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7.3.2 nci-irb requirements for pi

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.
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7.4 safety reporting criteria to

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)
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.
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7.5 data and safety monitoring

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). Followup 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.
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8 statistical considerations 8.1 phase

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 (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.  
| Number of Patients with  DLT      | Escalation Decision Rule                                                                                                                                                                                                                                                                                                                                                                                           |
|-----------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| at a Given Dose Level  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       | This is the MTD and is generally the recommended                                                                                                                                                                                                                                                                                                                                                                   |
| level                             | phase 2 dose. At least 6 patients must be entered at  the recommended phase 2 dose.                                                                                                                                                                                                                                                                                                                                |
| 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 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.
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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 23 years. Therefore, overall study is expected to have completed accrual within 4-5 years.
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9 collaborative agreements 9.1 cooperative

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. 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.
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10 human subjects protections 10.1

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.
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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.
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10.2 participation of subjects unable

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 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.
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10.3 evaluation of benefits and

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.
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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.
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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.
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10.4 alternative treatments

Patients will be apprised of other therapeutic options, both experimental and those of standard of care.
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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.
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10.5.2 informed consent of non-english

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.
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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.
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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, 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.
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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.
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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.
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11.2.1 source

Metformin is commercially available and manufactured by Bristol-Myers Squibb Company (Princeton, NJ) under the trade name GLUCOPHAGE®.
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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: abnormal stools, hypoglycemia, myalgia, lightheadedness, dyspnea, nail disorder, rash, diaphoresis, changes in taste, chest discomfort, palpitations, chills, flu syndrome, and flushing.
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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.
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11.2.4 stability and storage

Metformin should be stored at approximately 20º-25ºC, with excursion permitted to 15º-30ºC.
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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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| 13                                                                                                                                                              | APPENDIX A: PERFORMANCE STATUS CRITERIA  ECOG Performance Status Scale Karnofsky Performance Scale  Grade Descriptions Percent Description  100 Normal, no complaints,   | no                                                                 |                 |           |             |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------|-----------------|-----------|-------------|
| evidence of disease.                                                                                                                                            |                                                                                                                                                                          |                                                                    |                 |           |             |
| Normal activity. Fully active, able                                                                                                                             |                                                                                                                                                                          |                                                                    |                 |           |             |
| 0                                                                                                                                                               | to                                                                                                                                                                       | carry                                                              | on              | all       | pre-disease |
| performance without restriction.                                                                                                                                | Able to carry on normal activity;                                                                                                                                        |                                                                    |                 |           |             |
| 90                                                                                                                                                              | minor                                                                                                                                                                    | signs                                                              | or              | symptoms  | of          |
| disease.                                                                                                                                                        |                                                                                                                                                                          |                                                                    |                 |           |             |
| 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.   |                 |           |             |
| 1                                                                                                                                                               | Cares for self, unable to carry on                                                                                                                                       |                                                                    |                 |           |             |
| 70                                                                                                                                                              | normal activity or to do active  work. Requires occasional assistance,                                                                                                   |                                                                    |                 |           |             |
| 60                                                                                                                                                              | but is able to care for most of  his/her needs.                                                                                                                          |                                                                    |                 |           |             |
| 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.                            |                                                                                                                                                                          |                                                                    |                 |           |             |
| 2                                                                                                                                                               | 50                                                                                                                                                                       | Requires considerable assistance  and frequent medical care.       |                 |           |             |
| 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.                   |                 |           |             |
| 3                                                                                                                                                               | 30                                                                                                                                                                       | Severely disabled, hospitalization  indicated. Death not imminent. |                 |           |             |
| 20                                                                                                                                                              | Very                                                                                                                                                                     | sick,                                                              | hospitalization |           |             |
| indicated. Death not imminent.                                                                                                                                  |                                                                                                                                                                          |                                                                    |                 |           |             |
| 100%                                                                                                                                                            | bedridden.                                                                                                                                                               | Completely                                                         |                 |           |             |
| disabled.                                                                                                                                                       | Cannot carry on any                                                                                                                                                      |                                                                    |                 |           |             |
| self-care. Totally confined to bed  or chair.                                                                                                                   |                                                                                                                                                                          |                                                                    |                 |           |             |
| 4                                                                                                                                                               | 10                                                                                                                                                                       | Moribund,                                                          | fatal           | processes |             |
| progressing rapidly.                                                                                                                                            |                                                                                                                                                                          |                                                                    |                 |           |             |
| 5                                                                                                                                                               | Dead.                                                                                                                                                                    | 0                                                                  | Dead.           |           |             |  
Version Date: *05/01/2018*
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14 appendix b new york

