to similar therapeutic interventions. 
 
1.2.3 Vandetanib 
 
Vandetanib (ZD6474) is an orally administered receptor tyrosine kinase inhibitor with potent 
activity against VEGFR2 as well as activity against EGFR (13, 14).  This agent is an FDA-
approved (2011) for the treatment of symptomatic or progressive medullary thyroid cancer in 
patients with unresectable locally advanced or metastatic disease. 
Murine preclinical human xenograft models have demonstrated activity of vandetanib against a 
variety of tumors including those arising in the lung, prostate, ovary, breast and colon.  Reductions 
in tumor blood flow, vascular density and vascular permeability have been seen in a mouse 
xenograft model, suggesting inhibition of the VEGF pathway by the drug (15).  The following is 
a summary of pre-clinical and clinical studies with vandetanib: 
In vitro studies  
In isolated enzyme assays, vandetanib was found to be a potent inhibitor of KDR tyrosine kinase 
activity (IC50=40nM), with additional activity against Flt-4 (IC50=110nM) and EGFR (IC50= 
500nM).  Less potent activity was seen against a range of other tyrosine kinases including PDGFR, 
Tie-2, FGFR1, MEK, CDK2, c-kit, ErbB2, FAK, PDK-1, AKT and IGF-1R, with IC50 ranging 
from 1μM to >200μM (14).  
Vandetanib inhibited the proliferation of both VEGF-stimulated and EGF-stimulated human 
endothelial cell lines (HUVEC), while basal HUVEC proliferation was not significantly affected 
(16).  When co-cultured with human fibroblasts, endothelial tube formation by HUVEC cells was 
inhibited at similar concentrations of vandetanib.  Direct inhibition of tumor growth was 
demonstrated against established lung, colon, ovarian, breast, and prostate cancer cell lines, but 
only at higher concentrations, with IC50s in the 0.6 to 13.5 μM range.  
The effect of vandetanib on cardiovascular function has been investigated in vitro using the human 
ether-a-go-go gene assay as well as by assessment of action potential parameters recorded from 
canine Purkinje fibers. A concentration dependent increase in action potential duration was seen 
in these assays. The parent compound as well as the N-oxide and N-desmethyl metabolites were 
active in the above assays.  
Pre-clinical studies (15) 
Pharmacokinetic Studies and metabolism  
Pharmacokinetic studies were performed in rats and dogs. In both species, >50% of the drug was 
absorbed when administered orally.  Time to peak plasma concentration was 3-8 hours. Plasma 
clearance was rapid and was greater in male than in female rats.  The drug was rapidly and 
extensively distributed with apparent volumes of distribution of approximately 30L/kg in both 
male and female rats.  The highest concentrations were found in the GI tract, liver, adrenal glands, 
Harderian glands, pituitary, spleen and pigmented tissue.  Delayed clearance from adrenal, kidney 


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and testes was observed.  The terminal half-life was estimated at 16 hours in male and 31 hours in 
female rats, and at 8.27 hours in dogs.  The drug is eliminated both by biliary excretion and in 
urine.  Two metabolites have been identified in samples from rats and dogs- the N-oxide of 
vandetanib and the N-desmethyl of vandetanib.  The drug underwent minimal metabolism in rat 
and dog hepatocytes and no metabolism in human hepatocytes or human microsomes.  No 
inhibitory effects on the activity of human P450 isoenzymes CYP1A2, 2C9, 2C19 or 3A4 were 
observed but the drug inhibited activity of CY 2D6.  Plasma protein binding ranged from 83% in 
the rat to 90% in human.  Vandetanib was found to bind both human serum albumin and alpha-1-
glycoprotein.  
Toxicology  
Single oral doses of 2000mg/kg in mice and rats were not tolerated. A single oral dose of 
1000mg/kg was tolerated in rats and produced premature death in 1/10 mice. A single IV dose of 
50mg/kg induced early death in 1/10 mice. The following organ-specific toxicities were seen in 
multiple-dose studies: 
x Dose-related dysplasia of the epiphyseal growth plates of the femoro-tibial joint was 
seen in rats receiving 25-75mg/kg/day and in dogs dosed at 40mg/kg/day by one month.  
x Elevated ALT, AST and LDH as well as histopathologic changes consistent with 
hepatocellular necrosis and acute cholangitis were seen in the one-month rat study at a 
dose of 75mg/kg/day. 
x Gastro-intestinal toxicity in the form of emesis, diarrhea and weight loss was observed 
in the 1 and 9-month dog studies. No accompanying histopathologic changes were 
noted, and the toxicity was reversible on cessation of drug use. 
x Renal papillary necrosis was seen in the rat 1-month study at doses of 25-75mg/kg/day. 
x Decreased numbers of corpora lutea, increased post-implantation loss, embryo/fetal 
loss, delayed fetal development, heart vessel abnormalities, and precocious ossification 
of skull bones reflect the range of reproductive and embryo/fetal toxicity observed in 
rats. 
x Reversible 
histopathologic 
and 
ultrastructural 
changes 
consistent 
with 
phospholipidosis was seen in the rat 1-month and 6-month studies, but were not 
observed in the dog studies. 
x Reversible, dose-related acute folliculitis and epidermal microabscess formation in the 
muzzle region of skin was noted in both the 1-month and 6-month rat toxicity studies. 
x In dog studies, following single oral doses of 5, 15, or 40mg/kg, an increase in heart 
rate 75-360 minutes following the largest dose was observed. In the dose range studies, 
no clear effects on blood pressure, PR interval, QRS duration, RR interval, QT interval, 
waveform or rhythm were seen  
Biologic effects and efficacy against tumors  
The following effects consistent with VEGF inhibition were seen in animal studies: 
x When administered at a dose of 50mg/kg to Alderley Park rats, vandetanib inhibited 
the hypotension normally induced by administration of bolus VEGF. 


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x Dose-dependent increases in the hypertrophic chondrocyte zone of the epiphyseal 
growth plates of growing rats were seen. 
x Vandetanib inhibited tumor-associated angiogenesis in athymic mice intradermally 
implanted with A549 lung cancer cells. 
x Vandetanib inhibited tumor vascular flow, volume and permeability as assessed by K 
trans measurements in established PC-3 prostate tumor xenografts using dynamic 
contrast-enhanced MRI  
x In human tumor xenograft models (lung, prostate, ovary, breast, vulval, colon), 
vandetanib inhibited the growth of established subcutaneous tumors in mice. 
x Tumor regression by vandetanib was observed in established PC-3 prostate tumor 
xenografts, but not in a Calu-6 (lung) tumor xenograft model.  
x In murine spontaneously metastatic tumor models (melanoma and RCC), 
administration of vandetanib reduced both primary tumor growth and the incidence of 
pulmonary metastases.  
x Anti-tumor effects of vandetanib were also identified in a human colon tumor xenograft 
in athymic rats and in two syngeneic tumor models (melanoma, lung) in 
immunocompetent mice.  
x Inhibition of angiogenesis as evidenced by changes in microvascular architecture was 
seen in a murine orthotopically implanted renal cell cancer model.  
Human Studies 
Phase I Studies 
Several phase I trials have been conducted in human subjects. Trial 6474IL/0001 (Western study) 
was conducted as a multicenter, dose escalation phase I trial evaluating vandetanib at 50, 100, 200, 
300, 500 and 600mg doses administered orally as a daily single dose.  A total of 77 patients have 
been treated on this trial at various dose levels, including an expanded cohort of 19 and 25 patients 
at the 100mg and 300mg dose levels, respectively, who were enrolled to better evaluate the effect 
of vandetanib on QT interval and ST, T wave changes.  This study helped establish 300 mg/day as 
the MTD (17).  A second phase I trial of 18 patients conducted in Japan (TVE-15-11) followed a 
dose escalation pattern evaluating 100, 200, 300 and 400mg daily oral doses.  The data from this 
study suggested that 400 mg/day dose likely exceeded the MTD (18).   
Pharmacokinetics 
Pharmacokinetic data obtained from the Western and Japanese studies were comparable.  
Absorption was highly variable, with individual patients having a Tmax as late as 24 hours post-
dose.  Following achievement of maximum plasma concentration, Cmax declined in a biphasic 
manner.  Terminal half-life was estimated to be about 4-5 days and appeared to be independent of 
dose.  Both mean AUC and Cmax increased with increasing dose in a linear manner with about 2 
to 6 fold in inter-individual variability in AUC for a given dose.  A comparison of the mean weekly 
trough levels suggest that steady state was achieved by day 29, with marked accumulation between 
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Adverse Events  
The most common adverse events seen on both trials were:  
x Rash- At least 2 distinct types of rash were seen – A macular erythema and a follicular 
(acneiform) rash.  Rash was reported in 54 (72%) patients in the Western and 14 
(77.8%) patients in the Japanese study.  The occurrence of rash appeared to be dose-
dependent.  
x Gastrointestinal toxicity – Diarrhea was reported in 42 (56%) of the Western patients 
and 10 (56%) of the Japanese patients.  Other common GI side effects seen the western 
and Japanese studies included nausea (39% in the Western and 22% in the Japanese 
studies), vomiting (22% and 17% respectively), anorexia (29% and 28% respectively) 
and constipation (24% in the Western study).  
x Central nervous system – Headaches were reported by 19 (25%) patients and dizziness 
by 14 (17%) patients in the Western study.  27% of the patients in the Japanese study 
reported headaches. 
x Cardiovascular toxicity 
o In the western trial, 6 patients (8%) had T-wave or ST-segment changes consistent 
with repolarization abnormalities. 
o QT/QTc prolongation – In the Western study, in the initial 49 patients enrolled, 
QTc prolongation occurred in 0 of 9 patients at 50mg, 1 of 8 patients at 100mg, 2 
of 8 patients at 200mg, 1 of 8 patients at 300mg, 2 of 8 patients at 500mg, and 1 
of 8 patients at 600mg. The protocol was subsequently amended to include 11 
additional patients at the 100mg dose level and 12 patients at the 300mg dose level, 
along with the use of extensive ECG monitoring to assess QTc prolongation. In 
the expanded cohorts, 1/11 patients at the 100mg dose level and 2/12 patients at 
the 300mg dose level had QTc prolongation. In the Japanese study, 11/18 patients 
(61%) developed QTc prolongation. A PK-PD correlation for QTc prolongation 
appears to exist. The relationship is best described by a direct linear effect model 
with a concentration of 1ng/ml causing an increase of 0.0243 ms in QTc interval. 
None of the QTc prolongations were considered to symptomatic  
o Hypertension was seen in 21% of the patients in the two trials and on average 
involved a 5mm Hg increase in mean arterial pressure.  
o Other commonly occurring adverse events (occurring in >10%) include: fatigue 
(36%), abdominal pain (35%), back pain (15%), fever (14%), cough (14%), 
peripheral edema (12%), insomnia (12%), hematuria (11%), dyspnea (11%), 
proteinuria (11%).  
Dose limiting toxicity 
In Trial 6474IL/001, dose levels of 50, 100, 200, 300, 500, and 600 mg/day were evaluated.  At 
600 mg/day, 3 of 8 patients developed dose limiting toxicity (DLT), which specifically included 
thrombocytopenia and diarrhea.  Later phases of development used doses less than 500mg because 
plasma levels observed in subjects in the 500 mg group overlapped considerably with those at 600 
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In Trial TVE-15-11, dose levels of 100, 200, 300 and 400 mg/day were evaluated.  DLT was seen 
in 2 of 3 subjects in the 400 mg/day cohort (increased alanine aminotransferase and hypertension) 
and 2 of 6 subjects in 300 mg/day cohort (grade 3 diarrhea, hypertension, and headache in one 
patient, and grade 2 rash lasting longer than 7 days in a second subject).  Therefore, in both trials 
a dose of 300 mg/day was identified as the highest well-tolerated dose of vandetanib.  
Withdrawal from Study 
Sixty-seven patients were withdrawn from study in the 6474IL/0001 trial and 56 of these 
withdrawals were a result of disease progression.  Six patients were withdrawn from study due to 
adverse events.  One patient was withdrawn because of a rash, one patient due to fatigue, one due 
to folliculitis, and one patient was withdrawn on account of abdominal pain.  A 72 year old female 
with colorectal cancer and pre-existing hypertension and edema developed congestive heart failure 
and was withdrawn from study as a consequence.  The etiology of the heart failure is unclear and 
a contribution from vandetanib could not be ruled out.  One patient was withdrawn from protocol 
due to abnormal QTc prolongation.  Three patients withdrew consent and were taken off study 
consequently.  
In the Japanese study, 5/18 patients were withdrawn from study due to disease progression.  In 
addition, one patient with QTc prolongation and one with dose limiting alanine aminotransferase 
elevation were withdrawn. 
Efficacy 
Phase I study results  
Two phase I studies have been completed in the West and Japan (6474IL/0001 and 6474JP/0001), 
in which 90 (72 Western and 18 Japanese) patients with malignant tumors have been exposed to 
vandetanib (50 to 600 mg).  By the end of July 2002, safety data were available from 70 patients 
(40 males and 30 females).  Cohorts received doses ranging from 50 mg/day to 600 mg/day in the 
Western phase I study and from 15 patients receiving doses ranging from 100 mg/day to 400 
mg/day (9 males and 6 females) in the Japanese trial.  In the Japanese Phase I trial, nine patients 
with non-small cell lung cancer (NSCLC) who were heavily pre-treated and failed all prior therapy 
regimens (seven adenocarcinomas, one squamous cell, and one carcinoma not otherwise specified) 
were treated with vandetanib; four achieved a partial response at doses ranging from 200-300 mg.  
This data suggested that vandetanib may have activity as monotherapy in otherwise chemoresistant 
NSCLC and could be equally as efficacious in other cancers.   
The data from the Phase I studies confirm that vandetanib is safe for further study in patients with 
cancer.  Dose limiting toxicity in greater than 33% of patients was observed at doses above 300 
mg in both the Western and Japanese Phase I trials.  Plasma concentrations of vandetanib achieved 
at steady state with 300 mg cover the theoretical IC50 and KDR as extrapolated from in vitro data 
in the VEGF-stimulated umbilical vein endothelial cells in 100% of patients.  A dose of 300 mg, 
with options for stepwise dose reductions to ensure tolerability, is therefore recommended.  The 
clinical effect of vandetanib was shown in preliminary results from the Phase I study in Japan, in 
four of nine patients with NSCLC who received up to 300 mg of vandetanib and had objective 
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Phase II study results  
Several phase II studies involving vandetanib have been performed.  A randomized double-blind 
phase II trial comparing vandetanib monotherapy with gefitinib monotherapy in 168 patients with 
advanced NSCLC as second or third line therapy demonstrated that patients receiving vandetanib 
300mg had a statistically significant prolongation of progression free survival (PFS) compared 
with gefitinib 250mg, with a mean PFS of 11.0 weeks and 8.1 weeks respectively.  The adverse 
event profile of vandetanib was similar to that seen in previous trials, and included diarrhea (CTC 
grade 3/4, 8.4%), rash (CTC grade 3/4, 4.8%) and asymptomatic QTc prolongation (all CTC grade 
1, 20.5%).  A higher incidence of cardiac, gastrointestinal and respiratory serious adverse events 
was noted in the vandetanib arm compared with the gefitinib arm, although it is unclear if this 
increase can be attributed to vandetanib (19). 
Another randomized double blind phase II study evaluated PFS in second-line treatment of 127 
patients with advanced NSCLC, and demonstrated that vandetanib 100mg or 300mg plus docetaxel 
increased PFS to 18.7 weeks and 17 weeks, respectively, compared with 12.0 weeks for doctexael 
plus placebo.  No difference in OS was detected between the two arms.  The toxicities were similar 
to those expected in patients treated with docetaxel and those observed in other vandetanib studies, 
but the vandetanib arm had a greater frequency of rash and asymptomatic QTc prolongation (20).  
In another randomized double-blind phase II dose-finding study, 53 Japanese patients with NSCLC 
were given vandetanib as monotherapy at escalating doses between 100 and 300 mg/day.  Results 
from this study demonstrated a 17.6%, 5.6%, and 16.7% partial response (PR) rate for the 100, 
200, and 300 mg/day dosing, respectively, and a 49% disease control rate (PR + stable disease).  
The toxicity profile was similar to that seen in other trials with vandetanib, although the 
investigators reported a death related to interstitial lung disease that was considered to be related 
to vandetanib (21).  
Results from a phase II trial to assess objective tumor response in patients with hereditary 
metastatic medullary thyroid cancer (MTC) having mutations in the RET proto-oncogene receiving 
vandetanib monotherapy (300mg/day) were recently reported.  Six of thirty patients (20%) 
enrolled had a partial response, while an additional 16 patients (53%) demonstrated stable disease 
for at least 24 weeks.  Greater than 50% reduction in the serum tumor markers calcitonin and CEA 
was observed in 24 and 16 patients, respectively (22).  Another phase II trial to evaluate objective 
tumor response was performed in 19 patients with metastatic MTC, all receiving vandetanib 
monotherapy at an initial dose of 100 mg/day and escalation to 300 mg/day in the setting of disease 
progression.  Partial responses and stable disease (lasting at least 24 weeks) were seen in 3 (16%) 
and 10 (53%) patients, respectively.  Reductions in serum tumor markers and rates of adverse 
events were similar to the previously described study (23). 
Two phase II trials have also been performed in patients with metastatic breast cancer who have 
failed first-line therapy.  No objective responses were seen in these studies, suggesting minimal 
clinical benefit of vandetanib in this patient population (24, 25).   
Phase III study results 
The promising results of the phase II studies of vandetanib in patients with MTC provided the 
groundwork for a recently published randomized double-blind phase III trial.  Over an 11 month 
period, 331 patients with advanced MTC were randomly assigned in a 2:1 ratio to receive 


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vandetanib 300 mg/day or placebo with the primary endpoint being PFS based on RECIST criteria.  
Vandetanib therapy demonstrated significantly improved PFS compared to placebo with a hazard 
ratio (HR) of 0.46 (p < 0.01), as well as advantages in objective response rate, disease control rate, 
and biochemical response.  Overall survival data could not be analyzed because of data were not 
mature at the point of trial cutoff (26).   
Four randomized double-blind phase III studies involving vandetanib in the NSCLC population 
have also been reported.  The most recent study evaluated vandetanib therapy in patients with 
advanced NSCLC who failed prior therapy with an EFGR inhibitor and prior chemotherapy.  
Overall, 924 patients received vandetanib 300 mg/day or placebo in a 2:1 ratio with the primary 
endpoint being OS.  Median overall survival was not significantly different between the two groups 
(8.5 months versus 7.8 months, HR = 0.95, p = 0.53), but there was a statistically significant 
improvement in PFS and objective response rate in the group receiving vandetanib (27).  
Another phase III study compared the efficacy of vandetanib versus erlotinib in improving PFS in 
patients with NSCLC who had failed prior cytotoxic chemotherapy.  A total of 1240 patients were 
randomly assigned to receive vandetanib 300 mg/day (n = 623) or erlotinib 150 mg/day (n = 617).  
While vandetanib did demonstrate antitumor activity by objective response criteria, there was no 
advantage of vandetanib therapy in improving PFS compared to erlotinib.  Of note, there was a 
10% higher rate of grade 3 or higher AEs in the vandetanib group (28).  
Finally, two phase III studies sought to evaluate the role of vandetanib use in combination with 
another agent as second-line therapy in advanced NSCLC.  The first study randomized 1391 
patients with stage IIIB-IV NSCLC who had failed first-line chemotherapy to vandetanib 
(100mg/day) + docetaxel versus placebo + docetaxel.  Median PFS was significantly longer in the 
vandetanib/docetaxel group compared to the placebo/docetaxel group (4.0 vs. 3.2 months, 
respectively; HR = 0.79, p < 0.0001) (29).  The second trial compared the efficacy of vandetanib 
(100mg/day) + pemetrexed to placebo + pemetrexed in a similar patient population.  Five hundred 
thirty four patients were randomly assigned in a 1:1 fashion to the aforementioned treatment 
groups.  In contrast to the previous trial, there was no significant difference in PFS between the 
treatment arms (HR = 0.86, p = 0.11), but there was a statistically significant improvement in 
objective response rate and time to deterioration of symptoms in the arm receiving vandetanib 
(30). 
Emerging Safety Profile/ Composite List of Adverse Events  
Notable and/or frequent side effects associated with the above phase I and phase II studies have 
been described along with each study. The following is a system-wise list of adverse events 
encountered on all completed or currently accruing studies as summarized in the most current 
Investigators’ Brochure provided by the drug sponsor. Reported adverse events that may be related 
to vandetanib are listed below by body system.  
x General – fatigue, weight loss, fever, pain, and asthenia.   
x Cardiovascular – Abnormal ECG (with or without QT prolongation; i.e., either T-wave 
or ST-segment changes consistent with repolarization abnormalities), torsade-de-
pointes, ventricular tachycardia, and hypertension. 
x Central Nervous System – Headache or dizziness, and reversible posterior 
leukoencephalopathy syndrome. 


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x Gastrointestinal – Constipation, diarrhea, non-specific abdominal pain, nausea, 
gastroesophageal reflux, stomatitis esophageal candidiasis, vomiting, and biliary or 
bowel obstruction or perforation.  Elevated liver function tests were also demonstrated, 
generally CTC/CTCAE grade 1-2. Preliminary data suggests these are reversible, in 
some cases even while continuing therapy. 
x Hematologic and lymphatic – Ecchymosis, anemia, neutropenia, thrombocytopenia, 
and hemorrhage. 
x Electrolyte and nutritional abnormalities – Anorexia, weight loss, dehydration, 
hypokalemia, hypomagnesemia and hypophosphatemia.  
x Dermatologic – acneiform rash, pruritus, macular or maculopapular rash (generalized 
or localized), erythema, photosensitivity reaction, and sweating. On occasion, 
especially when given with chemotherapy, these have progressed to more serious 
conditions, including exfoliative dermatitis, skin desquamation, erythroderma, 
toxicoderma, toxic epidermal necrolysis, erythema multiforme and necrotizing 
fasciitis. Wound healing complications and hand-foot syndrome have also been 
reported. 
x Respiratory – Interstitial lung disease, pulmonary effusion and pneumonia. A very 
small number of patients with lung cancer receiving vandetanib have developed 
shortness of breath and cough because of inflammation or scar tissue formation in the 
lungs, although this could be due to the underlying lung cancer. 
x Renal – Proteinuria, hematuria and renal failure.  
x Vascular – Arterial ischemic events (including myocardial infarction, stroke, peripheral 
ischemia), intracranial bleeding, and venous thromboembolism (including pulmonary 
embolism). The latter may have ostensibly been due to the hypercoagulability 
associated with a concurrent neoplastic process or other systemic illness.  However, it 
is considered possible that vandetanib might increase the risk for developing blood 
clots.  
x Psychiatric –  Mood disorders (anxiety, depression, insomnia). It is possible that these 
events are not direct effects of vandetanib, but rather are secondary to symptoms of 
cancer or to other effects of vandetanib (rash, anorexia, etc.). 
x Ophthalmologic – Corneal changes, including ulceration; detached retina.  
 
In addition, a number of other side effects have been reported in clinical trials using vandetanib 
alone, in combination with other chemotherapy agents or radiation. It is unclear whether these side 
effects are related to vandetanib, or are caused by other factors (such as chemotherapy or 
radiation). These side effects include:  
x Infections, including life-threatening bacterial infections  
x Seizures and facial nerve palsies  
x Syncope  
x Left ventricular dysfunction  
x Respiratory insufficiency  


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x Esophageal fistula  
Hemorrhage from both tumor and non-tumor sites have been described with several agents 
targeting the VEGF pathway (such as sunitinib, sorafenib, bevacizumab etc.). Episodes of bleeding 
with the above agents have been occasionally life-threatening or fatal.  Gingival bleeding as well 
as one case each of hemoptysis and cerebellar hemorrhage has been described in studies with 
vandetanib, although it is unclear whether these events are attributable to the agent.  A recent 
randomized, placebo-controlled, phase II study of vandetanib in advanced thyroid cancer was 
performed; 72 subjects were allocated to the vandetanib arm and one of these individuals died 
from hemorrhage from skin metastases, which was deemed treatment-related (31).  Finally, a 
recent meta-analysis of four randomized controlled trials of vandetanib in non-small cell lung 
cancer demonstrated no significant difference in the incidence of hemorrhagic events between the 
subjects receiving vandetanib compared to those receiving other agents (32).  While it appears that 
the risk of hemorrhage attributable to vandetanib is low based on previous studies, the possibility 
of life-threatening hemorrhage cannot be excluded in subjects receiving this drug.  
1.2.4 Combined Blockade of the VEGF and EGFR pathways in HLRCC 
The recognition that HIF upregulation may play an important role in the formation and propagation 
of renal cancer associated with HLRCC suggests that interventions directed against components 
of this pathway, such as VEGF and TGF-α/EGFR, may be of benefit in this patient population. 
Additionally, given the exquisite sensitivity of FH-/- cancer cell lines to glucose withdrawal, we 
hypothesized that therapeutic strategies aimed at limiting glucose delivery to tumors (for instance, 
targeting tumor vasculature) might be associated with anti-tumor effects. 
Our group has explored targeting HIF and its downstream transcriptional targets as a rational 
therapeutic strategy in HLRCC. We hypothesized that combined VEGF and EGFR-pathway 
blockade would constrain glucose delivery to tumors and inhibit critical HIF-driven downstream 
targets. In addition to inhibiting angiogenesis, agents targeting the VEGF axis might permit us to 
exploit the dependence of these tumors on glucose by impairing delivery of this critical metabolic 
substrate. Recent evidence suggests that EGFR, in addition to its role as a growth factor receptor, 
also serves as a heterodimeric partner for SGLT1, a cell surface glucose transporter. Targeting 
EGFR might, therefore, limit glucose uptake by tumor cells in addition to blunting an important 
autocrine growth signal. 
 