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. |
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15 appendix c medications known

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:
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15.1 group 1 drugs that

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;      | Females>Males                           |
| increase GI motility |                                                   |                                         |
| Escitalopram         | Major depression/anxiety disorders                |                                         |  
| 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                    | Not available in U.S.               |
| dependence                                   |                                                          |                                     |
| Mesoridazine                                 | Anti-psychotic/schizophrenia                             | Not available in U.S.               |
| Methadone                                    | Opiate agonist/pain control, narcotic                    | Females>Males                       |
| dependence                                   |                                                          |                                     |
| 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 |                                     |  
Version Date: *05/01/2018* 87
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15.2 group 2 drugs that

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+    | Anti-malarial                                                |                                                                          |
| piperaquine 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                              |                                                                          |  
Version Date: *05/01/2018*  
| 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         | Imaging contrast agent/Echocardiography          |                        |
| microspheres 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                                       |                        |  
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                  | Orphan drug in US |
| (Huntington's disease) |                                                          |                   |
| 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 |                   |
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16 appendix d patient drug

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.  
| 6.                                                                            | Please bring your pill bottles and this form to your physician when you go for your next appointment. Time of  Drug(s) Comments/ Time of  Drug(s) Comments/   |        |       |          |        |       |          |
|-------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------|--------|-------|----------|--------|-------|----------|
| Date                                                                          | Day                                                                                                                                                           | Dose 1 | taken | Symptoms | Dose 2 | taken | Symptoms |
| -14                                                                           | M                                                                                                                                                             | M      |       |          |        |       |          |
| V                                                                             |                                                                                                                                                               |        |       |          |        |       |          |
| -13                                                                           | M                                                                                                                                                             | M      |       |          |        |       |          |
| V                                                                             |                                                                                                                                                               |        |       |          |        |       |          |
| -12                                                                           | M                                                                                                                                                             | M      |       |          |        |       |          |
| V                                                                             |                                                                                                                                                               |        |       |          |        |       |          |
| -11                                                                           | M                                                                                                                                                             | M      |       |          |        |       |          |
| V                                                                             |                                                                                                                                                               |        |       |          |        |       |          |
| -10                                                                           | M                                                                                                                                                             | M      |       |          |        |       |          |
| V                                                                             |                                                                                                                                                               |        |       |          |        |       |          |
| -9                                                                            | M                                                                                                                                                             | M      |       |          |        |       |          |
| V                                                                             |                                                                                                                                                               |        |       |          |        |       |          |
| -8                                                                            | M                                                                                                                                                             | M      |       |          |        |       |          |
| V                                                                             |                                                                                                                                                               |        |       |          |        |       |          |
| -7                                                                            | M                                                                                                                                                             | M      |       |          |        |       |          |
| V                                                                             |                                                                                                                                                               |        |       |          |        |       |          |
| -6                                                                            | M                                                                                                                                                             | M      |       |          |        |       |          |
| V                                                                             |                                                                                                                                                               |        |       |          |        |       |          |
| -5                                                                            | M                                                                                                                                                             | M      |       |          |        |       |          |
| V                                                                             |                                                                                                                                                               |        |       |          |        |       |          |
| -4                                                                            | M                                                                                                                                                             | M      |       |          |        |       |          |
| V                                                                             |                                                                                                                                                               |        |       |          |        |       |          |
| -3                                                                            | M                                                                                                                                                             | M      |       |          |        |       |          |
| V                                                                             |                                                                                                                                                               |        |       |          |        |       |          |