1.2.5 Vandetanib in combination with Metformin 
To our knowledge, there are no studies evaluating the safety or efficacy of vandetanib in 
combination with metformin administered in multiple doses.  
A phase 1 study to assess the pharmacokinetics of single dose metformin when administered in 
combination with single-dose vandetanib was conducted by the previous manufacturer Astra-
Zeneca (Confidential Information). This was a single-center, open-label, nonrandomized, 2 
sequential period study to evaluate the plasma metformin concentration-time profiles and the 
resulting PK parameters in 14 healthy adult male and female volunteers.  13 volunteers received 
all planned doses of vandetanib and metformin.  The primary objective of this study was to assess 
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extrapolated to infinity (AUC) in healthy volunteers (wild type for OCT2) for metformin 
administered alone and in combination with vandetanib 800 mg. 
On Day 1 in Period 1 volunteers received a single oral dose of metformin 1000 mg alone followed 
by an at least 7-day washout period.  On Day 1 in Period 2, all volunteers received a single oral 
dose of vandetanib 800 mg alone.  Three hours after the dose of vandetanib, all volunteers received 
a single oral dose of metformin 1000 mg. 
On Day 1 in Period 1, volunteers received a light breakfast 4 hours prior to metformin dose and 
continued to abstain from food until 4 hours postdose.  Water was withheld for 1 hour predose 
until 2 hours postdose.  On Day 1 in Period 2, volunteers received a light breakfast 1 hour prior to 
vandetanib dose and continued to abstain from food until 4 hours after the metformin dose.  Water 
was withheld for 1 hour prior to the vandetanib dose until 2 hours after the vandetanib dose and 1 
hour before the metformin dose. 
Serial blood samples for PK analysis of metformin were collected for 96 hours following the 
metformin dose in Period 1.  In Period 2, blood samples for PK analysis of vandetanib and 
metformin were collected for 72 hours and 96 hours following the vandetanib and metformin dose, 
respectively.  Urine was collected for metformin PK in Periods 1 and 2 on Day 1 (continuing 
through Day 2) from 0 to 24 and 24 to 48 hours following the metformin dose. 
In wild-type OCT2 healthy volunteers, exposure to metformin, as assessed by AUC and Cmax, 
was increased by 74% and 50%, respectively, when vandetanib was given in combination with 
metformin, a probe substrate for OCT2. The results indicate that vandetanib influences the PK of 
metformin.Geometric mean metformin CL/F and Vz/F appeared to be lower (by 42% and 39%, 
respectively) when a single dose of metformin was given with a single dose of vandetanib 
compared to metformin given alone.   There appeared to be no change in metformin geometric 
mean t1/2,λz and median tmax.  Coadministration with vandetanib appeared to cause a 52% decrease 
in geometric mean metformin CLR.  This decrease was observed in all volunteers individually.
Following dosing, there were 15 AEs in 9 (64.3%) volunteers overall.  The numbers of volunteers 
with AEs was higher during the combination treatment than during the metformin alone 
treatment.  However, no clinically relevant differences between the treatments were noted for any 
individual preferred term. 
1.2.6 Preclinical Studies of Vandetanib in Kidney Cancer 
Vandetanib Induces Cell Death in FH-Deficient Kidney Cancer with an IC50 16nM 
Vandetanib has a unique ability to inhibit invasion as well as viability of UOK262 FH-deficient 
type 2 papillary kidney cancer with an IC50 of only 16nM. (Figure 4 and Figure 5). 
 


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Figure 4: Vandetanib (5nM) significantly inhibits invasion of UOK262 fumarate hydratase deficient type 2 papillary 
kidney cancer in an in-vitro model system. 
 
 
Figure 5.  Vandetanib induces death in FH-deficient type 2 papillary kidney cancer, with an IC50 on 16NM.  In a 
synthetic lethal screen, Vandetanib does not affect the viability of UOK262WT, which is the FH-deficient kidney 
cancer cell line with FH replaced. 
Vandetanib Inhibits Glucose Uptake and Reverses the Biochemical Phenotype FH-Deficient Type 
2 Papillary Kidney Cancer 
Vandetanib reverses the biochemical phenotype in FH-deficient type 2 papillary kidney cancer.  
Vandetanib decreases glucose uptake, lactate production, ATP production, and increases AMPKα 
and AMPKβ, which we have shown are essential elements of the metabolic shift in this form of 
kidney cancer.  Vandetanib also decreases the expression of HIF1α and the glucose transporters, 
GLUT1 and GLUT4 (Figure 6 and Figure 7).   


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Figure 6.  Vandetanib decreases glucose uptake (left panel), decreases lactate secretion (which is a surrogate for 
glycolysis) (middle panel) and decreases ATP production in UOK262 fumarate hydratase type 2 papillary kidney 
cancer cell line in-vitro. 
 
Figure 7.  Vandetanib reverses the biochemical metabolic phenotype of UOK 262 fumarate hydratase-deficient type 
2 papillary kidney cancer in-vitro.  With Vandetanib treatment, AMPKα and AMPKβ increase, ACC and PACC 
increase (indicating a decrease in fatty acid synthesis that is essential for rapid anabolic growth) (upper left and left 
middle panels).  Vandetanib treatment decreases HIF1α (right middle panel) and decreases the expression of the 
glucose transporters, GLUT 1 and GLUT4 (right upper and lower panels).   
Vandetanib Inhibits Cell Viability in SDH-Deficient Kidney Cancer 
In order to develop a therapeutic approach to treatment of patients with SDH-deficient kidney 
cancer, we developed an SDH-deficient kidney cancer cell line model, UOK269, which was 
derived from a patient with SDHB-deficient kidney cancer.  We subsequently developed 
UOK269WT1 and UOK269WT2, which are cell lines with a “wild type” copy of SDHB replaced.  
UOK269EV1 and UOK269EV2 are cell lines with “empty vector” to act as a control for 
UOK269WT1 and UOK269WT2.  In synthetic lethal in-vitro studies, while vandetanib had little 
effect on UOK296WT, it significantly inhibited cell viability of UOK269EV (Figure 8 and Figure 
9). 


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Figure 8. Vandetanib had a significant effect on viability of the succinate dehydrogenase-deficient kidney cancer cell 
lines, UOK269-EV1 and UOK269-EV2. 
 
Figure 9. In a synthetic lethal study, while Vandetanib had a significant effect on viability of the succinate 
dehydrogenase-deficient kidney cancer cell lines, UOK269-EV1 and UOK269-EV2, it had little effect on the 
UOK269-WT1 and UOK269-WT2 SDHB replaced cell lines. 
Vandetanib Induces Complete Regression of Fumarate Hydratase-Deficient Type 2 Papillary 
Kidney Cancer Xenograft Models 
In our in-vivo, mouse xenograft models, vandetanib (100mg/kg) induces complete regression of 
this aggressive form of type 2 papillary kidney cancer (Figure 10). 
269-EV1
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Figure 10.  Vandetanib reverses the biochemical metabolic phenotype of UOK 262 fumarate hydratase-deficient 
type 2 papillary kidney cancer in-vitro (left panel).  The right panel is the result of two different experiments.   
In the xenograft tumors, vandetanib increases AMPKα and AMPKβ, and decreases pS6R 
(suggesting downregulation or normalization of the mTORC1 pathway).  We have shown above 
that decreased AMPKα and AMPKβ, and increased pS6R are a part of the metabolic shift in FH-
deficient type 2 papillary kidney cancer (Figure 11).  Glut 1 and VEGF-A are also decreased in 
xenografts from vandetanib-treated mice; secreted VEGF-A is also decreased in serum from 
xenograft-bearing animals treated with vandetanib (Figure 12). 
 
 
Figure 11.  Vandetanib reverses the biochemical metabolic phenotype of UOK 262 fumarate hydratase-deficient 
type 2 papillary kidney cancer in-vivo.  With Vandetanib treatment, there is increased AMPKα and AMPKβ and 
increased pS6R in the xenograft tumors. 


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Figure 12.  In the Vandetanib-treated mouse bearing the UOk262 fumarate hydratase-defieicnet type 2 papillary 
kidney cancer there is less GLUT1 and VEFGA expression and there is decreased secreted VEGFA in the serum of 
the Vandetanib treated xenograft bearing animals. 
1.2.7 Role of Metformin in Cancer 
Retrospective epidemiologic studies in diabetic patients receiving metformin have shown a 
reduced lifetime incidence of cancer in this population (33, 34).  As a result, metformin and other 
biguanides are being evaluated as potential anticancer agents.  The precise molecular target of 
metformin is unknown, but it acts to inhibit complex I of the mitochondrial electron transport chain 
to block oxidative respiration (35).  This increases cellular AMP-to-ATP ratios and activates the 
AMP-activated protein kinase (AMPK) (36).  AMPK coordinates the activity of several metabolic 
and growth pathways that are important in cellular energy balance. For example, AMPK increases 
GLUT1 expression to promote glucose uptake and phosphorylates phosphofructokinase-2 to 
promote energy generation through increased glycolysis.  Conversely, AMPK phosphorylates 
proteins such as TSC2 and Raptor (components of the mammalian target of rapamycin [mTOR] 
cascade) to inhibit protein synthesis and it phosphorylates acetyl-CoA carboxylase to inhibit lipid 
synthesis, thereby suppressing energy-consuming processes (37, 38). 
1.2.8 Synergistic Effects of Metformin and Vandetanib in HLRCC 
Preclinical studies with UOK 262 have demonstrated synergistic antitumor activity when 
vandetanib is combined with metformin (unpublished data). These data provide the basis for 
evaluating this combination in HLRCC. 
Treatment of FH -/- deficient type 2 papillary kidney cancer with metformin reverses the FH -/- 
biochemical phenotype (i.e., it increases AMPK and inhibits the enzymes that drive fatty acid 
synthesis) and significantly inhibits HLRCC FH -/- kidney cancer UOK262 cellular invasion 
(Figure 13).   


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Figure 13.  Metformin (and a similar agent which also activates AMPK, AICAR) reverse the biochemical phenotype 
of FH-deficient kidney cancer; AMPK levels increase and fatty acid synthesis enzymes are decreased (left panel).  
Metformin and AICAR have a significant effect on in-vitro growth of the fumarate hydratase-deficient kidney 
cancer cell line, UOK262.   
In vitro, we have shown that the combination of metformin and vandetanib has significantly greater 
effect on cell viability than either agent alone (Figure 14).  We have also shown that the 
combination of metformin plus vandetanib has a greater effect in reversing the biochemical 
metabolic phenotype of fumarate hydratase-deficient type 2 papillary kidney cancer than either 
agent alone.  The combination has a greater effect in increasing AMPKα, PACC and ACC (which 
indicate a decrease in fatty acid synthesis) than either agent alone. 
 
Figure 14.  The combination of metformin plus Vandetanib has a greater effect on cell viability (left panel) and on 
pAMPKα, pACC and ACC (right panel) than either agent alone. 
In our in vivo models we found significant synergy with metformin plus vandetanib versus 
vandetanib or metformin alone (Figure 15 and Figure 16). When combined with metformin, 
vandetanib induces complete tumor regression at doses that are a log lower than those used in 
single agent vandetanib studies. 
Cell Index
UOK262
UOK262 + metformin
UOK262 + AICAR
HK-2
UOK262-WT
-
0.5
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loading ctrl
AMPKD-p
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IRP1
IRP2
UOK 262


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Figure 15.  The combination of metformin plus Vandetanib has a greater effect on UOK262 fumarate hydratase-
deficient type 2 papillary kidney cancer xenograft tumor growth than either metformin or Vandetanib alone (left 
panel).  The right panel is the sum of two different animal experiments.  The dose of Vandetanib in these 
experiments is 10 mg/kg/week; which is 1/10th the dose used above as a single agent and 1/35th the dose used in 
published xenograft studies with this agent. 
 
Figure 16.  This figure, a close up of from the preceding figure, demonstrates the synergistic effect of the 
combination of metformin and Vandetanib in the UOK262 fumarate hydratase-deficient type 2 papillary kidney 
cancer xenograft model.  This combination induced complete regression of the tumors.   
1.2.9 Rationale and Summary  
Despite the availability of several agents with activity in clear cell RCC, there are no standard 
treatments of proven benefit for patients with advanced papillary RCC.  Several agents have been 
shown to have limited activity in retrospective or small phase II studies involving subjects with 
advanced papillary RCC.  Most recently, the efficacy of foretinib (a dual MET/VEGFR2 inhibitor) 
in patients with advanced papillary RCC was assessed in a multi-institutional study, which 
demonstrated a median progression-free survival of 9.3 months (39).  Of note, the agent was most 
effective in those subjects with a germline MET mutation, which may limit the applicability of this 
agent to individuals with this specific mutation.  While sunitinib is approved for patients with 
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advanced kidney cancer, the benefit in patients with non-clear cell histology appears to be limited.  
Several phase II studies have evaluated the efficacy of sunitinib in patients with papillary RCC, 
and most demonstrate a median PFS between 1.6 and 6 months, and overall response rates between 
0-12%.  Temsirolimus also has limited efficacy in advanced papillary RCC, with one study 
reporting a median PFS of 3.8 months and overall response rate of 5.4% 
Patients with HLRCC or SDH associated metastatic RCC as well as most patients with sporadic 
papillary RCC have particularly aggressive disease that is usually not responsive to currently 
available targeted agents.  Impairment of Krebs cycle function leads to a metabolic switch whereby 
affected tumor cells are reliant on aerobic glycolysis as the primary source of energy production; 
since glycolysis is a less efficient means of ATP synthesis than is oxidative phosphorylation, a 
constant supply of glucose is necessary to fuel the energy needs of the cell. The Krebs cycle 
substrates of both FH and SDH (fumarate and succinate) inhibit hydroxylation of HIF, leading to 
an increase in intracellular HIF1α, which augments the angiogenesis pathway via upregulation of 
VEGF, and glucose uptake via overexpression of GLUT1 and GLUT4.  Furthermore, the 
metabolic shift towards aerobic glycolysis leads to decreased AMPK activity, which serves as the 
primary energy sensing complex within the cell.  This alteration in AMPK regulation leads to 
activation of the mTOR pathway and fatty acid synthesis, which further drives tumor development 
and progression.   
Based on the previously described preclinical observations from our group and others, we 
hypothesize that combined VEFGR and EGFR blockade would inhibit critical HIF-driven 
downstream targets including those mediating tumor angiogenesis.  Recent evidence also suggests 
that EGFR serves as a heterodimeric partner for SGLT1, a cell surface glucose transporter, and 
can thus affect cellular glucose delivery.  We hypothesize that combined VEGFR/EGFR blockage 
will constrain glucose delivery to tumors, thus effectively limiting energy production by aerobic 
glycolysis.  An ongoing NCI phase 2 trial of bevacizumab in combination with erlotinib (10-C-
0114) was undertaken based on this premise.  
Vandetanib has shown activity in several preclinical tumor models and has demonstrated an 
acceptable toxicity profile in phase I and phase II studies. Vandetanib has demonstrated potent 
activity as a single agent in preclinical models of FH -/- and SDH -/- tumors. Metformin has also 
been shown in preclinical models to reverse some aspects of the FH-deficient phenotype in 
HLRCC cells by increasing AMPK activity and inhibiting the enzymes responsible for fatty acid 
synthesis.  In combination, vandetanib and metformin show synergistic anti-tumor activity in 
relevant preclinical models.  This drug combination thus provides an exciting opportunity for 
exploring a targeted approach in a cancer with essentially no available curative options.  
As part of this study, we also propose to evaluate the activity of this regimen in patients with 
sporadic papillary RCC, in whom there is currently no evidence of a heritable germline FH or SDH 
defect. As previously mentioned, there are currently no standard treatment options for patients 
with advanced papillary RCC. Given the relatively recent identification of Krebs cycle alterations 
in hereditary forms of papillary RCC, we propose to explore the possibility that some variants of 
sporadic papillary RCC may share common clinical/molecular features with HLRCC/SDH-
associated renal tumors that may render them amenable to treatment with this regimen. As part of 
this trial, an attempt will be made to further characterize these sporadic tumors, particularly with 
regard to the prevalence of somatic FH/SDH inactivation and VEGF/EGFR pathway activation. 


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2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT  
2.1 
ELIGIBILITY CRITERIA 
2.1.1 Inclusion Criteria  
2.1.1.1 Diagnosis/Histology 
a. Phase I Component – Histologically confirmed advanced RCC of any subtype.   
b. Phase II Component – Advanced RCC associated with 1) HLRCC or SDH (Cohort 1); 
OR 2) advanced non HLRCC-related papillary RCC (Cohort 2). 
2.1.1.2 Phase 1: Patients must have evaluable disease 
Phase 2: Patients must have measurable disease based on RECIST 1.1 criteria.  See 
Section 6.2 for the evaluation of measurable disease. 
2.1.1.3 Prior Therapy 
a. 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. 
b. Phase 2- No more than two prior VEGF-pathway targeted agents 
c. No previous treatment with vandetanib. Previous or ongoing treatment with 
metformin is allowed.   
2.1.1.4 Age ≥18 years. 
2.1.1.5 ECOG performance status <2 (Karnofsky >60%, see Appendix A). 
2.1.1.6 Negative pregnancy test (urine or serum) for female patients of childbearing potential. 
2.1.1.7 Patients must have normal organ and marrow function as defined below: 
 absolute neutrophil count  
≥1,500/mcL 
 platelets  
 
 
 
 
 
≥100,000/mcL 
 total bilirubin 
 
 
 
 
≤ 1.5x upper limit of reference range (< 3x 
upper limit of reference range in patients with Gilbert’s disease) 
 AST(SGOT)/ALT(SGPT)  
≤ 2.5 X institutional upper limit of normal 
 eGFR (CKD-EPI)  
 
 
≥50 mL/min/1.73 m2   
2.1.1.8 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. 
2.1.1.9 Ability of subject to understand and the willingness to sign a written informed consent 
document. 
2.1.2 Exclusion Criteria 
2.1.2.1 Known serious allergic reaction to vandetanib or metformin. 


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2.1.2.2 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. 
2.1.2.3 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. 
2.1.2.4 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). 
2.1.2.5 Unacceptable electrolyte values, including: 
x Potassium <4.0 mmol/L despite supplementation, or elevated potassium above the 
CTCAE Grade 1 upper limit. 
x Magnesium below the lower limit of normal range despite supplementation, or 
elevated magnesium above the CTCAE Grade 1 upper limit. 
x Ionized calcium or corrected calcium values below the normal range or 
hypercalcemia above the CTCAE Grade 1 upper limit. 
2.1.2.6 Significant cardiac event (e.g., myocardial infarction), New York Heart Association 
(NYHA) classification of heart disease ≥2 within 12 weeks before starting treatment (see 
Appendix B), or presence of cardiac disease that in the opinion of the Investigator 
increases the risk of ventricular arrhythmia. 
2.1.2.7 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. 
2.1.2.8 Hypertension not controlled by medical therapy (systolic blood pressure greater than 140 
millimeters of mercury [mmHg] or diastolic blood pressure greater than 90 mmHg). 
2.1.2.9 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.  
2.1.2.10 Proteinuria > 1gram/24 hrs. 
2.1.2.11 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. 
2.1.2.12 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). 
2.1.2.13 Congenital long QT syndrome. 


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2.1.2.14 Any concomitant medications that are known to be associated with Torsades de Pointes 
(see Appendix C) Drugs listed in Appendix C, Table 3, that in the investigator’s opinion 
cannot be discontinued, are allowed however, must be monitored closely 
2.1.2.15 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).  
2.1.2.16 History of QT prolongation associated with other medications that required 
discontinuation of that medication. 
2.1.2.17 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 ≤450 ms in order for the patient to be eligible for the study).  
2.1.2.18 Women that are currently breast feeding. 
2.1.2.19 Active treatment-refractory diarrhea that may affect the ability of the patient to absorb 
the trial agents or tolerate further diarrhea. 
2.1.2.20 HIV-positive patients on combination antiretroviral therapy are ineligible because of the 
potential for pharmacokinetic interactions with vandetanib/metformin.  
2.1.2.21  Patients with active hemoptysis, clinically significant non hemorrhoidal GI bleeding or 
those with bleeding diathesis 
 
2.2 
SCREENING EVALUATION 
The following screening studies must be performed within 4 weeks prior to enrollment on study: 
x A complete history and physical with documentation of measurable disease and 
performance status 
x Pathology confirmation of diagnosis from any certified laboratory of pathology although 
every effort will be made to obtain slides and confirm the diagnosis with NIH pathology 
department. 
x 12 lead ECG 
x Echocardiogram 
 
The following must be performed within 2 weeks prior to enrollment on study: 
x Imaging studies: CT of the chest abdomen and pelvis (or MRI scans when indicated) 
x MRI (or CT with contrast) of the brain 
x Targeted history and physical examination focusing on any salient changes from baseline  
x CBC with differential, Hepatic Panel, Acute Care Panel, Mineral Panel, urinalysis, spot 
urine protein:creatinine ratio (patients with 1+ or greater proteinuria on UA and a spot urine 
protein:creatinine ratio of > 0.5 will undergo a 24 hour urine collection for quantitation of 
proteinuria) 
x Urine or serum pregnancy test in women of childbearing potential 


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2.3 
RECRUITMENT STRATEGIES 
Patients will be recruited through clinical referrals to the UOB branch and the clinical trial will be 
listed on www.clinicaltrials.gov.  Recruitment letters and other recruitment tools available to CCR 
investigators may also be used. Both men and women of all races are eligible for this trial.  
 
2.4 
REGISTRATION PROCEDURES 
Authorized staff must register an eligible candidate with NCI Central Registration Office (CRO) 
within 24 hours of signing consent.  A registration Eligibility Checklist from the web site 
(http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) must be completed and sent via 
encrypted email to:  NCI Central Registration Office ncicentralregistration-l@mail.nih.gov.  
After confirmation of eligibility at Central Registration Office, CRO staff will call pharmacy to 
advise them of the acceptance of the patient on the protocol prior to the release of any 
investigational agents.  Verification of Registration will be forwarded electronically via e-mail to 
the research team. A recorder is available during non-working hours.  
2.5 
TREATMENT ASSIGNMENT PROCEDURES 
Cohorts: 
Number 
Name 
Description 
1 
Phase I Component 
Subjects with advanced RCC enrolled to determine 
the MTD 
2 
Phase II component/Cohort I 
Subjects with metastatic HLRCC/SDH associated 
renal cancer enrolled after the MTD has been 
identified 
3 
Phase II component/Cohort II 
Subjects with sporadic/non-HLRCC papillary renal 
cancer enrolled after the MTD has been identified 
Arms 
Number 
Name 
Description 
1 
Phase I component 
Vandetanib and metformin 
2 
Phase II component 
Vandetanib and metformin 
 
Subjects in cohort 1 will be directly assigned to arm 1.  Subjects in cohort 2 and 3 will be directly 
assigned to arm 2. 
3 
STUDY IMPLEMENTATION 
3.1 
STUDY DESIGN 
The phase I component is designed as a single arm, fixed order dose-escalation study of various 
doses of vandetanib and metformin using a modified Fibonacci schema until MTD is reached or 
the highest proposed dose level is tested without reaching MTD (see details below).  The design 
for the phase II component will be an open label, single arm study utilizing a fixed starting dose 


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of vandetanib and metformin, which will be determined based on the MTD established by the 
phase I component of the study.  The duration of each cycle will be 28 days.   
For metformin doses above 250 mg bid there will be a lead-in period of approximately 2 weeks to 
help minimize GI side effects associated with this drug.  Metformin will be started at a dose of 250 
mg bid on Day -14 and over a course of approximately 2 weeks the agent will be titrated to the 
target dose.  Vandetanib will also be taken starting on Day -13 during the lead in period at the 
assigned dose.  Once the lead in period is complete and both agents are at the assigned dose level, 
cycle 1 will begin.   
For metformin doses ≤ 250 mg bid (without metformin lead-in), metformin will be taken starting 
on Cycle 1 Day 1 and vandetanib will be taken starting on Cycle 1 Day 2.   
The lead in will not be required in cases of intrapatient dose escalation. 
Patients who are on metformin will have their metformin discontinued prior to study entry. Once 
enrolled, metformin will be dosed/titrated as appropriate for the relevant dose level. 
Patients will undergo clinical and laboratory evaluation prior to the start of drug administration. 
While the patient’s local physician outside the NIH Clinical Center may evaluate the patient for 
new complaints or ongoing medical issues, the patient will return to the NIH Clinical Center for 
formal evaluation after each cycle.   
Patients will be evaluated radiologically for evidence of response or progression approximately 8 
weeks after initiation of therapy, every 8 weeks thereafter for the first 32 weeks, and then every 
12 weeks while on treatment.  Patients with evidence of disease response or stable disease will 
continue to receive therapy in the absence of unacceptable toxicity.   
 
 


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Figure 17: Cycle 1 for metformin doses > 250 mg BID 
 
Lead In 
Cycle 1 
 
 
 
Days 
Figure 18: Cycle 1 for metformin doses ≤ 250 mg BID and Cycles 2 onward 
for all metformin doses 
 
 
Cycle X 
 
 
 
 
 
Days 
 
3.1.1 Phase I Component 
3.1.1.1 Definition of Dose-Limiting Toxicity 
Dose-limiting toxicity (DLT) is defined as an adverse event that is related (possibly, probably, or 
definitely) to administration of vandetanib and/or metformin. DLTs (defined as those occurring 
within the first 42 days of treatment after the intended dose of metformin is achieved for a given 
dose level; based on CTCAE Version 4.0) will include:  
-14
-7
0
7
14
21
28
35
42
Metformin Lead In
Assigned Metformin
Dose
Assigned Vandetanib
Dose
DLT assessment
0
7
14
21
28
35
42
Assigned
Metformin dose
Assigned
Vandetanib dose
DLT assessment
Dose 
Dose 
250 mg 


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x grade IV or greater hematological toxicity  
x neutropenic fever 
x grade III or greater nonhematological toxicity with the following exceptions. For the AEs 
below, DLT is defined as:  
o grade III or greater diarrhea leading to hospitalization or lasting > 48 hours despite 
optimal anti-diarrheal medication; grade IV diarrhea despite optimal anti-diarrheal 
prophylaxis 
o grade III or greater nausea or vomiting despite optimal antiemetics  
o grade III hypertension that is not controlled (to 140/90 mmHg or below) despite 
optimal antihypertensive therapy 
o grade III elevated serum creatinine that cannot be corrected to grade 1 or better with 
hydration within 48 hours 
o electrolyte abnormalities that cannot be corrected with medical management within 
72 hours 
 
3.1.1.2 Dose Escalation 
Dose escalation will proceed in cohorts of 3-6 patients each as outlined below.  The MTD is the 
dose level at which no more than 1 of up to 6 patients experience DLT during 1 cycle of treatment 
(42 days from the time the intended dose of metformin is reached for a given dose level), and the 
dose below that at which at least 2 (of ≤6) patients have DLT as a result of the experimental 
regimen.  Patients are considered evaluable for toxicity for the purpose of cohort dose escalation 
decisions if they either 1) experienced DLT or 2) have received at least 75% of the planned dose 
of treatment in one cycle of therapy and have been followed for one full cycle without DLT.  All 
toxicities will be reported for all patients who receive any amount of study drug on this study.  
Additional dose levels may be considered if dose level 3 is well tolerated and will require an 
amendment to allow further dose escalations. Additional dose levels with serial escalation of 
metformin may also be considered if DLT at dose level 1 necessitates reduction in the dose of 
vandetanib to below 300mg as long as no more than 1/6 patients at the lower dose level experience 
a DLT (for instance, if <1/6 pts at dose level -1 experience DLT, one or more additional dose levels 
with 200mg of vandetanib and escalating doses of metformin. (250mg BID, 500mg BID etc. may 
be considered, via a protocol amendment. In addition, based on PK parameters ascertained from 
earlier dose levels, the protocol may be amended to evaluate once daily dosing of metformin in 
dose levels 2-4. Determination of DLT for the purposes of establishing a maximum tolerated dose 
(MTD) will be done taking into consideration the toxicities observed in cycle 1.   
 
If a DLT is encountered during dose escalation of metformin in the lead-in period, it will count as 
a DLT at the corresponding dose level. This may require declaring a lower dose level as the MTD 
or accruing additional patients at that dose level before further dose escalation.  


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Dose escalation schedule: 
The starting Dose Level (Dose Level 1) = vandetanib 300mg PO daily and metformin 250mg 
PO daily 
Dose Level 
Vandetanib 
Metformin 
-3 
100mg every other day 
250mg QD 
-2 
100mg daily 
250mg QD 
-1 
200mg daily 
250mg QD 
 1 
300mg daily 
250mg QD 
2 
300 mg daily 
250 mg BID 
 3 
300mg daily 
500mg BID 
 4 
300mg daily 
850mg BID 
 
Dose escalation will follow the rules outlined below. 
 
Once three patients have been enrolled at a given dose level, no additional patients will be enrolled 
until evaluation for DLT is complete in those patients. If a DLT is seen in no more than one of 
three patients, an additional three patients will be enrolled at the dose level; no further patients will 
be enrolled until DLT evaluation in the additional patients is complete. 
Number of Patients with 
DLT 
at a Given Dose Level 
Escalation Decision Rule 
0 out of 3 
Enter up to 3 patients at the next dose level 
> 2 
Dose escalation will be stopped.  This dose level will 
be declared the maximally administered dose (highest 
dose administered).  Up to three (3) additional patients 
will be entered at the next lowest dose level if only 3 
patients were treated previously at that dose. 
1 out of 3 
Enter up to 3 more patients at this dose level. 
x If 0 of these 3 patients experience DLT, 
proceed to the next dose level. 
x If 1 or more of this group suffer DLT, then 
dose escalation is stopped, and this dose is 
declared the maximally administered dose.  
UP to three (3) additional patients will be 
entered at the next lowest dose level if only 3 
patients were treated previously at that dose. 
<1 out of 6 at highest dose 
level  
This is the MTD and is generally the recommended 
phase 2 dose.  At least 6 patients must be entered at 
the recommended phase 2 dose.   


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3.1.1.3 Intra-patient dose modifications 
Dose-Escalation:  Intra-patient dose escalation may be allowed at the discretion of the principal 
investigator if the following conditions are met: a) the patient has not experienced drug-related 
toxicity > grade 2 after one course of study treatment at the initial dose level; b) the higher dose 
level has been completed by all patients in that cohort and no more than 1/6 patients experienced 
a DLT, and c) there is no evidence of disease progression as defined by RECIST.  If patients 
experience DLT at the higher dose level, dose modifications will be made as outlined in sections 
3.3.3 and 3.3.4. Once the MTD has been established that will serve as the ceiling and apply to 
every patient thereafter. That is, intra-patient dose escalations will not exceed the established 
MTD. 
Dose-Reduction: Patients who experience DLTs (during the first or subsequent cycles of therapy), 
may be allowed to continue on study with dose reductions if there is a prospect of benefit from 
continuing therapy. The agent to be dose-reduced and the dose levels to be used are outlined in 
sections 3.3.3 and 3.3.4. 
3.2 
DRUG ADMINISTRATION 
The duration of each cycle will be 28 days.  For metformin doses above 250 mg bid there will be 
a lead-in period of approximately 2 weeks to help minimize GI side effects associated with 
metformin.  Metformin will be started at a dose of 250 mg bid on Day -14 and over a course of 
approximately 2 weeks the agent will be titrated to the target dose.  Vandetanib will also be taken 
starting on Day -13 during the lead in period at the assigned dose.  Once the lead in period is 
complete and both agents are at the assigned dose level, cycle 1 will begin.  For metformin doses 
≤ 250 mg bid (without metformin lead-in), metformin will be taken starting on Cycle 1 Day 1 and 
vandetanib will be taken starting on Cycle 1 Day 2. If a DLT is encountered during dose escalation 
of metformin in the lead-in period, it will count as a DLT at the corresponding dose level. This 
may require declaring a lower dose level as the MTD or accruing additional patients at that dose 
level before further dose escalation. 
The study drugs will be dispensed by the NIH pharmacy and will be given to the subjects for daily 
self-administration with detailed instructions.  For the phase I component of the study, the dose of 
each agent will depend on the dose level at which the subject is enrolled.  The dose for the phase 
II component will be determined following completion of the phase I component of the study. 
Vandetanib and metformin will be administered on an outpatient basis and the drugs will be self-
administered by the patient.  The prescribed dose of the drugs will be taken orally and should be 
taken with some food and water to help minimize GI effects.  Vandetanib tablets should be taken 
whole or dispersed in water, without crushing.  If vandetanib cannot be taken whole, the tablets 
can be dispersed in a glass containing approximately 60 mL of non-carbonated water and stirred 
for approximately 10 minutes until the tablets are dispersed (will not completely dissolve).  No 
other liquids should be used.  The mixture should be swallowed immediately.  To ensure the full 
dose is received, the patient should refill the glass with an additional half glass of water and mix 
with any remaining drug and drink it.  If the subject inadvertently does not take the dose in the 
morning, he or she may take that day’s dose any time up to10 p.m. that same day. However, if a 
subject misses taking their scheduled dose and is unable to take the missed dose on the same day, 
he or she must take the next scheduled dose and the missed dose will not be made up.  


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Patient compliance will be tracked using a pill count/administration form which the patient will be 
instructed to complete and which will be reviewed at each clinic visit.  
Patients will be required to maintain a diary (see Appendix D) documenting when the doses of 
vandetanib and metformin were taken and any associated side effects.   
3.3 
TREATMENT MODIFICATIONS 
3.3.1 General Plan to Manage Safety 
A number of measures will be taken to ensure the safety of patients participating in this trial.  These 
measures will be addressed through exclusion criteria (see Section 2.1.2) and routine monitoring 
as follows. 
Patients enrolled in this study will be evaluated clinically and with standard laboratory tests before 
enrollment on trial and at regular intervals during their participation in this study.  Safety 
evaluations will consist of medical interviews, recording of adverse events, physical examinations, 
daily blood pressure monitoring, and laboratory measurements.  Patients will be evaluated for 
adverse events (all grades), serious adverse events, and adverse events requiring study drug 
interruption or discontinuation at each study visit for the duration of their participation in the study.  
Patients discontinued from the treatment phase of the study will be evaluated approximately 60 
days after the decision to discontinue treatment as outlined in section 3.6.  The safety monitoring 
is incorporated into the study calendar in section 3.5.  
Hypertension will be monitored through routine evaluation of blood pressure at each clinic visit, 
as well as by patient self-monitoring.  Optimal control of blood pressure according to standard 
public health guidelines is recommended for patients on treatment with or without 
vandetanib/metformin. 
Renal function will be monitored by serum creatinine measurement. Proteinuria will be monitored 
by urine protein:creatinine (UPC) ratio or dipstick.  
If patients on treatment with vandetanib require elective major surgery, it is recommended that 
vandetanib be held for 4 weeks prior to the surgical procedure. Patients undergoing a major 
surgical procedure should not begin/restart vandetanib until 4 weeks after that procedure and/or 
adequate wound healing has occurred (in the case of high risk procedures such as liver resection, 
thoracotomy, or neurosurgery, it is recommended that chemotherapy be restarted no earlier than 6 
weeks after surgery). Patients can continue taking metformin until the day before surgery and can 
resume following surgery as long as they maintain a creatinine clearance/eGFR of ≥ 50 ml/min 
and have resumed normal p.o. intake. 
Skin toxicities will be monitored by routine physical examination and managed symptomatically.  
The following agents may be used to treat rash:  alcohol-free emollient cream, diphenhydramine, 
topical or oral corticosteroids, and topical (clindamycin) or oral antibiotics (tetracycline, 
minocycline, doxycycline).  Topical drying agents are not recommended.   
Both vandetanib and metformin can cause diarrhea.  Diarrhea will be monitored and managed 
symptomatically.  Guidelines for management include administration of loperamide and 
vandetanib/metformin dose reduction/interruption as described in Sections 3.3.3 and 3.3.4. These 
symptoms will be self-reported and inquiries will be made at clinic visits, also outlined in the study 
calendar in section 3.5. 


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Liver function abnormalities, including elevated serum ALT, AST, and/or alkaline phosphatase, 
have been observed with single-agent vandetanib.  Periodic monitoring of liver function will be 
performed on study.  Vandetanib dosing should be interrupted if changes in liver function are 
severe (as outlined in section 3.3.3). 
While lactic acidosis is a rare metabolic complication that can occur due to metformin 
accumulation, serum lactate will be evaluated periodically and dose reduction/interruption will 
proceed as described in Section 3.3.4. 
Intravascular contrast studies with iodinated materials can lead to acute alteration of renal function 
and have been associated with lactic acidosis in patients receiving metformin. Therefore, 
metformin should be temporarily discontinued at the time of or prior to the procedure, and withheld 
for 48 hours subsequent to the procedure and reinstituted only after renal function has been re-
evaluated and found to be normal. 
Alcohol is known to potentiate the effect of metformin on lactate metabolism. Patients will be 
warned against excessive alcohol intake, acute or chronic, while receiving metformin. 
Decrease in vitamin B12 levels can occur infrequently with chronic metformin use.  Hematologic 
parameters that are consistent with vitamin B12 deficiency (i.e. megaloblastic anemia) should be 
appropriately investigated.  Certain individuals (those with inadequate vitamin B12 or calcium 
intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels. In 
these patients, routine serum vitamin B12 measurements at 2- to 3-year intervals is recommended 
by the manufacturer. 
Hypoglycemia does not occur in patients receiving metformin alone under usual circumstances of 
use, but could occur when caloric intake is deficient, when strenuous exercise is not compensated 
by caloric supplementation, or during concomitant use with other glucose-lowering agents (such 
as sulfonylureas and insulin) or ethanol.  Elderly, debilitated, or malnourished patients, and those 
with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to 
hypoglycemic effects. 
3.3.2 Dose Modifications 
Patients will be asked to record side effects/symptoms developing or worsening on therapy on a 
Side Effect Diary (see Appendix D) which will be reviewed by the research nurse/PI/associate 
investigator during clinic visits. Treatment modifications will be made in the event of toxicities 
(graded based on NCI Common Toxicity Criteria for Adverse Events, version 4.0) related to either 
vandetanib or metformin according to the guidelines below.  For grade 1 and 2 adverse events 
(AEs) related to the investigational agents, one or both agents may be held if the AE is determined 
to be intolerable. Agents may be restarted at the same dose or one dose level lower once the AE 
improves. Dose modifications for laboratory abnormalities will be required only if these 
abnormalities are clinically significant (regardless of grade). There will be no dose modifications 
for electrolyte abnormalities (potassium, sodium, calcium, magnesium, phosphorus) that can be 
corrected (to ≤ grade 1 or baseline) within 72 hours. In the event metformin is discontinued 
permanently, the patient can continue to receive vandetanib in the absence of an indication 
requiring permanent discontinuation of that agent. 
 


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3.3.3 Dose Modifications for Toxicities Related to Vandetanib  
The following dose levels will be used to guide reductions in vandetanib dosage: 
 
Current Dose 
Reduce to 
300 mg po qd 
200 mg po qd 
200 mg po qd 
100 mg po qd 
100 mg po qd 
100 mg po qod 
 
Any permanent discontinuation of vandetanib will also result in a permanent discontinuation of 
metformin. 
3.3.3.1 Cardiac toxicity - QTc prolongation 
Electrocardiograms will be evaluated by suitably qualified personnel for the presence of QTc 
(using Fridericia’s correction; the term QTc will refer to QTc calculated by this method unless 
otherwise specified) prolongation or other abnormalities, in particular, any changes in the T-wave 
morphology that would suggest a higher likelihood for the development of any arrhythmia.  Any 
clinically significant abnormal findings or QTc prolongations will be recorded as AEs. The 
schedule of monitoring is provided in the study calendar in section 3.5. 
In addition to scheduled ECG, additional ECGs should also be performed in the event of QTc 
prolongation, both during and post the prolongation period. 
x During the QTc prolongation period: For a single QTc value of >500 ms, vandetanib 
must be withheld.  Electrocardiograms will be followed at least once per week (done on 
the same day each week +/- 2 days) along with electrolytes, until QTc falls ≤450 ms.  
Vandetanib treatment may be resumed at a permanently lower dose (reduced one dose 
level as outlined above) after the QTc returns to ≤450 ms.  
x Post the QTc prolongation period: If vandetanib (at the reduced dose) is restarted after the 
QTc prolongation has resolved, ECGs and electrolytes (including calcium and 
magnesium) must be obtained at 3, 8, and 12 weeks following the start of the lower dose.  
Serum potassium levels should be maintained at 4 mEq/L or higher, and serum 
magnesium and serum calcium should be kept within normal range to reduce the risk of 
QT prolongation and torsades.  ECG and electrolyte monitoring can then resume every 4 
weeks at the normal visit schedule for the patient. 
x If a patient is on 100 mg vandetanib dose and has QTc >500 ms, vandetanib must be 
permanently discontinued. 
3.3.3.2 Gastrointestinal toxicity 
Nausea, vomiting, or both may be controlled with anti-emetic therapy.  The use of somatostatin or 
a somatostatin analogue is allowed to control diarrhea.  Diarrhea should be treated with standard 
medications to avoid dose modification or interruption, if possible.  No dose modifications will be 


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made for Grade 1 or 2 diarrhea; however, electrolyte supplementation with regular laboratory 
monitoring should be used, when appropriate, to maintain electrolytes within normal limits and 
prevent an increased risk of QTc prolongation. If CTCAE Grade 3 nausea or vomiting develops 
despite optimal prophylaxis/treatment, vandetanib should be withheld until resolution to CTCAE 
Grade 1 or baseline; vandetanib can then be restarted at a permanently reduced dose (reduced one 
dose level).   
If CTCAE Grade 3 diarrhea develops despite optimal prophylaxis/treatment, vandetanib should be 
withheld until diarrhea resolves to CTCAE Grade 1 or baseline; vandetanib can then be restarted 
at a permanently reduced dose (reduced one dose level).  Any electrolyte imbalance must be 
promptly corrected since hypokalemia and hypomagnesemia are potential risk factors for drug-
induced arrhythmia.  
Vandetanib will be permanently discontinued in the event of grade 4 nausea, vomiting or diarrhea 
occurring despite optimal prophylaxis/treatment. 
3.3.3.3 Cutaneous toxicity 
It is strongly recommended that all patients follow a program of sun protective measures (wearing 
additional clothing and/or sunscreen) while receiving study treatment and for 3 to 4 weeks after 
discontinuing study treatment.  The aim is to reduce the risk of development of skin rash, or 
minimize the severity of skin rash, and to minimize the requirement for dose reduction of study 
therapy. 
If a patient develops a skin rash, the following actions are recommended to the Investigator for the 
management of this reaction: 
x A variety of agents can be used to manage skin rashes.  These include mild to moderate 
strength steroid creams or systemic glucocorticoids, either topical or systemic antibiotics, 
topical or systemic antihistamines, and occasionally retinoid creams. 
x The rash should be graded as soon as possible according to the CTCAE cutaneous 
toxicity criteria. 
x If a rash of CTCAE Grade 2 or higher is detected, immediate symptomatic treatment 
should be provided. 
x If a rash of CTCAE Grade 3 is detected, vandetanib should be withheld until recovery to 
CTCAE Grade 1 or baseline; vandetanib can then be restarted at a permanently reduced 
dose (reduced one dose level as outlined above).  
x Vandetanib will be permanently discontinued if grade 4 rash related to the agent develops 
 
3.3.3.4 Hypertension 
Hypertension is one of the most common toxicities experienced with vandetanib. Subjects will 
be asked to monitor their blood pressure at home at least once a day and contact the UOB team 
for elevated readings. Elevated BP readings should be confirmed by a qualified health care 


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professional when possible and decisions regarding grading of hypertension and 
initiation/intensification of antihypertensive therapy will generally be driven by BP 
measurements performed by a health care professional.  
Table 1 outlines the management plan for patients developing hypertension on therapy. 
Although the active version of CTCAE criteria will be used to grade hypertension, the scheme 
outlined in the table below will be used to guide dose modifications. Early treatment of grades 1-
2 hypertension to prevent or minimize the risk of developing more persistent or clinically 
significant hypertension is allowed and is not considered a grade 3 event. 
The choice of agents and dosage used may vary based on individual circumstances. Calcium 
channel blockers, beta blockers, diuretics, ACE inhibitors, and angiotensin receptor blockers are 
examples of classes of antihypertensive agents that may be used. 
Table 1: Hypertension will be managed in accordance with the guidelines outlined in the table 
below: 
 
BP Measurements - Systolic/Diastolic Treatment/Dose Modification 
A 
>140 mmHg (systolic)  
OR 
>90 mmHg (diastolic)  
OR 
Increase of diastolic BP by ≥20 mmHg 
over baseline BP 
x Add new or additional antihypertensive 
medications or increase dose of existing 
medications. 
x Maintain dose of vandetanib and metformin. 
x If unable to control BP to <140/90 in two 
weeks, hold vandetanib and follow guidelines 
under row C 
B 
>160 mmHg (systolic) 
OR 
>100 mmHg (diastolic) 
OR 
Symptomatic 
 
x Hold vandetanib. 
x Add new or additional antihypertensive 
medications or increase dose of existing 
medications. 
x Resume treatment at same dose level when 
BP falls to <140/90 or baseline. 
C 
>140 mmHg (systolic) 
OR 
>90 mmHg (diastolic) 
Despite therapy for at least 2 weeks  
x Hold vandetanib. 
x Maintain or intensify antihypertensive therapy 
x Resume treatment at same dose level when 
BP falls to <140/90 or baseline 
D 
Life-threatening consequences (e.g., 
malignant hypertension, transient or 
permanent neurologic deficit, 
hypertensive crisis); urgent intervention 
indicated 
x Discontinue vandetanib  
x No further treatment with vandetanib allowed 
except in patients benefiting from therapy in 
whom treatment may be restarted if  BP is 
controlled to <140/90 within 3 weeks and 
there are no permanent sequelae. Patient will 
be removed from study if a second episode of 
grade 4 hypertension occurs 


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3.3.3.5 Pulmonary toxicity 
Although relatively rare, ILD associated with EGFR inhibitors, including vandetanib can be life 
threatening. Therefore, patients should be monitored closely for symptoms consistent with ILD, 
such as new onset dyspnea without an obvious cause. In the event that ILD is suspected, vandetanib 
treatment should be discontinued and the patient should receive appropriate medical management. 
Although there is no proven therapy, systemic corticosteroids are often used. Vandetanib should 
not be restarted in those patients with drug-related ILD. 
 
3.3.3.6 Other toxicity  
Patients who experience any other CTCAE (version 4) Grade 3 toxicity that is considered related 
to vandetanib will have their study drug temporarily stopped until resolution of the toxicity.  When 
the toxicity has recovered to CTCAE Grade 1 (or baseline) the patient may restart treatment at a 
permanently reduced dose (reduced one dose level as outlined above). Vandetanib will be 
permanently discontinued in patients who develop grade 4 toxicities thought to be related to the 
agent. All SAEs and study drug-related AEs must be followed until resolution to grade 1 or 
less/baseline unless in the Investigator’s opinion, the event has stabilized or is unlikely to resolve 
due to the patient’s underlying condition or other factors.  
If the patient has been off treatment for greater than 6 weeks due to toxicity, he/she must be 
withdrawn from vandetanib. 
 
3.3.4 Dose Modifications for Toxicities Related to Metformin  
The following dose levels will be used to guide reductions in metformin dosage: 
 
Current Dose 
Reduce to 
850 mg po bid 
500 mg po bid 
500 mg po bid 
250 mg po bid 
 
3.3.4.1 Gastrointestinal toxicity 
Both vandetanib and metformin can cause gastrointestinal issues, particularly diarrhea.  Nausea, 
vomiting, or both may be controlled with anti-emetic therapy. Diarrhea should be treated with 
standard medications to avoid dose modification or interruption, if possible.  No dose 
modifications will be made for Grade 1 or 2 diarrhea, however, electrolyte supplementation with 
regular laboratory monitoring should be used, when appropriate, to maintain electrolytes within 
normal limits and prevent an increased risk of QTc prolongation. 
If CTCAE Grade 3 diarrhea develops, metformin should be withheld until diarrhea resolves to 
CTCAE Grade 1 or baseline.  If metformin is thought to be causative (typically occurs within the 
first few weeks of therapy), it can then be restarted at a reduced dose as outlined in the dose 
modification scheme in this section (above).  Metformin will be discontinued permanently in the 


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event of grade 4 diarrhea related to the agent. Any electrolyte imbalance must be promptly 
corrected since hypokalemia and hypomagnesemia are potential risk factors for drug-induced 
arrhythmia. 
3.3.4.2 Lactic acidosis 
Patients taking metformin can rarely develop lactic acidosis. Lactic acidosis is characterized by 
elevated blood lactate levels (>5 mmol/L), decreased blood pH, electrolyte disturbances with an 
increased anion gap, and an increased lactate/pyruvate ratio. When metformin is implicated as the 
cause of lactic acidosis, metformin plasma levels >5 μg/mL are generally found. 
Lactic acidosis is a medical emergency that must be treated in a hospital setting. In a patient with 
lactic acidosis who is taking metformin, the drug should be discontinued immediately and general 
supportive measures promptly instituted. Because metformin is dialyzable (with a clearance of up 
to 170 mL/min under good hemodynamic conditions), prompt hemodialysis may be used to correct 
the acidosis and remove the accumulated metformin. Such management often results in prompt 
reversal of symptoms and recovery.  
If lactic acidosis develops, it will be assumed to be due to metformin and the study drug will be 
permanently stopped. Since vandetanib has been associated with impaired renal function 
(potentially exacerbating lactic acidosis) and since acidosis might lead to electrolyte disturbances 
that can potentiate vandetanib-associated cardiac toxicity, vandetanib will be held in patients with 
lactic acidosis until resolution of the event but can be resumed thereafter at the previous dose level. 
3.3.4.3 Other toxicity 
Patients who experience a CTCAE (version 4) Grade 3 toxicity that is considered related to 
metformin will have their study drug temporarily stopped until resolution of the toxicity.  When 
the toxicity has recovered to CTCAE Grade 1 (or baseline) the patient may restart treatment at a 
permanently reduced dose (reduced one dose level as outlined above). 
The Investigator can reduce the dose of metformin to the lowest dose of 250 mg BID.  If a patient 
experiences a Grade 3 or 4 toxicity that is considered related to metformin while on the 250 mg 
dose, they will have study drug permanently stopped.  
Metformin will be withheld under the following circumstances, regardless of whether these 
events are related to the agent: 
1) Although metformin is not associated with renal impairment, patients with impaired renal 
function are at higher risk for lactic acidosis. Therefore, metformin should be temporarily 
discontinued in all patients with an eGFR of 40 ml/min or less regardless of causality. 
Metformin can be restarted at the previous dose once the eGFR improves to 50 ml/min or 
higher.  
2) The risk of lactic acidosis from metformin may be increased in patients with hepatic 
dysfunction. Therefore, patients with grade 3 or higher AST/ALT elevations or 
hyperbilirubinemia will have their metformin held until these values return to grade 
1/baseline. 
3) Patients receiving iodinated IV contrast agents (for CT scans etc.) will have their 
metformin held on the morning of the planned procedure. A serum creatinine/eGFR will 
be rechecked approximately 2 days after the procedure and metformin may be restarted if 
the eGFR is >40 ml/min. 