| -2                                                                            | M                                                                                                                                                             | M      |       |          |        |       |          |
| V                                                                             |                                                                                                                                                               |        |       |          |        |       |          |
| -1                                                                            | M                                                                                                                                                             | M      |       |          |        |       |          |
| V                                                                             |                                                                                                                                                               |        |       |          |        |       |          |
| Signature: ________________________________ Date_____________________________ |                                                                                                                                                               |        |       |          |        |       |          |  
Version Date: *05/01/2018*
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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.  
| Time   | Drug(s)   | Comments/   |          |
|--------|-----------|-------------|----------|
| of     |           |             |          |
| Date   | Day       | taken       | Symptoms |
| Dose   |           |             |          |
| 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      |             |          |  
| Version Date: 05/01/2018  Time   | Drug(s)   | Comments/   |          |
|----------------------------------|-----------|-------------|----------|
| of                               |           |             |          |
| Date                             | Day       | taken       | Symptoms |
| Dose                             |           |             |          |
| 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: ___________________
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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.  
| Time    | Time      |         |           |       |          |
|---------|-----------|---------|-----------|-------|----------|
| Drug(s) | Comments/ | Drug(s) | Comments/ |       |          |
| of      | of        |         |           |       |          |
| Date    | Day       | taken   | Symptoms  | taken | Symptoms |
| Dose 1  | Dose 2    |         |           |       |          |
| 1       | M         | M       |           |       |          |
| V       |           |         |           |       |          |
| 2       | M         | M       |           |       |          |
| V       |           |         |           |       |          |
| 3       | M         | M       |           |       |          |
| V       |           |         |           |       |          |
| 4       | M         | M       |           |       |          |
| V       |           |         |           |       |          |
| 5       | M         | M       |           |       |          |
| V       |           |         |           |       |          |
| 6       | M         | M       |           |       |          |
| V       |           |         |           |       |          |
| 7       | M         | M       |           |       |          |
| V       |           |         |           |       |          |
| 8       | M         | M       |           |       |          |
| V       |           |         |           |       |          |
| 9       | M         | M       |           |       |          |
| V       |           |         |           |       |          |
| 10      | M         | M       |           |       |          |
| V       |           |         |           |       |          |
| 11      | M         | M       |           |       |          |
| V       |           |         |           |       |          |
| 12      | M         | M       |           |       |          |
| V       |           |         |           |       |          |
| 13      | M         | M       |           |       |          |
| V       |           |         |           |       |          |  
| Version Date: 05/01/2018  Time   | Time      |         |           |       |          |
|----------------------------------|-----------|---------|-----------|-------|----------|
| Drug(s)                          | Comments/ | Drug(s) | Comments/ |       |          |
| of                               | of        |         |           |       |          |
| Date                             | Day       | taken   | Symptoms  | taken | Symptoms |
| Dose 1                           | Dose 2    |         |           |       |          |
| 14                               | M         | M       |           |       |          |
| V                                |           |         |           |       |          |
| 15                               | M         | M       |           |       |          |
| V                                |           |         |           |       |          |
| 16                               | M         | M       |           |       |          |
| V                                |           |         |           |       |          |
| 17                               | M         | M       |           |       |          |
| V                                |           |         |           |       |          |
| 18                               | M         | M       |           |       |          |
| V                                |           |         |           |       |          |
| 19                               | M         | M       |           |       |          |
| V                                |           |         |           |       |          |
| 20                               | M         | M       |           |       |          |
| V                                |           |         |           |       |          |
| 21                               | M         | M       |           |       |          |
| V                                |           |         |           |       |          |
| 22                               | M         | M       |           |       |          |
| V                                |           |         |           |       |          |
| 23                               | M         | M       |           |       |          |
| V                                |           |         |           |       |          |
| 24                               | M         | M       |           |       |          |
| V                                |           |         |           |       |          |
| 25                               | M         | M       |           |       |          |
| V                                |           |         |           |       |          |
| 26                               | M         | M       |           |       |          |
| V                                |           |         |           |       |          |
| 27                               | M         | M       |           |       |          |
| V                                |           |         |           |       |          |
| 28                               | M         | M       |           |       |          |
| V                                |           |         |           |       |          |  
Signature: ______________________________ Date: ___________________
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17 appendix e patient instructions

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
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18 appendix f blood pressure

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_____________________________ |        |                  |
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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  
| Cycle Day   | Date   | Blood Pressure   |
|-------------|--------|------------------|
| 1           | /      |                  |
| 2           | /      |                  |
| 3           | /      |                  |
| 4           | /      |                  |
| 5           | /      |                  |
| 6           | /      |                  |
| 7           | /      |                  |
| 8           | /      |                  |
| 9           | /      |                  |
| 10          |        | /                |
| 11          |        | /                |
| 12          |        | /                |
| 13          |        | /                |
| 14          |        | /                |
| 15          |        | /                |  
| Version Date: 05/01/2018  Cycle Day   | Date   | Blood Pressure   |
|---------------------------------------|--------|------------------|
| 16                                    |        | /                |
| 17                                    |        | /                |
| 18                                    |        | /                |
| 19                                    |        | /                |
| 20                                    |        | /                |
| 21                                    |        | /                |
| 22                                    |        | /                |
| 23                                    |        | /                |
| 24                                    |        | /                |
| 25                                    |        | /                |
| 26                                    |        | /                |
| 27                                    |        | /                |
| 28                                    |        | /                |  
Version Date: *05/01/2018* Signature: ______________________________ Date: ___________________