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All SAEs and study drug-related AEs must be followed until resolution to grade 1 or less/baseline 
unless in the Investigator’s opinion, the event has stabilized or is unlikely to resolve due to the 
patient’s underlying condition or other factors.  
If the patient has been off treatment for greater than 6 weeks due to toxicity, he/she must be 
withdrawn from metformin. 
 
3.3.5 Treatment interruptions unrelated to toxicity 
Surgery 
Major elective surgical procedures should not be scheduled during protocol treatment or within 4 
weeks of the last dose of vandetanib. Patients undergoing unexpected major surgical procedures 
should have the study agents withheld. Treatment may be resumed at a later date at the discretion 
of the PI (vandetanib should not be resumed earlier than 4 weeks post-operatively, with adequately 
healed incisions). Patients requiring surgical resection of one or more of their metastatic lesions 
will discontinue treatment permanently. 
Radiation 
Patients requiring radiation therapy for RCC will permanently discontinue study treatment. 
3.3.6 Management of Female Study Subjects 
Women of childbearing potential should have a negative pregnancy test prior to starting therapy 
with vandetanib/metformin and should use adequate contraception during and for at least 6 months 
after vandetanib/metformin therapy as indicated in section 2.1.1.8.  Women who become pregnant 
while on vandetanib/metformin will discontinue the drug combination.  It is not known whether 
vandetanib is excreted in human milk.  Low amounts of metformin (generally ≤1% of the weight-
adjusted maternal dose) are excreted into breast milk.  Women will not be permitted to breast-feed 
while receiving vandetanib/metformin therapy.   
 
3.4 
STUDY EVALUATION 
3.4.1 Baseline Evaluation 
Baseline studies need not be repeated if they have been performed within the timeframes listed 
below at screening. 
The following baseline studies must be performed within 4 weeks prior to enrollment on study: 
x A complete history and physical with documentation of measurable disease and 
performance status 
x 12 lead ECG 
x Photographic evaluation of skin leiomyoma (only in patients with HLRCC associated 
cutaneous leiomyomas) 
 
The following must be performed within 2 weeks prior to enrollment on study: 


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x Imaging studies: CT of the chest abdomen and pelvis (or MRI scans when indicated) 
x MRI (or CT with contrast) of the brain 
x PET scan 
x Bone Scan 
x Targeted history and physical examination focusing on any salient changes from baseline  
x CBC with differential, Acute Care Panel, Hepatic Panel, Mineral Panel, LDH, total protein, 
creatine kinase, uric acid, PT/PTT, urinalysis, spot urine protein:creatinine ratio (patients 
with 1+ or greater proteinuria on UA and a spot urine protein:creatinine ratio of > 0.5 will 
undergo a 24 hour urine collection for quantitation of proteinuria) 
x Urine or serum pregnancy test in women of childbearing potential 
x TSH, T3 and T4 tests 
 
3.4.2 Each cycle 
All patients must be seen at NIH Clinical Center at the beginning of each cycle. Interim 
assessments may be performed by a local laboratory/physician. For patients requiring a metformin 
lead-in, a visit to the NIH Clinical Center will also be required on Day 15 of Cycle 2. See Study 
Calendar for labs done if C2D15 if required. 
Assessments may be performed within ± 7 days of what is indicated with exception of ECG.  
x Limited history and physical focusing on relevant changes from initial H&P (performed on 
days 15 and 28 in cycle 1 and on day 28 of subsequent cycles) 
x CBC, Hepatic Panel, LDH, total protein, creatine kinase, uric acid, urinalysis, spot urine 
protein:creatinine ratio (performed on days 15 and 28 in cycle 1 and on day 28 of 
subsequent cycles) 
x Acute Care Panel, Mineral Panel, lactate (performed weekly in cycle 1 & days 15 and 28 
in cycle 2, then on day 28 of subsequent cycles) 
x Pregnancy test in women of childbearing potential 
x 12-lead ECG within 4-8 hours after first dose of vandetanib on day -13 for metformin lead-
in patients and cycle 1 day 2 for patients without metformin lead-in, then weekly during 
the first cycle & days 15 and 28 in cycle 2, then on day 28 of subsequent cycles) 
x Research PET scan on Cycle 1 Day 15, if positive at baseline 
x TSH, T3 and T4 tests at 2-4 weeks, 8-12 weeks, and then every 3 months thereafter. 
3.4.3 Restaging cycles  
Every two cycles (every 8 weeks) during first 8 cycles (first 32 weeks), then every three cycles 
(every 12 weeks) thereafter 
x Imaging studies: CT/MRI evaluation of known/suspected disease sites, bone scan (if 
positive for metastatic bony disease at baseline) 
x PET scan (only when necessary to supplement CT/MRI, for instance new lesions of 
uncertain etiology, to confirm CR etc.)  
x Dermatology Consult with photographic evaluation of skin leiomyoma (only in patients 
with HLRCC associated cutaneous leiomyomas) 
 


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3.4.4 Daily Monitoring 
Blood Pressure- Patient will be asked to measure and record his/her blood pressure at least once a 
day and will be provided with an automated/semi-automated BP monitor. Patients will be 
instructed to record BP readings on a BP monitoring diary which will be provided (see Appendix 
F) and will be reviewed by the research nurse/PI/AI at each clinic visit. In addition, patients will 
call the UOB research team for readings above 140/90 mmHg and may be instructed to have 
elevated readings confirmed by a local health care provider. 
 


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3.5 
STUDY CALENDAR  
All patients must be seen at NIH Clinical Center at the beginning of each cycle. Interim assessments may be performed by a local 
laboratory/physician.  
Post baseline assessments may be performed within ± 7 days of what is indicated with exception of Day -13 (metformin lead-in)/C1D2 
(without metformin lead-in) ECG which must be performed 4 – 8 hours after first dose of vandetanib. 
 
Study Drug Administration  
For patients receiving >250 mg metformin (with metformin lead-in) 
Study Drug 
Lead In Period 
 
Cycle 1 
 
Subsequent Cycles 
Day -14  
Day -13  
through Day -1 
Day 1 to Day 28 
Day 1 to Day 28 
Metformin 
X 
 
 
 
 
Vandetanib  
 
X  
 
 
 
 
For patients receiving < 250 mg metformin (without metformin lead-in) 
Study Drug 
Cycle 1 
Subsequent Cycles 
Day 1  
Day 2  
through Day 28 
Day 1 to Day 28 
Metformin 
X 
 
 
 
Vandetanib 
 
X 
 
 
 


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Procedure8 
 
 
Screening1 
 
Baseline1 
 
 
Lead-
in 
Period 
 
 
Cycle 1 
 
Cycle 2 
Subsequent 
Cycles 
60 Day 
Safety 
Visit 
Long 
Term 
Follow 
Up7 
Day 
1 
Day 
7 
Day 
15 
Day 
21 
Day 
28 
Day 1 
(day 29 
of 
previous 
cycle) 
Day 
7 
Day 
15 
Day 
21 
Day 
28 
Day 28 
 
 
History and PE 
X 
X 
 
 
 
X 
 
X 
 
 
X2 
 
X 
X 
X 
 
Vital signs 
X 
X 
 
 
 
X 
 
X 
 
 
X2 
 
X 
X 
X 
 
Performance 
Score 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Acute Care Panel, 
Mineral Panel, 
lactate 
X 
X 
 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
CBC, Hepatic 
Panel, urinalysis, 
UPCR 
X 
X 
 
 
 
X 
 
X 
 
 
X2 
 
X 
X 
X5 
 
LDH, total 
protein, creatine 
kinase, uric acid, 
PT/PTT 
X 
X 
 
 
 
X 
 
X 
 
 
X2 
 
X 
X 
 
 
Serum or urine 
βHCG in women 
of child bearing 
potential only 
X 
X 
 
 
 
 
 
X 
 
 
 
 
X 
X 
 
 
TSH, T3 and T4 
 
X 
 
 
 
 
 
2-4 weeks 
 
 
 
 
 
8-12 weeks and 
every 3 months 
thereafter 
 
 


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Procedure8 
 
 
Screening1 
 
Baseline1 
 
 
Lead-
in 
Period 
 
 
Cycle 1 
 
Cycle 2 
Subsequent 
Cycles 
60 Day 
Safety 
Visit 
Long 
Term 
Follow 
Up7 
Day 
1 
Day 
7 
Day 
15 
Day 
21 
Day 
28 
Day 1 
(day 29 
of 
previous 
cycle) 
Day 
7 
Day 
15 
Day 
21 
Day 
28 
Day 28 
 
 
Pathology 
Confirmation of 
Diagnosis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT chest (and 
neck, if indicated) 
+ CT or MRI 
abdomen/pelvis9 
X 
X 
 
 
Every 2 cycles during the first 8 cycles, then every 3 
cycles thereafter 
 
 
Brain MRI or CT 
with contrast 
X 
X 
 
 
 
 
 
Bone Scan9 
 
X 
 
 
If positive at baseline, every 2 cycles during the first 
8 cycles, then every 3 cycles thereafter 
 
 
PET/CT scan9 
 
X 
 
 
 
X10 
 
 
  
 
 
 
 
X10 
 
 
Photographic 
evaluation of skin 
leiomyoma4, 9  
 
X 
 
 
Every 2 cycles during the first 8 cycles, then every 3 
cycles thereafter 
 
 
Echocardiogram 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
X 
X 
X3 
X3 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
 
Pharmacokinetic 
Studies 
 
 
X11 
X12 
 
 
 
 
X13 
 
 
 
 
 
 
 
Pharmacogenetic 
Studies 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Procedure8 
 
 
Screening1 
 
Baseline1 
 
 
Lead-
in 
Period 
 
 
Cycle 1 
 
Cycle 2 
Subsequent 
Cycles 
60 Day 
Safety 
Visit 
Long 
Term 
Follow 
Up7 
Day 
1 
Day 
7 
Day 
15 
Day 
21 
Day 
28 
Day 1 
(day 29 
of 
previous 
cycle) 
Day 
7 
Day 
15 
Day 
21 
Day 
28 
Day 28 
 
 
Optional biopsy 
of accessible 
tumor 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Correlative 
Research Studies7 
 
X 
 
 
At the end of every other cycle through cycle 8 and at the time of disease 
progression 
 
 
Adverse Events 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
Medications 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood pressure 
monitoring 
 
 
 
 
Performed daily by patient 
 
 
Annual phone 
calls 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
1 Baseline studies do not need to be repeated if already performed at appropriate time during screening. See sections 2.2 and 3.4.1 for 
timing of screening and baseline studies. 
2 Only required in patients that have had a metformin lead-in. 
  
3 Performed within 4 to 8 hours after first dose of vandetanib on day -13 for metformin lead-in patients and cycle 1 day 2 for patients 
without metformin lead-in 
4 Done only in patients with HLRCC associated cutaneous leiomyomas 
5 Only ALT, AST, total and direct bilirubin should be performed at safety visit 
6 Subjects will be contacted annually for an update and to determine survival status. Any scans performed outside of NIH will be 
obtained when possible. 


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7 5 – 10 ml of venous blood in sodium citrate CPT tubes collected at baseline, then at the end of every other cycle through cycle 8, then 
at the time of disease progression; See section 5.1.2 for assessments performed on these samples. 
8All laboratory studies will be performed within +/-5 days of the day indicated, imaging studies, optional biopsies and collection of 
samples for correlative studies will be performed within +/- 7 days of the indicated timepoint and ECGs within +/- 2 days of the 
indicated time points 
9 Restaging studies may be performed outside the indicated time period if necessitated by circumstances beyond the control of the 
investigators/research team.  
10 Cycle 1 Day 15 (+/- 7 days) research PET scan, if positive at baseline.  Follow-up PET scan only when necessary to supplement 
CT/MRI. 
11 On day -14 for patients receiving >250 mg metformin (with metformin lead-in) – at pre-dose, 0.5 (+/-10 minutes), 1 (+/-10 minutes), 
2 (+/-10 minutes), 3 (+/-30 minutes), 4 (+/-30 minutes), 8 (+/-30 minutes), 12 (+/-30 minutes), 18 (+/-30 minutes), and 24 (+/-30 minutes) 
hr post-dose.   
12 On cycle 1 day 1 for patients receiving < 250 mg metformin (without metformin lead-in) – at pre-dose, 0.5 (+/-10 minutes), 1 (+/-10 
minutes), 2 (+/-10 minutes), 3 (+/-30 minutes), 4 (+/-30 minutes), 8 (+/-30 minutes), 12 (+/-30 minutes), 18 (+/-30 minutes), and 24 (+/-
30 minutes) hr post-dose.   
13 After dose titration (if necessary) – at pre-dose, 0.5 (+/-10 minutes), 1 (+/-10 minutes), 2 (+/-10 minutes), 3 (+/-30 minutes), 4 (+/-30 
minutes), 8 (+/-30 minutes), 12 (+/-30 minutes), 18 (+/-30 minutes), and 24 (+/-30 minutes) hr post-dose. 
 


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3.6 
FOLLOW UP EVALUATIONS 
After subjects have stopped taking the study medication for any of the reasons listed in section 
3.7.1 they will be seen at NIH, if feasible, for a safety visit within approximately 60 days of drug 
discontinuation.  The safety assessments may be performed by a local physician and laboratory if 
patients unable to return to the NIH Clinical Center at this time or the patient may be contacted by 
phone for a status assessment.  
The following assessments will be performed at follow up if feasible. 
x History and Physical Examination 
x CBC with differential, acute care panel, AST, ALT, Total and Direct Bilirubin 
After the safety visit, if there are no unresolved grade 3 or higher AEs, we may, when feasible 
contact the patient annually by telephone to find out how they are doing and to determine survival 
status.  If there are unresolved grade 3 – 4 AEs, patients will be followed either at the NIH Clinical 
Center or by their local physician.  In the latter case, we will obtain the physician’s record of AEs. 
Any scans performed outside of the NIH will also be obtained when possible.   
3.7 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA    
Prior to removal from study, effort must be made to have all subjects complete a safety visit 
approximately 60 days following the last dose of study therapy. 
3.7.1 Criteria for removal from protocol therapy 
x Progressive disease 
x Patient is off vandetanib treatment for > 6 weeks due to toxicity 
x Participant requests to be withdrawn from active therapy 
x Unacceptable Toxicity as defined in sections 3.3.3 and 3.3.4  
x Requires radiation or surgery for RCC 
x Investigator discretion 
x Positive pregnancy test   
3.7.2 Off-Study Criteria 
x Patient lost to follow-up 
x Investigator discretion 
x Participant requests to be withdrawn from study 
x Death 
3.7.3 Off Protocol Therapy and Off Study Procedure 
Authorized staff must notify Central Registration Office (CRO) when a subject is taken off 
protocol therapy and when a subject is taken off-study. A Participant Status Updates Form from 
the web site (http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) main page must be 


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completed and sent via encrypted email to:  NCI Central Registration Office 
ncicentralregistration-l@mail.nih.gov. 
4 
CONCOMITTANT MEDICATION 
4.1 
CONCURRENT AND EXCLUDED THERAPIES 
At screening, all prior anti-cancer therapy and administration of all other concomitant medication 
in use on the day of enrolment (signature of the ICF) will be recorded.  All concomitant 
medications that the patient has been taking since the time of the last visit, medications the patient 
started between visits and all new medications will be recorded at each visit until the patient is 
permanently removed from study therapy.  If a patient discontinues the trial agents before the final 
analysis, all medications including any medications started within the 60 days after the last dose, 
will be recorded at the appropriate discontinuation visit and the 60-day follow-up visit. 
4.1.1 Prohibited medication 
Patients are not eligible to enter the study if they are on any of the medication specified in the 
exclusion criteria. 
4.1.2 Treatment for cancer 
While the patient remains on study treatment, patients must not be given any concurrent cancer 
therapy, including cytotoxic agents, radiotherapy, biological response modifiers (including 
cytokines), hormonal therapy (used specifically for cancer treatment), or any other investigational 
agents.  Bisphosphonates or other agents designed to minimize the risk of skeletal complications, 
such as denosumab, may be used. 
4.1.3 CYP3A4 inducers 
Concomitant use of known potent inducers of CYP3A4 (eg. rifampicin, phenytoin, 
carbamazepine, barbiturates, and St. John’s Wort) are not allowed; in subjects who have 
discontinued use of these drugs, at least five half-lives of the drug must have elapsed before the 
first scheduled dose of vandetanib.  Please see 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx for a continually updated list of CYP3A4 
inducers. 
4.1.4 Medication known to prolong QT interval and/or induce Torsades de Pointes 
Concomitant use of medications generally accepted as having a risk of causing Torsades de Pointes 
(see Appendix C) are not allowed during study; in subjects who have discontinued use of these 
drugs, at least five half-lives of the drug must have elapsed before the first scheduled dose of 
vandetanib (at least 4 weeks prior for levomethadyl).  It is also recommended that these drugs be 
avoided for at least 4 weeks following discontinuation of study treatment. 
4.1.5 Restricted medication 
All medications prohibited in this study as indicated in Appendix C and in the eligibility criteria 
in section 2.1 must have been withdrawn for a period equivalent to at least five half-lives of the 
drug before the first scheduled dose of vandetanib, and should be avoided for at least 4 weeks 
following discontinuation of study treatment. 


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Co-administration of drugs that in some reports might be associated with Torsades de Pointes but 
at this time lack substantial evidence of Torsades de Pointes (see Appendix C, Table 3) should be 
avoided during the study; in subjects who have discontinued use of these drugs, at least five half-
lives of the drug must have elapsed before the first scheduled dose of vandetanib.  However, these 
drugs will be allowed, at the discretion of the Investigator, if considered absolutely necessary.  In 
such cases, the patient must be closely monitored including regular checks of QTc and electrolytes.  
The electrolytes should be maintained within the normal range using supplements if necessary. 
Warfarin is allowed in therapeutic and low-doses and these patients should be monitored regularly 
for changes in their International Normalized Ratio, at the discretion of the Investigator. 
4.1.6 Other concomitant treatment 
Cationic drugs (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, 
triamterene, trimethoprim, or vancomycin) that are eliminated by renal tubular secretion 
theoretically have the potential for interaction with metformin by competing for common renal 
tubular transport systems.  While the interaction is theoretical and not well-studied, these agents 
should be avoided if alternatives exist while patients are taking metformin.  
4.2 
SUPPORTIVE CARE 
Other medication that is considered necessary for the patient’s safety and well-being, may be given 
at the discretion of the Investigator.  Supportive care measures and symptomatic treatment for any 
treatment-associated toxicity may be instituted once the first signs of toxicity occur. Supportive 
care will be provided in accordance with good medical practice.  
5 
BIOSPECIMEN COLLECTION  
5.1 
CORRELATIVE STUDIES FOR RESEARCH 
5.1.1 Tumor Biopsy (Optional) 
Although the genes for HLRCC and SDH-related RCC are known, the genetic and biochemical 
abnormalities underlying the majority of papillary tumors remains unclear. Recent data (40) 
suggests that components of the KEAP1/NRF2 pathway may be altered in some papillary tumors, 
but need further study. Additionally, there are currently no prognostic biomarkers or markers that 
predict response of papillary tumors to therapy. Targeted sequencing and immunohistochemical 
studies may be performed on available tumor tissues to identify somatic genetic alterations and 
explore potential biomarkers. Tumor biopsies may also be used to determine the effect of therapy 
on VEGFR, EGFR, abl, cAMPK/mTOR and other relevant pathways that may be impacted by 
therapy with the combination of vandetanib/metformin. 
Tumor biopsies (renal primary or metastases or cutaneous/uterine leiomyomas) may be obtained 
from patients who have easily accessible lesions. Core or excisional biopsy of an easily accessible 
sentinel lesion (such as cutaneous/subcutaneous lesions, percutaneously accessible hepatic lesions, 
lymph nodes etc.) may be performed at study entry and again at approximately 8 weeks following 
initiation of therapy. No more than 4 cores may be obtained from a single site. Biopsies that are to 
be used solely for research purposes will be obtained only if they can be performed with minimal 
risk of complications from the procedure and only after the procedure has been explained to the 
patient and informed consent obtained. Major surgical procedures such as laparotomy or 
laparoscopic procedures will not be performed solely to obtain biopsies for research purposes. The 


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biopsies will be performed by members of the interventional radiology, dermatology or surgical 
staff. A portion of the biopsies may be frozen in liquid nitrogen immediately and transferred to the 
UOB laboratory (Contact for receiving and processing specimen: Robert Worell/ Cathy Vocke, 
Ph.D. - Tel: 301-496-6353). Prior to freezing and depending on tissue availability, a small portion 
of the biopsy specimen may be transferred under sterile conditions to the UOB laboratory to be 
used to establish a tumor cell line. 
In addition, attempts will be made to obtain any available archived tumor tissue on all patients to 
help evaluate FH and SDH status, the activation of or mutations in the NRF2/KEAP1/CUL3 
pathway and/or relevant components of the VEGF/EGFR pathways. Either sequencing of 
individual genes or next gen sequencing as part of a limited gene panel (such as the one used by 
the Genetics Branch, CCR, NCI), will be used to identify the presence/absence of these somatic 
mutations. 
Samples will be processed for the following planned studies. In the event of limited sample 
availability, we plan to prioritize studies in the order listed below: 
x Analysis of somatic FH/SDH mutation, KEAP1, NRF2, Cul 3 and Sirt 1 mutations and 
IHC for markers indicating activation of the NRF2 pathway (such as NQ01) to attempt to 
correlate clinical effects of vandetanib and metformin with molecular abnormalities (may 
be performed on archived tumor tissue or tumor biopsies when available) 
x Analysis of relevant pathways such as AMPK and Abl at baseline and/or modulation of 
these pathways in response to therapy; techniques such as IHC, Western blotting etc. may 
be used. 
x Evaluation of HIF expression, EGFR expression, VEGFR2 expression and relevant 
downstream pathways; evaluation of components of the EGF and VEGF pathways may be 
performed to explore the correlation between these biomarkers and clinical response. 
x Analysis by RT- PCR and/or IHC of transcriptional targets affected by AMPK, EGFR, and 
VEGF signaling pathways, including p27 KIP1, E-cadherin, b-catenin, ACC etc. 
x cDNA arrays to compare gene expression profiles in tumor cells before and during 
treatment with vandetanib and metformin 
 
5.1.2 Blood Samples 
Collection of blood samples for research analysis may be obtained at periodic intervals which meet 
the NIH Guidelines for Blood Draw Limit (MAS - M95-9).  No more than 10.5 mL/kg or over 
550mL will be obtained from adults over an eight week period of time.   
x Blood samples for evaluation of basal plasma levels of angiogenesis biomarkers including 
VEGF and soluble VEGFR2 and to assess the effect of vandetanib and metformin on these 
biomarkers. These will be obtained prior to first dose, at 8, 16, 24 and 32 weeks, and at the 
time of disease progression. 5-10 cc of venous blood will be collected into CPT tubes 
containing sodium citrate and thoroughly mixed and then transferred to the UOB 
laboratories for further processing and storage. 
5.1.2.1 Correlative laboratory studies will be performed by investigators in the Urologic 
Oncology Branch (under the direction of Drs. Srinivasan, Linehan, Bottaro, Neckers) and 
may involve collaboration with other NIH intramural investigators including Jane Trepel. 


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Studies listed will be performed wherever possible and as permitted or dictated by clinical 
outcome and/or sample and resource availability. 
5.1.3 Collection, Storage, Use and Disposition of Human Specimens 
5.1.3.1 Clinical Samples 
Blood and urine samples for clinically relevant, non-research hematology, serum chemistry, 
urinalysis, and skin biopsy tissue will be prepared using standard procedures.  Routine clinical 
analyses will be performed by the NIH Clinical Center central laboratories or NCI Pathology 
department.  Samples will be processed and disposed according to standard laboratory procedure. 
5.1.3.2 Storage and research use of research human specimens 
x Sample Collection and Planned Research Studies: Research samples will be collected with 
a view to performing a variety of correlative/biomarker studies (as indicated in section 
5.1.2). 
x Sample Processing and Storage:  Each patient research sample will be assigned a unique 
patient identifier and relevant sample characteristics (such as timing of sample collection, 
treatment cycle and day identifiers) will be recorded. The location of all samples will be 
carefully tracked in the secure UOB database.  All stored samples will be coded and no 
identifying patient information will be on placed on sample containers. Stored samples will 
be kept in freezers / refrigerators or secure containers located in the Urologic Oncology 
Branch research laboratories or in the laboratories of collaborators.   
x Timeframe for research studies- Samples will be stored until requested by an authorized 
researcher(s).  All researchers are required to use the samples for research purposes 
associated with this trial (as per the NCI IRB approved protocol). Subjects will be given 
the option of consenting to future use of their research samples per the informed consent 
process with their option declared in the consent document.  Samples from those patients 
who consent to this will be stored permanently. However, these samples will be used only 
for research studies on active NCI IRB approved protocols covered by a valid informed 
consent document. Samples will be destroyed at the completion of the study from those 
subjects who decline future use of their samples. Once primary research objectives for the 
protocol are achieved, intramural researchers can request access to remaining samples 
provided they have an IRB approved protocol and patient consent. Any unused samples 
must be returned to the UOB laboratories as appropriate. The PI will report destroyed 
samples to the IRB if samples become unsalvageable because of environmental factors 
(e.g. broken freezer or lack of dry ice in a shipping container) or if samples are destroyed 
because a patient withdraws consent. Samples will also be reported as lost if they are lost 
in transit between facilities or misplaced by a researcher.  Any freezer problems, lost 
samples or other problems associated with samples will be reported to the IRB, the NCI 
Clinical Director, and the office of the CCR, NCI. 
 
5.2 
PHARMACOKINETIC/PHARMACOGENETIC STUDIES 
5.2.1 Pharmacokinetic Studies 
To identify a drug interaction between metformin and vandetanib on clinically-relevant doses, 
blood samples for the determination of metformin plasma concentrations will be obtained from 


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each patient either on day -14 (day 1 of lead in period for patients receiving >250 mg metformin) 
or cycle 1, day 1 (for patients receiving < 250 mg metformin), when metformin will be 
administered alone. Blood will be collected into a 6mL sodium heparin tube (BD, Franklin Lakes, 
NJ) at the following time points: pre-dose, 0.5 (+/-10 minutes), 1 (+/-10 minutes), 2 (+/-10 
minutes), 3 (+/-30 minutes), 4 (+/-30 minutes), 8 (+/-30 minutes), 12 (+/-30 minutes), 18 (+/-30 
minutes), and 24 hr (+/-30 minutes) post-dose.   
After dose titration (if necessary), patients will have blood drawn at pre-dose, 0.5 (+/-10 minutes), 
1 (+/-10 minutes), 2 (+/-10 minutes), 3 (+/-30 minutes), 4 (+/-30 minutes), 8 (+/-30 minutes), 12 
(+/-30 minutes), 18 (+/-30 minutes), and 24 hr (+/-30 minutes) post-dose on cycle 2, day 1, after 
being on the daily combination of metformin and vandetanib for at least 4 weeks to establish 
steady-state. Comparisons of metformin exposure between cycle 2 (with vandetanib) and first-
dose (alone) will determine the extent of drug-interaction (if any) with vandetanib. 
Bioanalytical measurements of metformin and vandetanib will be conducted on an ultra HPLC-
MSMS system using an assay developed and validated by the Blood Processing Core Lab. 
The PK sampling will also be used to monitor vandetanib and metformin exposure metrics in order 
to correlate to pharmacodynamic endpoints, clinical response, toxicity, and pharmacogenetic 
analyses.  
 
5.2.2 Pharmacogenetic Studies 
One blood sample per patient will be collected in a purple top tube for pharmacogenetic studies to 
analyze the genomic DNA and assess genotype of the most relevant drug metabolizing enzymes 
and transporters (DMET). DNA will be analyzed on a DMET Plus (Affymetrix) genotyping 
platform that tests for 1,936 genetic variations in 225 drug disposition genes, including 47 CYP 
(phase I metabolism) genes, 13 non-CYP (phase I metabolism) genes, 78 phase II metabolizing 
genes (including UGTs), 63 transporters, 4 genes involved in facilitation of drug transporters, 9 
genes involved in global regulation of drug metabolizing/transporting proteins, 4 drug binding 
proteins, and 4 drug targets. 
Of particular interest to vandetanib pharmacological actions (and hypothesized interaction with 
metformin) is the inhibition of MATE1, MATE2K, and OCT2. The presence of SNPs in the genes 
encoding these transporters may alter the PK of the drug combination and any interaction.  MATE1 
and MATE2K are not included in the DMET platform (OCT2 is), therefore genetic analysis for 
MATE1 and MATE2K will be performed using direct sequencing, Taqman genotyping, or 
multiplexed genotyping as needed.  
5.2.3 Handling and Processing of Specimens 
The samples will be placed immediately on wet ice and refrigerated. The date and exact time of 
each blood draw should be recorded on the sample tube and the PK sheet.  
Please e-mail Julie Barnes at Julie.barnes@nih.gov and Paula Carter pcartera@mail.nih.gov at 
least 24 hours before transporting samples (the Friday before is preferred). 
For sample pickup, page 102-11964. 


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For immediate help, call 240-760-6180 (main blood processing core number) or, if no answer, 
240-760-6190 (main clinical pharmacology lab number). 
For questions regarding sample processing, contact Julie Barnes by e-mail or at 240-760-6044. 
Upon arrival in the Blood Processing Core, samples will be centrifuged and the plasma transferred 
into cryovials for storage at -80 C until the time of analysis. In addition, samples will be barcoded 
as described in Section 5.2.4. 
 
5.2.4 Blood Processing Core (BPC)– Storage 
All samples will be bar-coded, with data entered and stored in the LABrador (aka LabSamples) 
utilized by the BPC. This is a secure program, with access to LABrador limited to defined Figg 
lab personnel, who are issued individual user accounts. Installation of LABrador is limited to 
computers specified by Dr. Figg. These computers all have a password restricted login screen. All 
Figg lab personnel with access to patient information annually complete the NIH online Protection 
of Human Subjects course.  
LABrador creates a unique barcode ID for every sample and sample box, which cannot be traced 
back to patients with LABrador access. The data recorded for each sample includes the patient ID, 
name, trial name/protocol number, time drawn, cycle time point, dose, material type, as well as 
box and freezer locations. Patient demographics associated with the clinical center patient number 
are provided in the system. For each sample, there are notes associated with the processing method 
(e.g. delay in sample processing, storage conditions on the ward, etc). 
Bar-coded samples are stored in bar-coded boxes in locked freezers at either -20 C or -80 C 
according to stability requirements. These freezers are located onsite in the BPC and offsite at NCI 
Frederick Central Repository Services in Frederick, MD. Visitors to the laboratory are required to 
be accompanied by laboratory staff at all times.  
Access to stored clinical samples is restricted. Samples will be stored until requested by a 
researcher named on the protocol. All requests are monitored and tracked in LABrador. All 
researchers are required to sign a form stating that the samples are only to be used for research 
purposes associated with this trial (as per IRB approved protocol) and that any unused samples 
must be returned to the BPC. It is the responsibility of the NCI Principal Investigator to ensure that 
the samples requested are being used in a manner consistent with IRB approval. 
Following completion of this study, samples will remain in storage as detailed above. Access to 
these samples will only be granted following IRB approval of an additional protocol, granting the 
rights to use the material. 
If, at any time, a patient withdraws from the study and does not wish for their existing samples to 
be utilized, the individual must provide a written request. Following receipt of this request, the 
samples will be destroyed (or returned to the patient, if so requested), and reported as such to the 
IRB. Any samples lost (in transit or by a researcher) or destroyed due to unknown sample integrity 
(i.e. broken freezer allows for extensive sample thawing, etc.) will be reported as such to the IRB. 
Sample bar-codes are linked to patient demographics and limited clinical information. This 
information will only be provided to investigators listed on this protocol, via registered use of the 
LABrador. It is critical that the sample remains linked to patient information such as race, age, 


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dates of diagnosis and death, and histological information about the tumor, in order to correlate 
genotype with these variables.  
6 
DATA COLLECTION AND EVALUATION  
6.1 
DATA COLLECTION 
All radiographic images will be stored in the Dept. of Radiology, Clinical Center, NIH and will be 
reviewed by NIH CC staff radiologists.   
The PI will be responsible for overseeing entry of data into an in-house password protected 
electronic system (C3D) and ensuring data accuracy, consistency and timeliness. The principal 
investigator, associate investigators/research nurses and/or a contracted data manager will assist 
with the data management efforts.  All data obtained during the conduct of the protocol will be 
kept in secure network drives or in approved alternative sites that comply with NIH security 
standards. Primary and final analyzed data will have identifiers so that research data can be 
attributed to an individual human subject participant. 
All Adverse events, including clinically significant abnormal findings on laboratory evaluations, 
regardless of severity, will be followed until return to baseline or stabilization of event. Patients 
will be followed for adverse events for 60 days after removal from study treatment or until off-
study, whichever comes first. 
An abnormal laboratory value will be recorded in the database as an AE only if the laboratory 
abnormality is characterized by any of the following: 
x 
Results in discontinuation from the study 
x 
Is associated with clinical signs or symptoms  
x 
Requires treatment or any other therapeutic intervention 
x 
Is associated with death or another serious adverse event, including hospitalization.  
x 
Is judged by the Investigator to be of significant clinical impact 
x 
If any abnormal laboratory result is considered clinically significant, the investigator will 
provide details about the action taken with respect to the test drug and about the patient’s 
outcome. 
 
End of study procedures: Data will be stored according to HHS, FDA regulations and NIH 
Intramural Records Retention Schedule as applicable.  
Loss or destruction of data: Should we become aware that a major breach in our plan to protect 
subject confidentiality and trial data has occurred, the IRB will be notified.  
 
6.1.1 Patient records and quality assurance 
Complete records must be maintained on each patient treated on the protocol.  These records will 
include primary documentation to confirm that: 
x The subject met all eligibility criteria 


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x Signed informed consent was obtained prior to treatment 
x Treatment was given according to protocol 
x Toxicity was assessed according to protocol 
x Response was assessed according to protocol 
 
6.2 
RESPONSE CRITERIA 
For the purposes of this study, patients should initially be re-evaluated for response every 8 weeks 
during the first 32 weeks and every 12 weeks thereafter.  In addition to a baseline scan, 
confirmatory scans should also be obtained ≥ 4 weeks following initial documentation of objective 
response.  (See section 3.4.3 for restaging assessments.) 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) [Eur J Ca 45:228-247, 2009].  Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes 
are used in the RECIST criteria. 
 
6.2.1 Definitions 
x Evaluable for toxicity:  All patients will be evaluable for toxicity from the time of their 
first treatment with vandetanib or metformin. 
x Evaluable for objective response: Only those patients who have measurable disease present 
at baseline, have received at least one cycle of therapy, and have had their disease re-
evaluated will be considered evaluable for response.  These patients will have their 
response classified according to the definitions stated below.  (Note:  Patients who exhibit 
objective disease progression prior to the end of cycle 1 will also be considered evaluable.) 
x Evaluable Non-Target Disease Response:  Patients who have lesions present at baseline 
that are evaluable but do not meet the definitions of measurable disease, have received at 
least one cycle of therapy, and have had their disease re-evaluated will be considered 
evaluable for non-target disease.  The response assessment is based on the presence, 
absence, or unequivocal progression of the lesions.  
6.2.2 Disease Parameters 
6.2.2.1 Measurable disease 
x Measurable lesions are defined as those that can be accurately measured in at least one 
dimension (longest diameter to be recorded) as: 
o By chest x-ray:  > 20 mm 
o By CT scan:   
 Scan slice thickness 5 mm or under: >10 mm   
 Scan slice thickness 5 mm or under: double the slice thickness 
o With calipers on clinical exam: > 10 mm   
All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters). 
x Malignant lymph nodes: To be considered pathologically enlarged and measurable, a 
lymph node must be >15 mm in short axis when assessed by CT scan (CT scan slice 


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thickness recommended to be no greater than 5 mm).  At baseline and in follow-up, only 
the short axis will be measured and followed. 
6.2.2.2 Non-measurable disease 
x All other lesions (or sites of disease), including small lesions (longest diameter <10 mm or 
pathological lymph nodes with ≥10 to <15 mm short axis), are considered non-measurable 
disease.  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not 
followed by CT or MRI), are considered as non-measurable. 
 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts 
 
should not be considered as malignant lesions (neither measurable nor non-measurable) 
 
since they are, by definition, simple cysts. 
 
“Cystic lesions” thought to represent cystic metastases can be considered as measurable 
 
lesions, if they meet the definition of measurability described above. However, if non-
 
cystic lesions are present in the same patient, these are preferred for selection as target 
 
lesions. 
 
6.2.2.3 Target Lesions 
x All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs, should be identified as target lesions and recorded 
and measured at baseline.  Target lesions should be selected on the basis of their size 
(lesions with the longest diameter), be representative of all involved organs, but in addition 
should be those that lend themselves to reproducible repeated measurements.  It may be 
the case that, on occasion, the largest lesion does not lend itself to reproducible 
measurement in which circumstance the next largest lesion which can be measured 
reproducibly should be selected.  A sum of the diameters (longest for non-nodal lesions, 
short axis for nodal lesions) for all target lesions will be calculated and reported as the 
baseline sum diameters.  If lymph nodes are to be included in the sum, then only the short 
axis is added into the sum.  The baseline sum diameters will be used as reference to further 
characterize any objective tumor regression in the measurable dimension of the disease. 
 
6.2.2.4 Non-target lesions 
x All other lesions (or sites of disease) including any measurable lesions over and above the 
5 target lesions should be identified as non-target lesions and should also be recorded at 
baseline.  Measurements of these lesions are not required, but the presence, absence, or in 
rare cases unequivocal progression of each should be noted throughout follow-up.  
 
6.2.3 Guidelines for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment.  The same method of assessment 


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and the same technique should be used to characterize each identified and reported lesion at 
baseline and during follow-up. Imaging-based evaluation is preferred to evaluation by clinical 
examination unless the lesion(s) being followed cannot be imaged but are assessable by clinical 
exam. 
x Clinical lesions:  Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and t 10 mm diameter as assessed 
using calipers (e.g., skin nodules).  In the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the lesion, is recommended. 
x Chest x-ray:  Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung.  However, CT is preferable. 
x Conventional CT and MRI:  This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm or less.  If CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable lesion should be 
twice the slice thickness.   
 
MRI is also acceptable in certain situations (e.g. for body scans).  Use of MRI remains a 
complex issue.  MRI has excellent contrast, spatial, and temporal resolution; however, 
there are many image acquisition variables involved in MRI, which greatly impact image 
quality, lesion conspicuity, and measurement.  Furthermore, the availability of MRI is 
variable globally.  As with CT, if an MRI is performed, the technical specifications of the 
scanning sequences used should be optimized for the evaluation of the type and site of 
disease.  Furthermore, as with CT, the modality used at follow-up should be the same as 
was used at baseline and the lesions should be measured/assessed on the same pulse 
sequence.  It is beyond the scope of the RECIST guidelines to prescribe specific MRI pulse 
sequence parameters for all scanners, body parts, and diseases.  Ideally, the same type of 
scanner should be used and the image acquisition protocol should be followed as closely 
as possible to prior scans.  Body scans should be performed with breath-hold scanning 
techniques, if possible. 
x PET-CT:  At present, the low dose or attenuation correction CT portion of a combined 
PET-CT is not always of optimal diagnostic CT quality for use with RECIST 
measurements.  However, if the site can document that the CT performed as part of a PET-
CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), then 
the CT portion of the PET-CT can be used for RECIST measurements and can be used 
interchangeably with conventional CT in accurately measuring cancer lesions over time.  
Note, however, that the PET portion of the CT introduces additional data which may bias 
an investigator if it is not routinely or serially performed. 
x Ultrasound:  Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement.  Ultrasound examinations cannot be reproduced in their 
entirety for independent review at a later date and, because they are operator dependent, it 
cannot be guaranteed that the same technique and measurements will be taken from one 
assessment to the next.  If new lesions are identified by ultrasound in the course of the 
study, confirmation by CT or MRI is advised.  If there is concern about radiation exposure 
at CT, MRI may be used instead of CT in selected instances. 
x Endoscopy, Laparoscopy:  The utilization of these techniques for objective tumor 
evaluation is not advised.  However, such techniques may be useful to confirm complete 


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pathological response when biopsies are obtained or to determine relapse in trials where 
recurrence following complete response (26) or surgical resection is an endpoint. 
x Cytology, Histology:  These techniques can be used to differentiate between partial 
responses (14) and complete responses (26) in rare cases (e.g., residual lesions in tumor 
types, such as germ cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or stable 
disease is mandatory to differentiate between response or stable disease (an effusion may 
be a side effect of the treatment) and progressive disease. 
 
x FDG-PET:  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis 
of FDG-PET imaging can be identified according to the following algorithm:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If 
the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal FDG-
PET scan).  If the positive FDG-PET at follow-up corresponds to a pre-existing site of 
disease on CT that is not progressing on the basis of the anatomic images, this is not 
PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy 
in cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring.  The use of FDG-PET in this circumstance should be prospectively described 
in the protocol and supported by disease-specific medical literature for the indication.  
However, it must be acknowledged that both approaches may lead to false positive CR 
due to limitations of FDG-PET and biopsy resolution/sensitivity. 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image. 
6.2.4 Response Criteria 
6.2.4.1 Evaluation of Target Lesions 
x Complete Response (CR): Disappearance of all target lesions.  Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to <10 mm. 
x Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum of diameters. 
x Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum if that 
is the smallest on study).  In addition to the relative increase of 20%, the sum must also 


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demonstrate an absolute increase of at least 5 mm.  (Note:  the appearance of one or more 
new lesions is also considered progressions). 
x Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD, taking as reference the smallest sum of diameters while on study. 
 
6.2.4.2 Evaluation of Non-Target Lesions 
x Complete Response (CR): Disappearance of all non-target lesions and normalization of 
tumor marker level.  All lymph nodes must be non-pathological in size (<10 mm short 
axis). 
Note:  If tumor markers are initially above the upper normal limit, they must normalize for a patient 
to be considered in complete clinical response. 
x Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of 
tumor marker level above the normal limits. 
x Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  Unequivocal progression should not normally 
trump target lesion status.  It must be representative of overall disease status change, not a 
single lesion increase.     
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should 
be confirmed at a later time by the review panel (or Principal Investigator). 
 
6.2.4.3 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started).  The patient's best response assignment will depend on the 
achievement of both measurement and confirmation criteria. 
 
For Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-
CR/Non-PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not 
evaluated 
No 
PR 
PR 
Non-
CR/Non-
PD/not 
evaluated 
No 
PR 


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SD 
Non-
CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once >4 
wks. from baseline** 
PD 
Any 
Yes or 
No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or 
No 
PD 
Any 
Any 
Yes 
PD 
* 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
** 
Only for non-randomized trials with response as primary endpoint. 
*** 
In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as 
disease progression. 
Note: 
Patients with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be reported as “symptomatic 
deterioration.”  Every effort should be made to document the objective progression even after 
discontinuation of treatment. 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
*  ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly used as 
an endpoint for assessment of efficacy in some trials so to assign this category when no lesions can be 
measured is not advised 
 
6.2.5 Confirmatory Measurement/Duration of Response 
6.2.5.1 Confirmation 
To be assigned a status of PR or CR, changes in tumor measurements must be confirmed 
by repeat assessments that should be performed ≥ 4 weeks after the criteria for response 
are first met.  In the case of SD, follow-up measurements must have met the SD criteria 
at least once after study entry at a minimum interval of 8 weeks.   
6.2.5.2 Duration of Response 
x Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date 
that recurrent or progressive disease is objectively documented (taking as reference for 


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progressive disease the smallest measurements recorded since the treatment started).  The 
duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that progressive disease is objectively documented. 
 
x Duration of stable disease:  Stable disease is measured from the start of the treatment until 
the criteria for progression are met, taking as reference the smallest measurements recorded 
since the treatment started, including the baseline measurements.  
x Progression-free survival (PFS) is defined as the duration of time from start of treatment 
to time of progression or death, whichever occurs first. 
http://www.ncbi.nlm.nih.gov/pubmed/18711427?dopt=Abstract 
 
6.3 
TOXICITY CRITERIA 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting.  All appropriate treatment 
areas should have access to a copy of the CTCAE version 4.0.  A copy of the CTCAE version 4.0 
can be downloaded from the CTEP web site (http://ctep.cancer.gov).  
 
7 
SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING 
PLAN 
7.1 
DEFINITIONS 
7.1.1 Adverse Event 
Any untoward medical occurrence in a human subject, including any abnormal sign (for example, 
abnormal physical exam or laboratory finding), symptom, or disease, temporally associated with 
the subject’s participation in research, whether or not considered related to the subject’s 
participation in the research.  
7.1.2 Suspected adverse reaction 
Suspected adverse reaction means any adverse event for which there is a reasonable possibility 
that the drug caused the adverse event. For the purposes of IND safety reporting, ‘reasonable 
possibility’ means there is evidence to suggest a causal relationship between the drug and the 
adverse event. A suspected adverse reaction implies a lesser degree of certainty about causality 
than adverse reaction, which means any adverse event caused by a drug. 
7.1.3 Unexpected adverse reaction 
An adverse event or suspected adverse reaction is considered “unexpected” if it is not listed in the 
investigator brochure or is not listed at the specificity or severity that has been observed; or, if an 
investigator brochure is not required or available, is not consistent with the risk information 
described in the general investigational plan or elsewhere in the current application. "Unexpected” 
also refers to adverse events or suspected adverse reactions that are mentioned in the investigator 
brochure as occurring with a class of drugs or as anticipated from the pharmacological properties 
of the drug, but are not specifically mentioned as occurring with the particular drug under 
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7.1.4 Serious  
An Unanticipated Problem or Protocol Deviation is serious if it meets the definition of a Serious 
Adverse Event or if it compromises the safety, welfare or rights of subjects or others. 
7.1.5 Serious Adverse Event 
An adverse event or suspected adverse reaction is considered serious if in the view of the 
investigator or the sponsor, it results in any of the following: 
x 
Death, 
x 
A life-threatening adverse drug experience 
x 
Inpatient hospitalization or prolongation of existing hospitalization 
x 
Persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions 
x 
A congenital anomaly/birth defect. 
x 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
7.1.6 Disability 
A substantial disruption of a person’s ability to conduct normal life functions. 
7.1.7 Life-threatening adverse drug experience 
Any adverse event or suspected adverse reaction that places the patient or subject, in the view of 
the investigator or sponsor, at immediate risk of death from the reaction as it occurred, i.e., it does 
not include a reaction that had it occurred in a more severe form, might have caused death. 
7.1.8 Protocol Deviation (NIH Definition) 
Any change, divergence, or departure from the IRB-approved research protocol.   
7.1.9 Non-compliance (NIH Definition) 
The failure to comply with applicable NIH Human Research Protections Program (HRPP) policies, 
IRB requirements, or regulatory requirements for the protection of human research subjects. 
7.1.10 Unanticipated Problem 
Any incident, experience, or outcome that: 
x  Is unexpected in terms of nature, severity, or frequency in relation to  
(a) the research risks that are described in the IRB-approved research protocol and 
informed consent document; Investigator’s Brochure or other study documents, and 
(b) the characteristics of the subject population being studied; AND 
x Is related or possibly related to participation in the research; AND 


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x Suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. 
 
7.2 
RELATEDNESS OF ADVERSE EVENT TO AN INTERVENTION  
The best estimate of the PI at the time of reporting of the causal relationship between an 
experimental intervention and an adverse event; the degree of certainty about causality is graded 
as follows:  
x Unrelated:  
Adverse event is clearly due to extraneous causes (e.g., underlying disease, environment)  
 
x Unlikely (must have 2):  
Adverse event:  
(1) does not have temporal relationship to intervention,  
(2) could readily have been produced by the subject’s clinical state,  
(3) could have been due to environmental or other interventions,  
(4) does not follow known pattern of response to intervention,  
(5) does not reappear or worsen with reintroduction of intervention  
 
x Possible (must have 2):  
Adverse event:  
(1) has a reasonable temporal relationship to intervention,  
(2) could not readily have been produced by the subject’s clinical state,  
(3) could not readily have been due to environmental or other interventions,  
(4) follows a known pattern of response to intervention  
 
x Probable (must have 3):  
Adverse event:  
(1) has a reasonable temporal relationship to intervention,  
(2) could not readily have been produced by the subject’s clinical state or have been due to 
environmental or other interventions,  
(3) follows a known pattern of response to intervention,  
(4) disappears or decreases with reduction in dose or cessation of intervention  
x Definite (must have all 4):  
Adverse event:  
(1) has a reasonable temporal relationship to intervention,  
(2) could not readily have been produced by the subject’s clinical state or have been due to 
environmental or other interventions,  


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(3) follows a known pattern of response to intervention,  
(4) disappears or decreases with reduction in dose or cessation of intervention and recurs 
with re-exposure 
 
7.3 
NCI IRB AND CLINICAL DIRECTOR (CD) REPORTING  
7.3.1 NCI-IRB and NCI CD Expedited Reporting of Unanticipated Problems and Deaths 
The Protocol PI will report in the NIH Problem Form to the NCI-IRB and NCI Clinical Director: 
x All deaths, except deaths due to progressive disease  
x All Protocol Deviations 
x All Unanticipated Problems 
x All non-compliance 
Reports must be received within 7 days of PI awareness via iRIS. Deviations from the protocol 
that are beyond the control of the investigators/research team or those that occur to accommodate 
reasonable patient needs or to ensure patient safety will not be reported. 
 
7.3.2 NCI-IRB Requirements for PI Reporting of Adverse Events at Continuing Review 
The protocol PI will report to the NCI-IRB:  
1. A summary of all protocol deviations in a tabular format to include the date the deviation 
occurred, a brief description of the deviation and any corrective action. 
2. A summary of any instances of non-compliance 
3. A tabular summary of the following adverse events: 
x 
All Grade 2 unexpected events that are possibly, probably or definitely related to the 
research;  
x 
All Grade 3 and 4 events that are possibly, probably or definitely related to the research;  
x 
All Grade 5 events regardless of attribution;  
x 
All Serious Events regardless of attribution.  
NOTE: Grade 1 events are not required to be reported. 
7.4 
SAFETY REPORTING CRITERIA TO THE PHARMACEUTICAL COLLABORATORS  
The Institution must report the following information to the Sanofi Genzyme Pharmacovigilance  
 
1. Routine transmission of SAEs related to the use of the Sanofi Genzyme product must be 
transmitted within 1 business day of the Institution's awareness or identification of the event 
via a MedWatch form.  When reporting, a cover page should accompany the MedWatch form 
indicating the following: 
 
x Investigator Sponsored Study (ISS) 


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x The investigator’s name and address 
x The trial name/title and Sanofi Genzyme ISS reference number 
x Investigative site must also indicate, either in the SAE report or the cover page, the 
causality of events in relation to all study medications and if the SAE is related to disease 
progression, as determined by the principal investigator. 
 
2. New Safety Findings in a study pertaining to safety of product must be transmitted within 1 
business day. 
 
Sanofi Genzyme Pharmacovigilance Contact 
CL-CPV-Receipt@sanofi.com 
Fax: + 33 1 60 49 70 70 
 
Institution will also inform Sanofi Genzyme on any complaints on the Product to Clinical 
Pharmacy Research Services (CPRS) at CPRSProductComplaints@genzyme.com), immediately, 
but in any event within one (1) business day, after becoming aware of the complaint. 
 
7.5 
DATA AND SAFETY MONITORING PLAN 
7.5.1 Principal Investigator/Research Team 
A committee made up of the Principal Investigator, Ramaprasad Srinivasan, M.D., Ph.D. (or 
designee), a Research Nurse associated with the trial and other UOB clinical staff will review the 
events of all patients on the protocol periodically (typically at least once every two weeks). Follow-
up of both on-going and previously treated patients and the reported adverse events in a given 
week will be reviewed (that is, adverse events, protocol adherence, tumor responses, and potential 
new patient eligibility etc.). Any safety concerns or new information that might affect either the 
ethical and/or scientific conduct of the trial, or protocol deviations will be reported to the NCI IRB 
and Sanofi Genzyme in written form. If trends are noted and/or risks warrant it, accrual will be 
interrupted and/or the protocol and/or the consent will be modified accordingly. 
The principal investigator will review adverse event and response data on each patient to ensure 
safety and data accuracy. The principal investigator will personally conduct or supervise the 
investigation and provide appropriate delegation of responsibilities to other members of the 
research staff.  
8 
STATISTICAL CONSIDERATIONS 
8.1 
PHASE I COMPONENT  
The objective of the phase 1 portion of the study is to establish the safety and maximum tolerated 
dose (MTD) of vandetanib and metformin when used in combination in patients with metastatic 
RCC. The study design is based on a single arm, fixed order dose-escalation Phase 1 study using 
a modified Fibonacci schema.   
Dose escalation will proceed in cohorts of 3-6 patients each as outlined below.  The MTD is the 
dose level at which no more than 1 of up to 6 patients experience DLT during 1 cycle of treatment 


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(42 days from the time the intended dose of metformin is reached for a given dose level), and the 
dose below that at which at least 2 (of ≤6) patients have DLT as a result of the experimental 
regimen.   
8.2 
PHASE II COMPONENT 
The goal of the phase II component of this study is to establish whether treatment with vandetanib 
and metformin in patients with metastatic HLRCC/SDH associated RCC and papillary renal cancer 
results in an adequate overall response rate to warrant further development. 
Patients will be enrolled in two cohorts: 
x Cohort I: Patients with metastatic HLRCC/SDH associated renal cancer 
x Cohort II: Patients with sporadic/non-HLRCC papillary renal cancer. 
The study will be designed with a Simon two-stage optimal design which will be stratified by the 
two cohorts (i.e., separate design for each cohort).  In each cohort, 7 patients will be accrued in the 
first stage. If there are no responses (either CR or PR) in 7 patients, accrual to the cohort will be 
terminated, and the treatment will be considered ineffective for the cohort. If at least one patient 
responds among the 7 patients then 14 additional patients will be accrued to the cohort. If 3 or 
more patients of 21 respond then the treatment will be considered worthy of future investigation 
Number of Patients with 
DLT 
at a Given Dose Level 
Escalation Decision Rule 
0 out of 3 
Enter up to 3 patients at the next dose level 
> 2 
Dose escalation will be stopped.  This dose level will 
be declared the maximally administered dose (highest 
dose administered).  Up to three (3) additional patients 
will be entered at the next lowest dose level if only 3 
patients were treated previously at that dose. 
1 out of 3 
Enter up to 3 more patients at this dose level. 
x If 0 of these 3 patients experience DLT, 
proceed to the next dose level. 
x If 1 or more of this group suffer DLT, then 
dose escalation is stopped, and this dose is 
declared the maximally administered dose.  
UP to three (3) additional patients will be 
entered at the next lowest dose level if only 3 
patients were treated previously at that dose. 
<1 out of 6 at highest dose 
level  
This is the MTD and is generally the recommended 
phase 2 dose.  At least 6 patients must be entered at 
the recommended phase 2 dose.   


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for that cohort.  In either cohort, if fewer than 3 patients respond, the treatment will not be 
considered worthy of additional investigation for that cohort. 
For each cohort, the two-stage optimal design is based on assuming an ineffective response rate of 
5% and a targeted effective response rate of 30%. We also assume that the probability of accepting 
an ineffective treatment and the probability of rejecting an effective treatment are each 10%.   With 
this design, we have a 70% chance of stopping accrual to a cohort at the end of the first stage if 
the response rate in that cohort is 5%. 
Secondary objectives are listed in Section 1.1.2.  The follow-up times for biomarker endpoints are 
given in Section 5.1.  Analyses will focus on comparing changes in these biomarkers on treatment 
from the pre-study measurement.  Longitudinal changes in continuous biomarkers or imaging 
outcomes will be analyzed using paired Wilcoxon-ranked sum tests (which compares 
measurements at a single post-treatment time point with measurements at the pre-treatment time 
point) as well as with linear mixed models (which incorporate all follow-up times when evaluating 
change).  Evaluation of time to progression and progression-free survival will be based on 
restaging studies performed as outlined and will be summarized using Kaplan-Meier curves. 
8.3 
ACCRUAL CEILING  
In the phase I portion of the study, up to 6 patients may be enrolled in a specific dose combination 
cohort.  Based on the assumption that 4 dose levels will be evaluated, the total number of evaluable 
patients will be 24.  To allow for a few patients who may be inevaluable, the accrual ceiling for 
this portion of the study will be set at 27. 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. 
The accrual ceiling for the phase II component of the study is 21 evaluable patients for each cohort. 
To allow for inevaluable patients, the accrual ceiling will be set at 23 patients in each phase II 
cohort.  
The overall accrual ceiling for the study including both the phase I and phase II components will 
therefore be set at 73. With an expected accrual in the phase I component of 12-15 patients per 
year, we expect to complete accrual for this portion of the study within 1–2 years. With an expected 
accrual of 8-12 patients per year for each phase II cohort, we expect to complete accrual within 2-
3 years. Therefore, overall study is expected to have completed accrual within 4-5 years. 
9 
COLLABORATIVE AGREEMENTS 
9.1 
COOPERATIVE RESEARCH AND DEVELOPMENT AGREEMENT (CRADA)   
The agent (vandetanib) supplied by Sanofi Genzyme used in this protocol is provided to the NCI 
CCR under a Cooperative Research and Development Agreement (CRADA) between Sanofi 
Genzyme [hereinafter referred to as Collaborator], CRADA# 02050 and NCI. Therefore, the 
following obligations/guidelines, in addition to the provisions in the Intellectual Property Option 
to Collaborator contained within the terms of award, apply to the use of Agents in this study:  
Agents may not be used for any purpose outside the scope of this protocol, nor can Agents be 
transferred or licensed to any party not participating in the clinical study. Collaborator data for 
Agents are confidential and proprietary to Collaborator and shall be maintained as such by the 
investigators. The protocol documents for studies utilizing investigational agents contain 
confidential information and should not be shared or distributed without the permission of the NCI. 


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If a copy of this protocol is requested by a patient participating on the study or patient’s family 
member, the individual should sign a confidentiality agreement.  
For a clinical protocol where there is an investigational Agent used in combination with other 
investigational Agents, each the subject of different collaborative agreements, the access to and 
use of data by each Collaborator shall be as follows (data pertaining to such combination use shall 
hereinafter be referred to as "Multi-Party Data”.)  
NCI must provide all Collaborators with prior written notice regarding the existence and nature of 
any agreements governing their collaboration with NIH, the design of the proposed combination 
protocol, and the existence of any obligations that would tend to restrict NCI's participation in the 
proposed combination protocol.  
Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial by any 
other Collaborator solely to the extent necessary to allow said other Collaborator to develop, obtain 
regulatory approval, or commercialize its own investigational agent  
Any Collaborator having the right to use the Multi-Party Data from these trials must agree in 
writing prior to the commencement of the trials that it will use the Multi-Party Data solely for 
development, regulatory approval, and commercialization of its own investigational agent. 
 
10 HUMAN SUBJECTS PROTECTIONS  
10.1 RATIONALE FOR SUBJECT SELECTION 
10.1.1 Research subject selection 
Subjects of both genders and from all racial and ethnic groups are eligible for this trial if they meet 
the eligibility criteria.  Pregnant women are excluded from participation in the trial because 
vandetanib can cause fetal harm when administered to a pregnant woman.  Efforts will be made to 
extend the accrual to a representative population.  If differences in outcome that correlate to 
gender, racial, or ethnic identity are noted, accrual may be expanded or additional studies may be 
performed to investigate those differences more fully. 
10.1.2 Participation of children   
This protocol will exclude children below 18 years of age since there are no safety data available 
in this group of patients. 
10.2 PARTICIPATION OF SUBJECTS UNABLE TO GIVE CONSENT 
Adults unable to give consent are excluded from enrolling in the protocol.  However, re-consent 
may be necessary and there is a possibility, though unlikely, that subjects could become 
decisionally impaired. For this reason and because there is a prospect of direct benefit from 
research participation (section 10.3.1), all subjects will be offered the opportunity to fill in their 
wishes for research and care, and assign a substitute decision maker on the “NIH Advance 
Directive for Health Care and Medical Research Participation” form so that another person can 
make decisions about their medical care in the event that they become incapacitated or 
cognitively impaired during the course of the study. Note: The PI or AI will contact the NIH 
Ability to Consent Assessment Team for evaluation.  For those subjects that become 
incapacitated and do not have pre-determined substitute decision maker, the procedures 


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described in MAS Policy 87-4 for appointing a surrogate decision maker for adult subjects who 
are (a) decisionally impaired, and (b) who do not have a legal guardian or durable power of 
attorney, will be followed. 
10.3 EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS 
10.3.1 Potential benefits 
The potential benefit to a patient who enters study is a reduction in the bulk of his/her tumor, which 
may or may not have a favorable impact on symptoms, risk of metastasis and/or survival.  
10.3.2 Potential risks 
Potential risks include the possible occurrence of any of a range of side effects that are listed in 
the pharmaceutical section, the product package inserts and the consent document. The procedure 
for protecting against or minimizing risks will be to medically evaluate patients on a regular basis 
as previously described. Experience with the agents to date suggests that these agents are 
associated with an acceptable toxicity profile. 
We will encourage all subjects to complete a research advance directive at enrollment.   
10.3.2.1 Optional Biopsies  
All care will be taken to minimize risks that may be incurred by tumor sampling. However, there 
are procedure-related risks (such as bleeding, infection and visceral injury) that will be explained 
fully during informed consent. If patients suffer any physical injury as a result of the biopsies, 
immediate medical treatment is available at the NCI’s Clinical Center in Bethesda, Maryland. 
Although no compensation is available, any injury will be fully evaluated and treated in keeping 
with the benefits or care to which patients are entitled under applicable regulations.  
10.3.2.2 Research Radiation Risks 
Biopsies may be performed with CT guidance and a PET scan for research may be performed.  If 
that is the case, then this research study involves exposure to radiation from 1 FDG PET/CT scan 
on cycle 1 day 15 and up to 2 CT scans for CT guided biopsy, with combined effective dose of 2.4 
rem. This is below the guideline of 5.0 rem per year allowed for research subjects by the NIH 
Radiation Safety Committee. 
10.4 ALTERNATIVE TREATMENTS 
Patients will be apprised of other therapeutic options, both experimental and those of standard of 
care. 
10.5 CONSENT PROCESSES AND DOCUMENTATION 
An associate or principal investigator on the trial will inform patients of the purpose, alternatives, 
treatment plan, research objectives and follow-up of this trial.  The patient will be provided an 
IRB-approved consent for review and his/her questions will be answered.  After a decision is made 
to enroll into the study, the patient will be asked to sign the consent document to indicate willing 
informed consent to participate in the trial.    For the optional biopsy for research in the protocol, 
the patient will consent at the time of the procedure.  If the patient refuses the optional biopsy at 
that time, the refusal will be documented in the medical record and in the research record. 


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10.5.1 Telephone -Consent 
In the case that reconsent is needed, we are requesting that the telephone consent process be used. 
In this case, the informed consent document will be sent to the subject.  An explanation of the 
study will be provided over the telephone after the subject has had the opportunity to read the 
consent form.  The subject will sign and date the informed consent. A witness to the subject’s 
signature will sign and date the consent.  The original informed consent document will be sent 
back to the consenting investigator who will sign and date the consent form with the date the 
consent was obtained via telephone.  A fully executed copy will be returned via mail for the 
subject’s records.  The informed consent process will be documented on a progress note by the 
consenting investigator. 
10.5.2 Informed Consent of Non-English Speaking Subjects 
If there is an unexpected enrollment of a research participant for whom there is no translated 
extant IRB approved consent document, the principal investigator and/or those authorized to 
obtain informed consent will use the Short Form Oral Consent Process as described in MAS 
Policy M77-2, OHSRP SOP 12, and 45 CFR 46.117 (b) (2).  The summary that will be used is 
the English version of the extant IRB approved consent document.  Signed copies of both the 
English version of the consent and the translated short form will be given to the subject or their 
legally authorized representative and the signed original will be filed in the medical record. 
 
Unless the PI is fluent in the prospective subject’s language, an interpreter will be present to 
facilitate the conversation (using either the long translated form or the short form). Preferably 
someone who is independent of the subject (i.e., not a family member) will assist in presenting 
information and obtaining consent. Whenever possible, interpreters will be provided copies of 
the relevant consent documents well before the consent conversation with the subject (24 to 48 
hours if possible).  
We request prospective IRB approval of the use of the short form process for non-English 
speaking subjects and will notify the IRB at the time of continuing review of the frequency of the 
use of the Short Form. 
 
11 PHARMACEUTICAL INFORMATION   
11.1 VANDETANIB 
(Please see vandetanib package insert for complete information) 
11.1.1 Source  
Vandetanib is commercially available under the trade name CAPRELSA®, but will be supplied 
by the manufacturer (Sanofi Genzyme) for the purposes of the study. 
11.1.2 Toxicity  
The following adverse events have been reported in patients treated with vandetanib: Rash, 
diarrhea, nausea and vomiting, ECG abnormalities (ST and T wave changes, QTc prolongation), 
hypertension, increased serum LDH, lymphopenia, elevation of AST/ALT/ alkaline phosphatase, 
anorexia, nausea, headache, elevation of serum creatinine, hypertriglyceridemia, leukopenia, 


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tinnitus, thrombocytopenia, fatigue, abdominal pain, back pain, fever , cough, peripheral edema , 
insomnia, hematuria, dyspnea, proteinuria.  
The most serious adverse event associated with metformin administration is lactic acidosis, which 
is overall a rare event (0.03 cases/1000 patient – years, with approximately 0.015 fatal cases/1000 
patient – years).  The risk of lactic acidosis associated with metformin is increased in patients with 
renal insufficiency, congestive heart failure, hepatic disease, recent surgery, or any condition 
associated with hypoxemia, severe dehydration, or sepsis. More common side effects that are 
associated with metformin administration include: Diarrhea, nausea and vomiting, flatulence, 
asthenia, indigestion, abdominal discomfort, and headache.  Less common side effects include: 
abnormal stools, hypoglycemia, myalgia, lightheadedness, dyspnea, nail disorder, rash, 
diaphoresis, changes in taste, chest discomfort, palpitations, chills, flu syndrome, and flushing. 
11.1.3 Formulation and preparation  
Vandetanib is available in 100mg and 300mg tablets. 
11.1.4 Stability and Storage  
Vandetanib should be stored at approximately 25ºC, with excursion permitted to 15º- 30ºC. 
11.1.5 Administration procedures  
Vandetanib is a tablet that is taken orally.   
11.1.6 Incompatibilities  
Co-administration of vandetanib and drugs with potent CYP3A4 inducer effects are not allowed. 
Agents with potent inhibitory effects on CYP3A4 should be avoided where possible. Other agents 
with some modulation of and/or metabolization through CYP3A4 can be used with caution at the 
discretion of the Principal Investigator.  Vandetanib should also not be administered in patients 
receiving drugs known to prolong QT interval or induce torsades de pointes. No concurrent 
systemic anti-neoplastic therapy for RCC will be allowed. 
 
11.2 METFORMIN 
(Please see metformin package insert for complete information) 
11.2.1 Source  
Metformin is commercially available and manufactured by Bristol-Myers Squibb Company 
(Princeton, NJ) under the trade name GLUCOPHAGE®. 
11.2.2 Toxicity  
The most serious adverse event associated with metformin administration is lactic acidosis, which 
is overall a rare event (0.03 cases/1000 patient – years, with approximately 0.015 fatal cases/1000 
patient – years).  The risk of lactic acidosis associated with metformin is increased in patients with 
renal insufficiency, congestive heart failure, hepatic disease, recent surgery, or any condition 
associated with hypoxemia, severe dehydration, or sepsis. More common side effects that are 
associated with metformin administration include: Diarrhea, nausea and vomiting, flatulence, 
asthenia, indigestion, abdominal discomfort, and headache.  Less common side effects include: 


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abnormal stools, hypoglycemia, myalgia, lightheadedness, dyspnea, nail disorder, rash, 
diaphoresis, changes in taste, chest discomfort, palpitations, chills, flu syndrome, and flushing. 
11.2.3 Formulation and preparation  
Metformin is available in 500mg, 850mg, and 1000mg tablets. Immediate-release formulation will 
be used.  If necessary to achieve desired dose, tablets will be split.  
11.2.4 Stability and Storage  
Metformin should be stored at approximately 20º-25ºC, with excursion permitted to 15º-30ºC. 
11.2.5 Administration procedures  
Metformin is a tablet that is taken orally.   
11.2.6 Incompatibilities  
Metformin is contraindicated in patients with 1. renal disease or renal dysfunction which may also 
result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and 
septicemia; 2.  Known hypersensitivity to metformin hydrochloride; 3. Acute or chronic metabolic 
acidosis, including diabetic ketoacidosis, with or without coma. 
Metformin should be temporarily discontinued in patients undergoing radiologic studies involving 
intravascular administration of iodinated contrast materials, because use of such products may 
result in acute alteration of renal function.  The NIH/CCC protocol for withholding of metformin 
during such procedures will be used. 
Concomitant administration of furosemide, nifedipine, and other cationic drugs can lead to 
increased plasma levels of metformin.  Close monitoring of subjects who take such medications 
will be undertaken to evaluate for potential toxicity.   
 


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 (24)  Boer K, Lang I, Llombart-Cussac A, Andreasson I, Vivanco GL, Sanders N, et al. 
Vandetanib with docetaxel as second-line treatment for advanced breast cancer: a double-
blind, placebo-controlled, randomized Phase II study. Invest New Drugs 2012;30:681-7. 
 (25)  Miller KD, Trigo JM, Wheeler C, Barge A, Rowbottom J, Sledge G, et al. A multicenter 
phase II trial of ZD6474, a vascular endothelial growth factor receptor-2 and epidermal 
growth factor receptor tyrosine kinase inhibitor, in patients with previously treated 
metastatic breast cancer. Clin Cancer Res 2005;11:3369-76. 


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Version Date: 05/01/2018 
 
 (26)  Wells SA, Jr., Robinson BG, Gagel RF, Dralle H, Fagin JA, Santoro M, et al. Vandetanib 
in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, 
double-blind phase III trial. J Clin Oncol 2012;30:134-41. 
 (27)  Lee JS, Hirsh V, Park K, Qin S, Blajman CR, Perng RP, et al. Vandetanib Versus placebo 
in patients with advanced non-small-cell lung cancer after prior therapy with an epidermal 
growth factor receptor tyrosine kinase inhibitor: a randomized, double-blind phase III trial 
(ZEPHYR). J Clin Oncol 2012;30:1114-21. 
 (28)  Natale RB, Thongprasert S, Greco FA, Thomas M, Tsai CM, Sunpaweravong P, et al. 
Phase III trial of vandetanib compared with erlotinib in patients with previously treated 
advanced non-small-cell lung cancer. J Clin Oncol 2011;29:1059-66. 
 (29)  Herbst RS, Sun Y, Eberhardt WE, Germonpre P, Saijo N, Zhou C, et al. Vandetanib plus 
docetaxel versus docetaxel as second-line treatment for patients with advanced non-small-
cell lung cancer (ZODIAC): a double-blind, randomised, phase 3 trial. Lancet Oncol 
2010;11:619-26. 
 (30)  de Boer RH, Arrieta O, Yang CH, Gottfried M, Chan V, Raats J, et al. Vandetanib plus 
pemetrexed for the second-line treatment of advanced non-small-cell lung cancer: a 
randomized, double-blind phase III trial. J Clin Oncol 2011;29:1067-74. 
 (31)  Leboulleux S, Bastholt L, Krause T, de la Fouchardiere C, Tennvall J, Awada A, et al. 
Vandetanib in locally advanced or metastatic differentiated thyroid cancer: a randomised, 
double-blind, phase 2 trial. Lancet Oncol 2012;13:897-905. 
 (32)  Xiao YY, Zhan P, Yuan DM, Liu HB, Lv TF, Shi Y, et al. Chemotherapy plus Vandetanib 
or chemotherapy alone in advanced non-small cell lung cancer: a meta-analysis of four 
randomised controlled trials. Clin Oncol (R Coll Radiol ) 2013;25:e7-e15. 
 (33)  Bodmer M, Meier C, Krahenbuhl S, Jick SS, Meier CR. Long-term metformin use is 
associated with decreased risk of breast cancer. Diabetes Care 2010;33:1304-8. 
 (34)  Evans JM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD. Metformin and 
reduced risk of cancer in diabetic patients. BMJ 2005;330:1304-5. 
 (35)  El-Mir MY, Nogueira V, Fontaine E, Averet N, Rigoulet M, Leverve X. 
Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory 
chain complex I. J Biol Chem 2000;275:223-8. 
 (36)  Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, et al. Role of AMP-activated 
protein kinase in mechanism of metformin action. J Clin Invest 2001;108:1167-74. 
 (37)  Marsin AS, Bertrand L, Rider MH, Deprez J, Beauloye C, Vincent MF, et al. 
Phosphorylation and activation of heart PFK-2 by AMPK has a role in the stimulation of 
glycolysis during ischaemia. Curr Biol 2000;10:1247-55. 


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Version Date: 05/01/2018 
 
 (38)  Winder WW, Wilson HA, Hardie DG, Rasmussen BB, Hutber CA, Call GB, et al. 
Phosphorylation of rat muscle acetyl-CoA carboxylase by AMP-activated protein kinase 
and protein kinase A. J Appl Physiol 1997;82:219-25. 
 (39)  Choueiri TK, Vaishampayan U, Rosenberg JE, Logan TF, Harzstark AL, Bukowski RM, 
et al. Phase II and biomarker study of the dual MET/VEGFR2 inhibitor foretinib in patients 
with papillary renal cell carcinoma. J Clin Oncol 2013;31:181-6. 
 (40)  Ooi A, Dykema K, Ansari A, Petillo D, Snider J, Kahnoski R, et al. CUL3 and NRF2 
mutations confer an NRF2 activation phenotype in a sporadic form of papillary renal cell 
carcinoma. Cancer Res 2013;73:2044-51. 
 
 
 


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Version Date: 05/01/2018 
 
13 APPENDIX A: PERFORMANCE STATUS CRITERIA 
ECOG Performance Status Scale 
 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to 
carry 
on 
all 
pre-disease 
performance without restriction. 
100 
Normal, 
no 
complaints, 
no 
evidence of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of 
disease. 
1 
Symptoms, 
but 
ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary 
nature 
(e.g., 
light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active 
work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, 
but is able to care for most of 
his/her needs. 
50 
Requires considerable assistance 
and frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care 
and assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very 
sick, 
hospitalization 
indicated. Death not imminent. 
10 
Moribund, 
fatal 
processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 


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Version Date: 05/01/2018 
 
14 APPENDIX B: NEW YORK HEART ASSOCIATION (NYHA) CARDIAC 
CLASSIFICATION 
The NYHA classification system relates symptoms to everyday activities and the patient’s quality of life. 
Class 
Symptoms 
Class I (Mild) 
No limitation of physical activity.  Ordinary physical activity does not cause undue 
fatigue, palpitation, or dyspnea (shortness of breath). 
Class II (Mild) 
Slight limitation of physical activity.  Comfortable at rest, but ordinary physical 
activity results in fatigue, palpitation, or dyspnea. 
Class III (Moderate) 
Marked limitation of physical activity.  Comfortable at rest, but less than ordinary 
activity causes fatigue, palpitation, or dyspnea. 
Class IV (Severe) 
Unable to carry out any physical activity without discomfort.  Symptoms of cardiac 
insufficiency at rest.  If any physical activity is undertaken, discomfort is increased. 
 
 
 
 


86 
Abbreviated Title: Vandetanib/Metformin in RCC 
Version Date: 05/01/2018 
 
15 APPENDIX C: MEDICATIONS KNOWN TO PROLONG THE QT INTERVAL 
AND/OR INDUCE TORSADES DE POINTES (TDP) 
It has been recognized for a number of years that certain prescription medications can prolong the 
QT/QTc interval and cause a form of acquired Long QT syndrome, known as drug induced LQTS.  
The drugs that prolong the QT interval and/or have a risk of inducing Torsades de Pointes (TdP) 
are listed below.  We have divided these into two groups based on their known or perceived risk 
of causing TdP:  
15.1 GROUP 1: DRUGS THAT ARE GENERALLY ACCEPTED BY AUTHORITIES TO HAVE A RISK OF 
CAUSING TORSADES DE POINTES 
Concomitant use of these drugs is not allowed during the study. In subjects who have discontinued 
use of these drugs, at least five half-lives of the drug must have elapsed before the first scheduled 
dose of vandetanib (at least four weeks for levomethadyl).  These drugs should also be avoided for 
up to 4 weeks following discontinuation of study treatment: 
Table 2 
Group 1 Drugsa 
Generic Name 
Class/Clinical Use 
Comments 
Amiodarone  
Anti-arrhythmic/abnormal heart rhythm 
Females>Males,TdP risk regarded as 
low 
Anagrelide 
Thromobocytopenia 
 
Arsenic trioxide  
Anti-cancer/Leukemia 
 
Astemizole  
Antihistamine/Allergic rhinitis 
No Longer available in U.S. 
Azithromycin 
Antibiotic/bacterial infection 
 
Bepridil  
Anti-anginal/heart pain 
Not available in U.S. 
Chloroquine 
Anti-malarial/malaria infection 
 
Chlorpromazine  
Anti-psychotic/Anti-emetic/schizophrenia/ 
nausea 
 
Cisapride 
GI stimulant/heartburn 
No longer available in U.S. 
  
Citalopram 
Anti-depressant/depression 
 
Clarithromycin 
Antibiotic/bacterial infection 
 
Cocaine 
Topical anesthetic 
 
Disopyramide  
Anti-arrhythmic/abnormal heart rhythm 
Females>Males 
Dofetilide  
Anti-arrhythmic/abnormal heart rhythm 
Females > Males 
Domperidone 
Anti-nausea/nausea 
Not available in U.S. 
Dronedarone 
Atrial fibrillation 
 
Droperidol  
Sedative;Anti-nausea/anesthesia adjunct, 
nausea 
 
Erythromycin  
Antibiotic;GI stimulant/bacterial infection; 
increase GI motility 
Females>Males 
Escitalopram 
Major depression/anxiety disorders 
 


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Table 2 
Group 1 Drugsa 
Generic Name 
Class/Clinical Use 
Comments 
Flecainide 
Anti-arrhythmic/abnormal heart rhythm 
 
Halofantrine  
Anti-malarial/malaria infection 
Females>Males 
Haloperidol  
Anti-psychotic/schizophrenia, agitation 
TdP risk with I.V. or excess dosage 
Ibutilide 
Anti-arrhythmic/abnormal heart rhythm 
Females>Males 
Levofloxacin 
Bacterial infection 
 
Levomethadyl 
Opiate agonist/pain control, narcotic 
dependence 
Not available in U.S. 
Mesoridazine 
Anti-psychotic/schizophrenia 
Not available in U.S. 
Methadone 
Opiate agonist/pain control, narcotic 
dependence 
Females>Males 
Moxifloxacin  
Antibiotic/bacterial infection 
 
Ondansetron 
Nausea, vomiting 
 
Pentamidine  
Anti-infective/pneumocystis pneumonia 
Females>Males 
Pimozide 
Anti-psychotic/Tourette's tics 
Females>Males 
Probucol 
Antilipemic/Hypercholesterolemia 
No longer available in U.S. 
Procainamide  
Anti-arrhythmic/abnormal heart rhythm 
 
Quinidine 
Anti-arrhythmic/abnormal heart rhythm 
Females>Males 
Sevoflurane 
General anesthetic 
 
Sotalol  
Anti-arrhythmic/abnormal heart rhythm 
Females>Males 
Sparfloxacin  
Antibiotic/bacterial infection 
No longer available in U.S. 
Sulpride 
Anti-psychotic/schizophrenia 
Not available in U.S. 
Terfenadine 
Antihistamine/Allergic rhinitis 
No longer available in U.S. 
Thioridazine 
Anti-psychotic/schizophrenia 
 
Vandetanib (*Does 
not apply to this 
study) 
Anti-cancer/Thyroid cancer 
 
a 
Source: www.QTdrugs.org. Last revised: 26 September 2014 
 
 
 
 
 


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Abbreviated Title: Vandetanib/Metformin in RCC 
Version Date: 05/01/2018 
 
15.2 GROUP 2: 
DRUGS THAT IN SOME REPORTS MAY BE ASSOCIATED WITH TORSADES DE 
POINTES BUT AT THIS TIME LACK SUBSTANTIAL EVIDENCE OF CAUSING TORSADES DE 
POINTES. 
Concomitant use of these drugs should be avoided when possible during the study.  In subjects 
who have discontinued use of these drugs, at least five half-lives of the drug must have elapsed 
before the first scheduled dose of vandetanib. These drugs will be allowed during the study, at the 
discretion of the Investigator, if considered absolutely necessary.  In such cases, the patient must 
be closely monitored, including regular checks of QTc and electrolytes (reference Section 3.3 of 
the protocol). 
Table 3 
Group 2 Drugsa 
Generic Name 
Class/Clinical Use 
Comments 
Alfuzosin 
Alpha1-blocker/Benign prostatic hyperplasia 
 
Apomorphine  
Dopaminergic/Anti-viral/Anti-infective/ 
Parkinson's Disease 
 
Aripiprazole 
Anti-psychotic/ Psychosis/Depression 
 
Atazanavir 
Protease inhibitor/HIV 
 
Bortezomib 
Proteasome inhibitor/Multiple myeloma/ 
lymphoma 
 
Bosutinib 
Tyrosine kinase inhibitor/ Leukemia 
 
Clozapine 
Anti-psychotic/schizophrenia 
 
Crizotinib 
Kinase inhibitor/ anti-cancer 
 
Dabrafenib 
Anti-cancer/ melanoma 
 
Dasatinib 
Tyrosine kinase inhibitor/ leukemia 
 
Dexmedetomine 
Anti-malarial 
 
Dihydroartemisinin+
piperaquine 
Anti-malarial 
 
Dolasetron 
Anti-nausea/nausea, vomiting 
 
Dronedarone 
Anti-arrhythmic/Atrial Fibrillation 
 
Eribulin 
Anti-cancer/metastatic breast neoplasias 
 
Famotidine 
H2-receptor antagonist/Peptic ulcer/ GERD 
 
Felbamate  
Anti-convulsant/seizure 
 
Fingolimod 
Immunosuppressant/Multiple Sclerosis 
 
Foscarnet  
Anti-viral/HIV infection 
 
Fosphenytoin 
Anti-convulsant/seizure 
 
Gatifloxacin 
Antibiotic/bacterial infection 
Oral/I.V. forms no longer available in 
U.S. and Canada, only ophthalmic 
Gemifloxacin 
Antibiotic/bacterial infection 
 
Granisetron 
Anti-nausea/nausea and vomiting 
 


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Table 3 
Group 2 Drugsa 
Generic Name 
Class/Clinical Use 
Comments 
Iloperidone 
Antipsychotic, atypical/Schizophrenia 
 
Isradipine 
Anti-hypertensive/high blood pressure 
 
Lapatinib 
Anti-cancer/breast cancer, metastatic 
 
Lithium 
Anti-mania/bipolar disorder 
 
Mifepristone 
Progesterone antagonist/ Pregnancy termination 
 
Mirabegron 
Beta3 adrenergic antagonist/ Overactive 
bladder 
 
Mirtazapine 
Anti-depressant, Tetracyclic/ Depression 
 
Moexipril/HCTZ  
Anti-hypertensive/high blood pressure 
 
Nicardipine  
Anti-hypertensive/high blood pressure 
 
Nilotinib 
Anti-cancer/Leukemia 
 
Norfloxacin 
Antibiotic 
 
Ofloxacin 
Antibiotic/bacterial infection 
 
Olanzapine 
Anti-psychotic, atypical/ Schizophrenia, bipolar 
 
Oxytocin 
Oxytocic/Labor stimulation 
 
Paliperidone 
Antipsychotic, atypical/Schizophrenia 
 
Pasireotide 
Somatostatin analog/ Cushings Disease 
 
Pazopanib 
Tyrosine kinase inhibitor/ Anti-cancer 
 
Perflutren lipid 
microspheres 
Imaging contrast agent/Echocardiography 
 
Pipamperone 
Anti-psychotic/schizophrenia 
Not available in U.S. 
Promethazine 
Anti-psychotic / Anti-emetic. nausea 
 
Quetiapine  
Anti-psychotic/schizophrenia 
 
Ranolazine 
Anti-anginal/chronic angina 
 
Rilpivirine 
Anti-viral/ HIV/AIDS 
 
Risperidone  
Anti-psychotic/schizophrenia 
 
Roxithromycin* 
Antibiotic/bacterial infection 
*Not available in U.S. 
Saquinavir 
Anti-viral/ HIV/AIDS 
 
Sertindole 
Antipsychotic, atypical/Anxiety, Schizophrenia 
Not available in U.S. 
Sorafenib 
Tyrosine kinase inhibitor/ Anti-cancer 
 
Sunitinib 
Anti-cancer/RCC, GIST 
 
Tacrolimus  
Immunosuppressant/Immune suppression 
 
Tamoxifen  
Anti-cancer/breast cancer 
 
Telavancin 
Antibiotic 
 


90 
Abbreviated Title: Vandetanib/Metformin in RCC 
Version Date: 05/01/2018 
 
Table 3 
Group 2 Drugsa 
Generic Name 
Class/Clinical Use 
Comments 
Telithromycin 
Antibiotic/bacterial infection 
 
Tetrabenazine 
Monoamine Transporter Inhibitor/ Chorea 
(Huntington's disease) 
Orphan drug in US 
Tizanidine  
Muscle relaxant/ 
 
Tolterodine 
Muscle relaxant/ Bladder spasm 
 
Toremifene 
Estrogen agonist/antagonist/ Anti-cancer 
 
Vardenafil 
phosphodiesterase inhibitor/vasodilator 
 
Vemurafenib 
Kinase inhibitor/ Anti-cancer 
 
Venlafaxine  
Anti-depressant/depression 
 
Vorinostat 
Anti-cancer/ lymphoma 
 
Ziprasidone 
Anti-psychotic/schizophrenia 
 
a 
Source: www.QTdrugs.org. Last revised: 26 September 2014 


91 
Abbreviated Title: Vandetanib/Metformin in RCC 
Version Date: 05/01/2018 
 
16 APPENDIX D: PATIENT DRUG AND SIDE EFFECTS DIARY 
16.1 LEAD IN CYCLE 
Patient Name________________________________   
INSTRUCTIONS TO THE PATIENT: 
1. Complete one form for each Cycle. 
2. You will take ___ vandetanib(V)  pill each day.   
3. You will take ___ metformin (M) pills twice each day. 
4. Record the date and time you took each dose of study medication. Take the medication together in the AM.   
5. If you have any comments or notice any side effects, please record them in the Comments column. 
6. Please bring your pill bottles and this form to your physician when you go for your next appointment. 
 
Date 
 
Day 
Time of 
Dose 1 
Drug(s) 
taken 
Comments/ 
Symptoms 
Time of 
Dose 2 
Drug(s) 
taken 
Comments/ 
Symptoms 
 
-14 
 
 M 
 V 
 
 
 M 
 
 
 
-13 
 
 M 
 V 
 
 
 M 
 
 
 
-12 
 
 M 
 V 
 
 
 M 
 
 
 
-11 
 
 M 
 V 
 
 
 M 
 
 
 
-10 
 
 M 
 V 
 
 
 M 
 
 
 
-9 
 
 M 
 V 
 
 
 M 
 
 
 
-8 
 
 M 
 V 
 
 
 M 
 
 
 
-7 
 
 M 
 V 
 
 
 M 
 
 
 
-6 
 
 M 
 V 
 
 
 M 
 
 
 
-5 
 
 M 
 V 
 
 
 M 
 
 
 
-4 
 
 M 
 V 
 
 
 M 
 
 
 
-3 
 
 M 
 V 
 
 
 M 
 
 
 
-2 
 
 M 
 V 
 
 
 M 
 
 
 
-1 
 
 M 
 V 
 
 
 M 
 
 
Signature:  ________________________________ Date_____________________________ 


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Version Date: 05/01/2018 
 
16.2 ALL OTHER CYCLES 
Level 1 
Cycle #_____________________ 
Patient Name________________________________   
 
INSTRUCTIONS TO THE PATIENT: 
1. Complete for each Cycle. 
2. You will take ___ vandetanib(V)  pill _______ each day.   
3. You will take ___ metformin (M) pill each day. 
4. Record the date and time you took each dose of study medication; take the medications together in the AM.   
5. If you have any comments or notice any side effects, please record them in the Comments column. 
6. Please bring your pill bottles and this form to your physician when you go for your next appointment. 
 
 
Date 
 
Day 
Time 
of 
Dose  
Drug(s) 
taken 
Comments/ 
Symptoms 
 
1 
 
 M 
 V 
 
 
2 
 
 M 
 V 
 
 
3 
 
 M 
 V 
 
 
4 
 
 M 
 V 
 
 
5 
 
 M 
 V 
 
 
6 
 
 M 
 V 
 
 
7 
 
 M 
 V 
 
 
8 
 
 M 
 V 
 
 
9 
 
 M 
 V 
 
 
10 
 
 M 
 V 
 
 
11 
 
 M 
 V 
 
 
12 
 
 M 
 V 
 
 
13 
 
 M 
 V 
 


93 
Abbreviated Title: Vandetanib/Metformin in RCC 
Version Date: 05/01/2018 
 
 
Date 
 
Day 
Time 
of 
Dose  
Drug(s) 
taken 
Comments/ 
Symptoms 
 
14 
 
 M 
 V 
 
 
15 
 
 M 
 V 
 
 
16 
 
 M 
 V 
 
 
17 
 
 M 
 V 
 
 
18 
 
 M 
 V 
 
 
19 
 
 M 
 V 
 
 
20 
 
 M 
 V 
 
 
21 
 
 M 
 V 
 
 
22 
 
 M 
 V 
 
 
23 
 
 M 
 V 
 
 
24 
 
 M 
 V 
 
 
25 
 
 M 
 V 
 
 
26 
 
 M 
 V 
 
 
27 
 
 M 
 V 
 
 
28 
 
 M 
 V 
 
 
 
Signature: ______________________________ 
 
Date: ___________________ 
 
 
 
 
 


94 
Abbreviated Title: Vandetanib/Metformin in RCC 
Version Date: 05/01/2018 
 
Level 2, Level 3, Level 4 
Cycle #_____________________ 
Patient Name________________________________   
 
INSTRUCTIONS TO THE PATIENT: 
1. Complete for each Cycle. 
2. You will take ___ vandetanib(V)  pill each day.   
3. You will take ___ metformin (M) pills each day. 
4. Record the date and time you took each dose of study medication; take the medications together in the AM.   
5. If you have any comments or notice any side effects, please record them in the Comments column. 
6. Please bring your pill bottles and this form to your physician when you go for your next appointment. 
 
 
Date 
 
Day 
Time 
of 
Dose 1 
Drug(s) 
taken 
Comments/ 
Symptoms 
Drug(s) 
taken 
Time  
of 
 Dose 2 
Comments/ 
Symptoms 
 
1 
 
 M 
 V 
 
 M 
 
 
 
 
2 
 
 M 
 V 
 
 M 
 
 
 
 
3 
 
 M 
 V 
 
 M 
 
 
 
 
4 
 
 M 
 V 
 
 M 
 
 
 
 
5 
 
 M 
 V 
 
 M 
 
 
 
 
6 
 
 M 
 V 
 
 M 
 
 
 
 
7 
 
 M 
 V 
 
 M 
 
 
 
 
8 
 
 M 
 V 
 
 M 
 
 
 
 
9 
 
 M 
 V 
 
 M 
 
 
 
 
10 
 
 M 
 V 
 
 M 
 
 
 
 
11 
 
 M 
 V 
 
 M 
 
 
 
 
12 
 
 M 
 V 
 
 M 
 
 
 
 
13 
 
 M 
 V 
 
 M 
 
 
 


95 
Abbreviated Title: Vandetanib/Metformin in RCC 
Version Date: 05/01/2018 
 
 
Date 
 
Day 
Time 
of 
Dose 1 
Drug(s) 
taken 
Comments/ 
Symptoms 
Drug(s) 
taken 
Time  
of 
 Dose 2 
Comments/ 
Symptoms 
 
14 
 
 M 
 V 
 
 M 
 
 
 
 
15 
 
 M 
 V 
 
 M 
 
 
 
 
16 
 
 M 
 V 
 
 M 
 
 
 
 
17 
 
 M 
 V 
 
 M 
 
 
 
 
18 
 
 M 
 V 
 
 M 
 
 
 
 
19 
 
 M 
 V 
 
 M 
 
 
 
 
20 
 
 M 
 V 
 
 M 
 
 
 
 
21 
 
 M 
 V 
 
 M 
 
 
 
 
22 
 
 M 
 V 
 
 M 
 
 
 
 
23 
 
 M 
 V 
 
 M 
 
 
 
 
24 
 
 M 
 V 
 
 M 
 
 
 
 
25 
 
 M 
 V 
 
 M 
 
 
 
 
26 
 
 M 
 V 
 
 M 
 
 
 
 
27 
 
 M 
 V 
 
 M 
 
 
 
 
28 
 
 M 
 V 
 
 M 
 
 
 
 
 
Signature: ______________________________ 
 
Date: ___________________ 
 
 


96 
Abbreviated Title: Vandetanib/Metformin in RCC 
Version Date: 05/01/2018 
 
17 APPENDIX E: PATIENT INSTRUCTIONS FOR METFORMIN / VANDETANIB 
You are a participant in a Clinical Trial of 2 medications: Metformin and Vandetanib. The following are 
important reminders while you are taking the medications. 
 
You will be responsible for maintaining 2 diaries while on the clinical trial; please bring your diaries with 
you to each visit: 
1. Blood Pressure Diary 
2. Pill and Side Effect Diary 
 
With the exception of the first day you are on the trial, you will be taking both medications every day. 
Take the medications together with a full glass of water after eating a light breakfast. Record the date and 
time you take the medications on your diary. If you are taking the Metformin in the AM and PM, take the 
evening dose of Metformin 12 hours after your AM dose. Do not start any NEW medications before 
checking with the study team. 
 
Record your Blood Pressure daily on your BP diary.  Sit quietly for 5 min before you check your BP. If 
your reading on the top is above 140, or the reading on the bottom is above 90, sit quietly for 10 min and 
recheck your BP. If it remains elevated, contact the team immediately at one of the numbers below. 
 
Please wear sunscreen (at least SPF 30) when outside, and minimize your sun exposure. 
 
Please have a thermometer in order to check your temperature if directed to do so. 
 
If you should need dental work or surgery, notify your team immediately. 
 
Do not drink alcohol (including beer and wine) unless approved by the doctor or nurse. 
 
If you are of reproductive age, you MUST practice birth control. 
 
When scheduled for a CAT Scan, do not take your Metformin the morning of the scan. Do not resume the 
metformin until you have had your labs to check your kidney function, and are told to resume the 
Metformin by the doctor or nurse. 
 
You will be given medication at the beginning of the trial to be used only as needed. If you need any of 
these medications, follow the directions on the label, and record that you have taken the medication in 
your diary. These medications are: 1.Chlorpromazine (Nausea); 2.Loperimide (Diarrhea); 3.Colace 
(Constipation)  
 
You will be obtaining bloodwork and an EKG at home once a week as directed by the Study Team. The 
EKG must be done at least 4-8 hours after your AM dose of Vandetanib, so be sure to schedule your 
appointments with your PCP at the correct time. 
 
Please call your study team with ANY questions or change in your condition. 
 
 
Martha Ninos RN (Study Coordinator)  
240-760-6248 (Mon-Fri: 8-4PM) *** 
 
Julia Friend PA-C  
 
 
 
301-240-4759 (Mon-Fri: 8-4PM) *** 
 
*** Evenings, weekends, and emergencies call Hospital paging @ 301-496-1211 and ask to speak to 
the Urology Fellow On Call 


97 
Abbreviated Title: Vandetanib/Metformin in RCC 
Version Date: 05/01/2018 
 
18 APPENDIX F: BLOOD PRESSURE MONITORING FORM 
18.1 LEAD IN CYCLE 
Instructions 
1. Take your blood pressure at least once per day during each cycle of study drug 
2. Record the date you took your blood pressure and your blood pressure below 
3. Bring this form with you at your next study visit 
 
Cycle Day 
Date 
Blood Pressure 
-14 
 
 
 
 
 
 
/ 
 
 
-13 
 
 
 
 
 
 
/ 
 
 
-12 
 
 
 
 
 
 
/ 
 
 
-11 
 
 
 
 
 
 
/ 
 
 
-10 
 
 
 
 
 
 
/ 
 
 
-9 
 
 
 
 
 
 
/ 
 
 
-8 
 
 
 
 
 
 
/ 
 
 
-7 
 
 
 
 
 
 
/ 
 
 
-6 
 
 
 
 
 
 
/ 
 
 
-5 
 
 
 
 
 
 
/ 
 
 
-4 
 
 
 
 
 
 
/ 
 
 
-3 
 
 
 
 
 
 
/ 
 
 
-2 
 
 
 
 
 
 
/ 
 
 
-1 
 
 
 
 
 
 
/ 
 
 
Signature:  ________________________________ Date_____________________________ 


98 
Abbreviated Title: Vandetanib/Metformin in RCC 
Version Date: 05/01/2018 
 
18.2 ALL OTHER CYCLES 
Instructions 
1. Take your blood pressure at least once per day during each cycle of study drug 
2. Record the date you took your blood pressure and your blood pressure below 
3. Bring this form with you at your next study visit 
 
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Abbreviated Title: Vandetanib/Metformin in RCC 
Version Date: 05/01/2018 
 
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Signature: ______________________________ 
 
Date: ___________________ 
 
 
 
 
 
 

ICF_001.pdf: 
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
INSTITUTE: 
National Cancer Institute 
STUDY NUMBER: 
15-C-0157 
PRINCIPAL INVESTIGATOR: 
Ramaprasad Srinivasan, M.D. 
STUDY TITLE:  
Phase I/II Trial of Vandetanib in Combination with Metformin in Subjects with 
HLRCC or SDH-Associated Kidney Cancer or Sporadic Papillary Renal Cell 
Carcinoma 
 
Continuing Review Approved by the IRB on 04/24/17 
Amendment Approved by the IRB on 09/30/16 (B) 
 
Date posted to web: 05/18/17 
Phase I Standard 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent (1) 
 
 
INTRODUCTION 
We invite you to take part in a research study at the National Institutes of Health (NIH). 
First, we want you to know that: 
Taking part in NIH research is entirely voluntary.  
You may choose not to take part, or you may withdraw from the study at any time.  In 
either case, you will not lose any benefits to which you are otherwise entitled.  However, 
to receive care at the NIH, you must be taking part in a study or be under evaluation for 
study participation. 
You may receive no benefit from taking part.  The research may give us knowledge that 
may help people in the future. 
Second, some people have personal, religious or ethical beliefs that may limit the kinds of 
medical or research treatments they would want to receive (such as blood transfusions).  If you 
have such beliefs, please discuss them with your NIH doctors or research team before you agree 
to the study. 
Now we will describe this research study.  Before you decide to take part, please take as much 
time as you need to ask any questions and discuss this study with anyone at NIH, or with family, 
friends or your personal physician or other health professional.   
 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:  15-C-0157 
CONTINUATION: page 2 of 17 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
Why is this study being done?  
There are no established treatments for patients with advanced non-hereditary papillary kidney 
cancers or for kidney cancers associated with Hereditary Leiomyomatosis and Renal Cell Cancer 
(HLRCC) or Succinate Dehydrogenase Renal Carcinoma (SDH-RCC). These tumors do not 
usually respond well to the treatments that are currently available and approved by the FDA for 
treatment of kidney cancer. Although several treatments are FDA-approved for treatment of the 
more common, clear cell form of kidney cancer, these treatments generally work for relatively 
short periods of time and are not curative. Vandetanib is an FDA approved agent for the 
treatment of advanced medullary thyroid cancer. It has been shown to have activity against a 
variety of tumors and has been shown to inhibit some forms of papillary renal cancer cells and to 
cause tumor shrinkage in mice with human papillary kidney cancer. Vandetanib also targets 
certain proteins thought to be important in mediating the more common form (clear cell) of 
kidney cancer. Metformin, an FDA approved agent for treatment of diabetes, has been shown in 
laboratory experiments to enhance the effect of vandetanib in some forms of papillary kidney 
cancer. Neither metformin nor vandetanib are approved for use in papillary kidney cancer. 
In this study, we will test the combination of metformin and vandetanib. In the first part of the 
study, called phase 1, we will determine a safe dose for the combination in patients with 
advanced kidney cancer of any subtype.  
Why are you being asked to take part in this study? 
You are being asked to participate in this study because you have been diagnosed with advanced 
kidney cancer. 
How many people will take part in this study?  
Up to 73 subjects will take part in the study. This includes up to 27 subjects in the dose finding 
portion (phase 1) of the study and up to 46 subjects in the phase 2 portion of the study. You will 
be taking part in the phase 1 portion of the study. 
Description of Research Study 
We will enroll 3 subjects to each dose level in the phase 1 portion of the study. If no subjects 
develop intolerable side effects in the first 28 days of the study combination at the lowest dose 
level, 3 more subjects will be enrolled at the next highest dose level. If 1 subject develops an 
intolerable side effect, 3 more subjects will be enrolled at this dose level. If no additional 
subjects have an intolerable side effect, the next 3 patients will be enrolled at the next (higher) 
dose level. This will continue until a dose level is reached at which 2 or more subjects experience 
intolerable side-effects. Once that level is reached, 3 more subjects will be enrolled at the dose 
level just below it. If no more than 1 out of the 6 subjects at this dose level experienced an 
intolerable side effect, then this will become the assigned dose for phase 2 portion of the study. 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:  15-C-0157 
CONTINUATION: page 3 of 17 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
What will happen if you take part in this research study?   
Before you begin the study 
You will need to have the following exams, tests and procedures if you can be in the study.  
These exams, tests and procedures are part of regular cancer care and may be done even if you 
do not join the study.  If you have had some of them done recently, they may not need to be 
repeated.  This will be up to the study team. 
• A complete medical history, including your cancer history and prior cancer treatments, all 
drugs that you may be taking, including over the counter drugs, vitamins and herbal 
supplements. 
• A complete physical examination, including assessing your ability to do physical 
activities and measuring your blood pressure, heart rate and breathing. 
• Standard blood and urine tests to evaluate your organs’ functioning (such as liver, 
kidneys, blood sugar and blood electrolytes). 
• Evaluation of your cancer, which will include an MRI and CT and other imaging tests as 
if clinically indicated.   
• ECG (electrocardiogram) to assess your heart. 
• A pregnancy test will be performed in women who are able to have children.  Women 
who are pregnant or breast-feeding will not be allowed to participate, as the effects of 
vaccine on a developing fetus or infant are not known. 
• Confirmation of diagnosis by NCI Laboratory of Pathology (a review of the slides 
showing your tumor will be sent to NIH and looked at here by our pathologist).  
During the study 
If you are determined to be eligible for this study and agree to take part, you will be enrolled on a 
certain dose level of vandetanib and metformin.  Your time in this study will be arbitrarily 
divided into cycles, with each cycle lasting 28 days. You will take vandetanib once a day and 
metformin once or twice every day depending on the level to which you are assigned.  
With the exception of the first day you are on the trial, you will be taking both medications every 
day. Take the medications together with a full glass of water after eating a light breakfast. 
Record the date and time you take the medications on your diary. If you are taking the metformin 
in the AM and PM, take the evening dose of Metformin 12 hours after your AM dose. 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:  15-C-0157 
CONTINUATION: page 4 of 17 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
If you have any procedure that requires the use of IV contrast such as a CT scan, you should not 
take metformin on the morning that the procedure is planned and should only resume when 
instructed to do so by your physician/medical team. You will continue to take metformin and 
vandetanib until your disease worsens, until you have intolerable side effects that require us to 
stop your vandetanib. If your side effects require us to permanently discontinue metformin, you 
may be able to continue on the study, taking vandetanib alone. 
In some instances, if you are doing well, your study doctor may decide to increase your dose 
level if it is determined that the higher dose is safe. 
If the dose of metformin you are assigned to take is high, there will be a metformin ‘lead in’.  
This means that you will take metformin twice a day for two weeks, starting from a lower dose 
and increasing gradually to your assigned dose.  You will also take vandetanib at the assigned 
dose during this time. Once this two week lead in period is complete, then the 28 day cycle 
begins and you will take both vandetanib and metformin at the assigned dose level.  
We will provide you with equipment and a diary to measure and record your blood 
pressure every day while you are on vandetanib. If you experience any worrisome side 
effects (e.g., headaches, chest pain, dizziness), or if your systolic blood pressure (upper or 
higher number) is above 140, or if your diastolic (lower number) is 90 or above, you should 
call your doctors at the NIH or seek medical attention from your local doctors as soon as 
possible. 
We will also obtain/test the items below while you are on study medication.  You will have some 
of these tests more frequently during the first cycle.  You will receive a specific calendar for each 
cycle from the study nurse. 
• History and physical examination  
• Routine blood tests  
• Routine urine tests  
• Pregnancy test (if you are a woman who could become pregnant) 
• Electrocardiogram (ECG)  
• CT scans or MRI  
• Bone scan  
• PET Scan  
• Photographs of skin tumors in patients with HLRCC associated skin tumors  
• 1 – 2 teaspoons of blood for research will be collected before you have taken any study 
medication, then at the end of each cycle through cycle 8. We will also collect blood for 
research if your disease worsens during the study. 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:  15-C-0157 
CONTINUATION: page 5 of 17 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
• An optional CT- or ultrasound-guided tumor biopsy may be done before you begin 
treatment and approximately 8 weeks following start of treatment.  We will only collect 
the biopsy if the tumor can be easily reached. The tumor samples we obtain will be used 
to look for special markers that may be helpful in the study of kidney cancer and in 
understanding the effect of the study drugs on the tumor.  We may also use the samples to 
grow tumor cell lines (cells which keep dividing and growing in the laboratory, 
sometimes for years allowing us to continually study those cells).  Results of research 
done on your specimens will not be available to you or and may not be available to your 
doctor.  A separate consent form will be provided to you at the time of the biopsy for you 
to grant permission to that procedure if you agree to the biopsies. 
During this study you will not be able to receive any other cancer treatments. You will be asked 
not to participate in any other clinical trials involving another experimental treatment while you 
are being treated in this study. 
Several medications (both prescription and non-prescription), ‘alternative/complementary’ or 
herbal preparations, dietary supplements, and foods such as grapefruit juice, can have 
undesirable interactions with the medications provided as part of this study. You will not be 
allowed to take certain medications, supplements, and grapefruit juice during your participation 
in this study.  Your doctor or the study staff will review the list of drugs that you are currently 
taking, as well as those that you took prior to participating in this study. Once you are on study, 
please talk to your NIH doctors prior to starting any new drugs, dietary supplements or 
herbal or complementary medications. 
Drugs that affect the normal growth of blood vessels can delay or complicate wound healing 
following injury or surgical procedures. You should not schedule any elective surgeries while 
you are being treated in this study.  If you have an unplanned surgery, inform you doctor 
immediately, as you may not be able to continue study drug treatment. 
You will be asked not to wear contact lenses while on this study since vandetanib can lead to 
changes in your eye that may be worsened by wearing contact lenses. 
Pharmacogenetic Testing 
For this study approximately 1 teaspoon of blood will be drawn (4 mL) before you start the 
treatment.  The purpose of this additional research study is to use the blood sample from you for 
research on genes, to see how genes and genetic variations are related to how the drug works 
and/or to learn more about your disease and the response to treatment.  To do this, we will 
analyze your blood sample.  
Pharmacogenetic research is an important way to try to understand the role of genetics in human 
disease and how genes impact the effectiveness of drugs. There are many differences, or 
variations, in genes from one person to another, which may affect a person’s chances of suffering 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:  15-C-0157 
CONTINUATION: page 6 of 17 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
from a particular disease. These differences in genes can also change the way a person responds 
to a particular drug.  
We would like to learn more about your type of tumor by measuring certain characteristics, so 
called “biological markers” in your blood sample.   “Markers” refer to different types of genetic 
material (DNA or RNA) found in your blood that is associated with disease and/or your response 
to treatment. The aim is to find out if there are markers, which may help in predicting how well 
the treatment works.  
This is voluntary and you are not required to participate in this blood study in order to be on this 
study.  You will be given the opportunity to decide whether you want to participate in the 
pharmacogenetic study.  The decision to participate in this part of the research is optional, and no 
matter what you decide to do, it will not affect your care. 
When you are finished taking the drugs (treatment) 
If you stop taking the study drugs, we would like to perform the following tests if possible within 
approximately 60 days after your last dose. The tests may be done at NCI or by your local 
physician: 
• History and physical exam 
• Routine blood tests 
If the tests cannot be performed, we would like to contact you by telephone to find out how you 
are doing. 
In addition, after the 60 day follow up visit/contact, when possible we would like to contact you 
once a year by phone to find out how you are doing. 
Birth Control 
If you are a woman who is breast feeding or pregnant, you may not take part in the study because 
we don’t know how this medicine would affect your baby or your unborn child. If you are a 
woman who can become pregnant, or are the partner of a woman who can become pregnant, you 
will need to practice an effective form of birth control before starting study treatment, during 
study treatment, and for 6 months after you finish study treatment.  If you think that you or your 
partner is pregnant, you should tell your study doctor or nurse at once.   
Effective forms of birth control include:  
• abstinence  
• intrauterine device (IUD) 
• hormonal [birth control pills, injections, or implants] 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:  15-C-0157 
CONTINUATION: page 7 of 17 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
• tubal ligation 
• vasectomy 
Risks or Discomforts of Participation 
If you choose to take part in this study, there is a risk that: 
• You may lose time at work or home and spend more time in the hospital or doctor’s 
office than usual 
• You may be asked sensitive or private questions which you normally do not discuss 
The drugs used in this study may affect how different parts of your body work such as your liver, 
kidneys, heart, and blood. The study doctor will be testing your blood and will let you know if 
changes occur that may affect your health. 
There is also a risk that you could have side effects from the study drugs. 
Here are important points about side effects: 
• The study doctors do not know who will or will not have side effects. 
• Some side effects may go away soon, some may last a long time, and some may never go 
away. 
• Some side effects may interfere with your ability to have children. 
• Some side effects may be serious and may even result in death. 
Here are important points about how you and the study doctor can make side effects less of a 
problem: 
• Tell the study doctor if you notice or feel anything different so they can see if you are 
having a side effect. 
• The study doctor may be able to treat some side effects. 
• The study doctor may adjust the study drugs to try to reduce side effects. 
The tables below show the most common and the most serious side effects that researchers know 
about. There might be other side effects that researchers do not yet know about. If important new 
side effects are found, the study doctor will discuss these with you. 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:  15-C-0157 
CONTINUATION: page 8 of 17 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
Possible Side Effects of Vandetanib  
COMMON, SOME MAY BE SERIOUS 
For every 100 people receiving Vandetanib, more than 20 and up to 100 may have: 
• Diarrhea, nausea, loss of appetite, constipation 
• Pain 
• Tiredness 
• Headache 
• Acne, rash 
• High blood pressure which may cause dizziness, blurred vision 
• Changes in the ECG 
• Weight loss 
• Depression or anxiety 
• Sleeplessness 
• Dizziness 
• Changes in measures of your kidney function, such as an increase in creatinine or 
increased protein in your urine 
• Delayed wound healing 
 
OCCASIONAL, SOME MAY BE SERIOUS 
For every 100 people receiving Vandetanib, from 4 to 20 may have: 
• Severe blood or other infection 
• Change in the heart rhythm, some of which may be life threatening 
• Dehydration 
• Changes in laboratory values of electrolytes and liver function tests 
• Low platelet counts, white blood counts or anemia 
• Itching 
• Pain, including pain associated with tumor 
• Brain damage which may cause headache, seizure, blindness (also known as Reversible 
Posterior Leukoencephalopathy Syndrome) 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:  15-C-0157 
CONTINUATION: page 9 of 17 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
OCCASIONAL, SOME MAY BE SERIOUS 
For every 100 people receiving Vandetanib, from 4 to 20 may have: 
• Damage to the lungs which may cause shortness of breath 
• Scarring of the lungs 
• Severe skin rash with blisters, ulcers can involve inside of mouth and other parts of the 
body 
• Bleeding 
• pain, redness, or peeling of the hands and feet 
• increased blood levels of calcium, a mineral normally found in blood 
• changes in levels of parathormone, a substance made in your body that regulates the levels 
of calcium and phosphorus 
• Inflammation of the pancreas 
• Inflammation/infection of the intestines 
• Abnormal accumulation of fluid in the brain 
• Development of an abnormal pathway between the esophagus (tube connecting the throat 
to the stomach) and trachea (windpipe) or surrounding structures 
• Development of an abnormal communication between the intestines and surrounding 
structures, including the urinary bladder 
• Decrease in thyroid function 
• Stroke 
• Mild nose bleeding 
• Abnormal taste in mouth 
• Dry or irritated eyes; vandetanib may also cause some visual changes or eye infections 
• Formation of clots, such as in the lung or in the legs 
• Lack of blood flow to heart (heart attack), brain (stroke), eye (blindness), legs, or bowel 
• Serious or life-threatening complications from rashes 
• Lung inflammation and stiffening, infections or fluid accumulation around the lungs 
• Blockage or penetration of the bowel or gall bladder duct 
 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:  15-C-0157 
CONTINUATION: page 10 of 17 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
RARE, AND SERIOUS 
For every 100 people receiving Vandetanib, 3 or fewer may have: 
• Heart failure which may cause shortness of breath, swelling of ankles, and tiredness 
• Stroke which may cause paralysis, weakness 
• Kidney stones 
• Life threatening problems resulting from abnormal heart rhythm 
• Detached retina 
Possible Side Effects of Metformin Hydrochloride  
COMMON, SOME MAY BE SERIOUS 
For every 100 people receiving Metformin Hydrochloride, more than 20 and up to 100 may 
have: 
• Diarrhea, nausea, vomiting 
 
OCCASIONAL, SOME MAY BE SERIOUS 
For every 100 people receiving Metformin Hydrochloride, from 4 to 20 may have: 
• Heartburn, passing gas 
• Headache 
• Tiredness 
 
RARE, AND SERIOUS 
In 100 people receiving Metformin Hydrochloride, 3 or fewer may have: 
• Lactic acid build up which may cause muscle aches, shortness of breath, or severe belly 
pain. If untreated this can lead to death 
 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:  15-C-0157 
CONTINUATION: page 11 of 17 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
Tumor Biopsy Risks 
The biopsy procedure usually causes only brief discomfort at the site from which the biopsy is 
taken.  Rarely, infection or bleeding may occur at the needle site. 
Research Radiation Risks   
This research study involves exposure to radiation from 1 FDG PET/CT scan of 10mCi of FDG 
on cycle 1 day 15 and up to 2 CT scans for CT guided biopsy.  This radiation exposure is not 
required for your medical care and is for research purposes only. From participating in this, the 
total amount of radiation you will receive is 2.4 rem which is below the guideline of 5.0 rem per 
year allowed for research subjects by the NIH Radiation Safety Committee.  The average person 
in the United States receives a radiation exposure of 0.3 rem per year from natural sources, such 
as the sun, outer space, and the earth's air and soil.  If you would like more information about 
radiation, please ask the investigator for a copy of the pamphlet, An Introduction to Radiation for 
NIH Research Subjects. 
While there is no direct evidence that the amount of exposure received from participating in this 
study is harmful, there is indirect evidence it may not be completely safe.  There may be a very 
slight increase in the risk of cancer.  
Please tell your doctor if you have had any radiation exposure in the past year, either from other 
research studies or from medical tests or care, so we can make sure that you will not receive too 
much radiation. Radiation exposure includes x-rays taken in radiology departments, cardiac 
catheterization, and fluoroscopy as well as nuclear medicine scans in which radioactive materials 
were injected into your body.  
If you are pregnant you will not be permitted to participate in this research study. If you are 
breast feeding and the protocol involves injection of radioactive material, you will not be 
permitted to participate.  It is best to avoid radiation exposure to unborn or nursing infants since 
they are more sensitive to radiation than adults.  
Potential Benefits of Participation 
Are there benefits to taking part in this study?  
The aim of this study is to establish a safe dose for the combination of vandetanib and metformin 
and also to determine whether this experimental combination will cause your tumors to shrink.    
We do not know if you will receive personal, medical benefit from taking part in this study.  
These potential benefits could include shrinking of your tumor or lessening of your symptoms, 
such as pain, that are caused by the cancer.  Because there is not much information about the 
drugs’ effect on your cancer, we do not know if you will benefit from taking part in this study, 
although the knowledge gained from this study may help others in the future who have cancer.   


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:  15-C-0157 
CONTINUATION: page 12 of 17 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
Alternative Approaches or Treatments 
What other choices do I have if I do not take part in this study?  
Instead of being in this study, you have these options: 
• Getting treatment or care for your cancer without being in a study 
• Taking part in another study 
• Getting comfort care, also called palliative care.  This type of care helps reduce pain, 
tiredness, appetite problems and other problems caused by the cancer.  It does not treat 
the cancer directly.  Instead, it tries to improve how you feel.  Comfort care tries to keep 
you as active and comfortable as possible. 
Please talk to your doctor about these and other options. 
Stopping Therapy  
Your doctor may decide to stop your therapy for the following reasons: 
• if he/she believes that it is in your best interest 
• if your disease comes back during treatment 
• if you have side effects from the treatment that your doctor thinks are too severe 
• if new information shows that another treatment would be better for you 
In this case, you will be informed of the reason therapy is being stopped. 
You can stop taking part in the study at any time. However, if you decide to stop taking part in 
the study, we would like you to talk to the study doctor and your regular doctor first. 
If you decide at any time to withdraw your consent to participate in the trial, we will not collect 
any additional medical information about you. However, according to FDA guidelines, 
information collected on you up to that point may still be provided to Sanofi Genzyme or 
designated representatives. If you withdraw your consent and leave the trial, any samples of 
yours that have been obtained for the study and stored at the NCI can be destroyed upon request. 
However, any samples and data generated from the samples that have already been distributed to 
other researchers or placed in the research databases cannot be recalled and destroyed. 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:  15-C-0157 
CONTINUATION: page 13 of 17 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
Research Subject’s Rights 
What are the costs of taking part in this study?  
If you choose to take part in the study, the following will apply, in keeping with the NIH policy: 
• 
You will receive study treatment at no charge to you. This may include 
surgery, medicines, laboratory testing, x-rays or scans done at the 
Clinical Center, National Institutes of Health (NIH), or arranged for you 
by the research team to be done outside the Clinical Center, NIH if the 
study related treatment is not available at the NIH.  
• 
There are limited funds available to cover the cost of some tests and 
procedures performed outside the Clinical Center, NIH.  You may have 
to pay for these costs if they are not covered by your insurance company. 
• 
Medicines that are not part of the study treatment will not be provided or 
paid for by the Clinical Center, NIH. 
• 
Once you have completed taking part in the study, medical care will no 
longer be provided by the Clinical Center, NIH. 
Will your medical information be kept private?  
We will do our best to make sure that the personal information in your medical record is kept 
private.  However, we cannot guarantee total privacy.  Organizations that may look at and/or 
copy your medical records for research, quality assurance, and data analysis include: 
• The National Cancer Institute (NCI) and other government agencies, like the Food and 
Drug Administration (FDA), which are involved in keeping research safe for people. 
• National Cancer Institute Institutional Review Board 
• Qualified representatives from Sanofi Genzyme, the pharmaceutical company that 
produces vandetanib. 
A description of this clinical trial will be available on http://www.Clinicaltrials.gov, as 
required by U.S. Law.  This Web site will not include information that can identify you.  At 
most the Web site will include a summary of the results.  You can search this Web site at any 
time. 
Certificate of Confidentiality  
To help us protect your privacy, we have obtained a Certificate of Confidentiality. The 
researchers can use this Certificate to legally refuse to disclose information that may identify you 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:  15-C-0157 
CONTINUATION: page 14 of 17 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
in any federal, state, or local civil, criminal, administrative, legislative, or other proceedings, for 
example, if there is a court subpoena. The researchers will use the Certificate to resist any 
demands for information that would identify you, except as explained below. 
You should also know that there are several circumstances in which the Certificate does not 
provide coverage. These include when information:  
• will be used for auditing or program evaluation internally by the NIH; or  
• must be disclosed to meet the legal requirements of the federal Food and Drug 
Administration (FDA).  
• is necessary for your medical treatment and you have consented to this disclosure;  
• is for other research.  
In addition, identifiable, sensitive information protected by this Certificate cannot be admissible 
as evidence or used for any purpose in any action, suit, or proceeding without your consent.  
You should understand that a Certificate of Confidentiality does not prevent you or a member of 
your family from voluntarily releasing information about yourself or your involvement in this 
research. If an insurer, employer, or other person obtains your written consent to receive research 
information, then the researchers will not use the Certificate to withhold that information. 
The Certificate of Confidentiality will not protect against the required reporting by hospital staff 
of information on suspected child abuse, reportable communicable diseases, and/or possible 
threat of harm to self or others. 
Conflict of Interest 
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts 
of interest.  This process is detailed in a Protocol Review Guide.  You may ask your research 
team for a copy of the Protocol Review Guide or for more information.  Members of the research 
team who do not work for NIH are expected to follow these guidelines but they do not need to 
report their personal finances to the NIH. 
Members of the research team working on this study may have up to $15,000 of stock in the 
companies that make products used in this study.  This is allowed under federal rules and is not a 
conflict of interest.  
The National Institutes of Health and the research team for this study are using vandetanib 
developed by Sanofi Genzyme, through a joint study with your researchers and the company.   
The company also provides financial support for this study. 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:  15-C-0157 
CONTINUATION: page 15 of 17 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
Use of Specimens and Data for Future Research 
To advance science, it is helpful for researchers to share information they get from studying 
human samples.  They do this by putting it into one or more scientific databases, where it is 
stored along with information from other studies. A researcher who wants to study the 
information must apply to the database and be approved.  Researchers use specimens and data 
stored in scientific databases to advance science and learn about health and disease.   
We plan to keep some of your specimens and data that we collect and use them for future 
research and share them with other researchers. We will not contact you to ask about each of 
these future uses.  These specimens and data will be stripped of identifiers such as name, address 
or account number, so that they may be used for future research on any topic and shared broadly 
for research purposes. Your specimens and data will be used for research purposes only and will 
not benefit you.  It is also possible that the stored specimens and data may never be used.  
Results of research done on your specimens and data will not be available to you or your doctor.  
It might help people who have cancer and other diseases in the future.   
If you do not want your stored specimens and data used for future research, please contact us in 
writing and let us know that you do not want us to use your specimens and/or data.  Then any 
specimens that have not already been used or shared will be destroyed and your data will not be 
used for future research. However, it may not be possible to withdraw or delete materials or data 
once they have been shared with other researchers. 
 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
STUDY NUMBER:  15-C-0157 
CONTINUATION: page 16 of 17 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH 
STUDY (Continuation Sheet) 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
 
File in Section 4:  Protocol Consent 
 
OTHER PERTINENT INFORMATION 
1. 
Confidentiality.  When results of an NIH research study are reported in medical journals 
or at scientific meetings, the people who take part are not named and identified.  In most cases, 
the NIH will not release any information about your research involvement without your written 
permission.  However, if you sign a release of information form, for example, for an insurance 
company, the NIH will give the insurance company information from your medical record.  This 
information might affect (either favorably or unfavorably) the willingness of the insurance 
company to sell you insurance. 
The Federal Privacy Act protects the confidentiality of your NIH medical records.  However, you 
should know that the Act allows release of some information from your medical record without 
your permission, for example, if it is required by the Food and Drug Administration (FDA), 
members of Congress, law enforcement officials, or authorized hospital accreditation 
organizations. 
2. 
Policy Regarding Research-Related Injuries.  The Clinical Center will provide short-
term medical care for any injury resulting from your participation in research here.  In general, 
no long-term medical care or financial compensation for research-related injuries will be 
provided by the National Institutes of Health, the Clinical Center, or the Federal Government.  
However, you have the right to pursue legal remedy if you believe that your injury justifies such 
action. 
3. 
Payments.  The amount of payment to research volunteers is guided by the National 
Institutes of Health policies.  In general, patients are not paid for taking part in research studies at 
the National Institutes of Health.  Reimbursement of travel and subsistence will be offered 
consistent with NIH guidelines. 
4. 
Problems or Questions.  If you have any problems or questions about this study, or 
about your rights as a research participant, or about any research-related injury, contact the 
Principal Investigator, Ramaprasad Srinivasan, M.D., Building 10, Room 2-5950, Telephone:  
240-760-6251. You may also call the Clinical Center Patient Representative at 301-496-2626. If 
you have any questions about the use of your specimens or data for future research studies, you 
may also contact the Office of the Clinical Director, Telephone: 240-760-6070.  
5. 
Consent Document.  Please keep a copy of this document in case you want to read it 
again. 
 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
STUDY NUMBER:  15-C-0157 
CONTINUATION: page 17 of 17 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH 
STUDY (Continuation Sheet) 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
 
File in Section 4:  Protocol Consent 
 
COMPLETE APPROPRIATE ITEM(S) BELOW: 
A. Adult Patient’s Consent 
B. Parent’s Permission for Minor Patient. 
I have read the explanation about this study 
and have been given the opportunity to 
discuss it and to ask questions.  I hereby 
consent to take part in this study. 
I have read the explanation about this study and 
have been given the opportunity to discuss it and 
to ask questions.  I hereby give permission for my 
child to take part in this study.   
(Attach NIH 2514-2, Minor’s Assent, if 
applicable.) 
 
 
  
 
 
 
Signature of Adult Patient/ 
Legal Representative 
Date 
Signature of Parent(s)/ Guardian 
Date 
 
 
Print Name 
 
 
Print Name 
C. Child’s Verbal Assent (If Applicable) 
The information in the above consent was described to my child and my child agrees to participate 
in the study. 
 
 
  
 
Signature of Parent(s)/Guardian 
Date 
Print Name 
THIS CONSENT DOCUMENT HAS BEEN APPROVED FOR USE  
FROM APRIL 24, 2017 THROUGH APRIL 23, 2018.  
 
  
 
 
 
 
 
Signature of Investigator 
Date 
Signature of Witness 
Date 
 
 
Print Name 
 
 
Print Name