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6.2 accrual ceiling

The accrual ceiling for this study was originally 20 evaluable patients for each cohort. With an expected accrual of 5-8 patients per year for the sporadic RCC cohort, we expect to complete accrual within 3-4 years, while we anticipate that it will take 4-5 years to complete accrual to the HLRCC cohort (4-5 patients per year). The accrual ceiling for Cohort 2 has been increased to 21; this is to enable replacement of one subject in this cohort, who is deemed inevaluable.  
Expansion Cohorts (Cohorts 3 and 4): The study was originally designed with a Simon twostage minimax design separately for each of two cohorts, assuming an ineffective response rate of 5% and a targeted effective response rate of 25%. In addition, it was assumed that the probability of accepting an ineffective treatment and the probability of rejecting an effective treatment were each 10%. With this design, in each cohort, 13 patients were to be accrued in the first stage. If at least one patient responded among the 13 patients, 7 additional patients were to be accrued to the cohort. If 3 or more patients of 20 respond, then the treatment will be considered effective and worthy of future investigation. As of May 2014, accrual for both cohorts had been completed; 20 patients had been enrolled on cohort 1 (patients with HLRCC associated RCC) and 21 patients had been enrolled in cohort 2 (non HLRCC/sporadic papillary RCC). The overall response rate at this time in cohort 1 was 60% (12/20 PRs) and that in cohort 2 was 29% (6/21 PRs). Additionally, there was one unconfirmed partial responder in each cohort. Since the number of responses in both arms has far exceeded the minimal 3 responses for the treatment to be deemed effective, further investigation of the treatment is warranted. We propose an expansion of the current study with two additional patient cohorts, one each for patients with HLRCC associated kidney cancer (cohort 3, N=20) and sporadic/non HLRCC papillary kidney cancer (cohort 4, N=20). We feel that several important issues can be better addressed by expanding the current protocol to include these additional cohorts. Some of these issues include: Estimating the true response rate in each cohort with higher precision. Allowing further exploratory biomarker analysis- While the response rates are high, particularly in the HLRCC cohort, the extent and duration of response was not uniform. This heterogeneity is particularly apparent in the non HLRCC cohort, with some patients experiencing significant and durable responses while others demonstrated rapidly progressive disease or appeared to derive only modest benefits. After this study was initiated, we have gained further insights into the molecular/biochemical pathways operating in HLRCC tumors; additionally, emerging data suggest that HLRCC tumors and some sporadic papillary tumors might share aberrant activation of some certain pathways, notably oxidative stress responses mediated by activation of the NRF2 pathway (53, 54). While the archival tissue obtained on the trial so far will allow us to study components of this pathway as potential biomarkers, additional samples obtained on the expanded trial will allow a more comprehensive evaluation. The sample size for the expanded study was established by determining the number of patients required to have a 95% confidence interval of specified width for a given response rate. We assume the true response rate is 50% and 30% for cohort 3 and cohort 4, respectively. In order to have the expected width of the Wilson's score confidence interval be 0.4 (e.g. to distinguish a response rate greater than 0.7 from a response rate less than 0.3), it requires approximately 20 patients in cohort 3. For cohort 4 with 20 patients the expected width of the Wilson's score confidence interval is 0.37 (e.g. to distinguish a response rate greater than 0.52 from a response rate less than 0.15). We will also estimate the response rate of combined samples from the current and expanded study. However, the response rate based on the naïve sample proportion of responses is biased, because it does not account for the fact that there has been at least one response in the first stage to continue to the second stage and more than 3 responses to expand the study for further investigation. We will derive a maximum likelihood estimate to take into account these truncation effects. Nevertheless, since the number of observed responses far exceeds these thresholds, the impact of these truncated effects is likely small (55). As a result, the sample proportion of response from the combined samples would likely be nearly unbiased and more precise (i.e. shorter 95% confidence interval) than the estimate based on either the original study or new added cohort alone. For example, without adjusting for the truncation effect, with the combined total of 40 patients in cohort 1, the expected width of the Wilson's score confidence interval would be 0.3. Results of cohorts 3 and 4 will be combined with the results of cohort 1 and 2, respectively. The combined response rate needs to account for the fact that there had been at least one response in the first stage to continue to the second stage and more than 3 responses to expand the study. This is accomplished by obtaining the maximum likelihood estimator for the combined response rate, where the likelihood function is the product of two truncated binomial probability function for the responses in the two stages of the first cohort times the binomial probability function for the expanded cohort. The product of the two truncated binomial probabilities equals the product of two binomial probabilities conditional on at least one response was observed in the first stage of the first cohort and at least 3 responses were observed in the entire first cohort. The maximum likelihood estimator of the combined response rate for the combined cohort 2 and cohort 4 will be obtained similarly. The maximum likelihood estimator does not have a closed-form solution and the NewtonRaphson algorithm would be used to obtain a numerical estimate of the combined response rate. A total of 40 additional evaluable patients will be accrued. To allow for inevaluable patients, the accrual ceiling will be set at 22 patients for each additional cohort (cohorts 3 and 4). The total accrual ceiling for the entire trial (cohorts 1-4) will therefore be 85 patients. We estimate that an additional 2 years will be needed to complete accrual to cohorts 3 and 4.
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7 human subjects protection 7.1

7.1.1 Research subject selection Patients of all races and ethnic origins will be eligible. 7.1.2 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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7.2 participation of subjects unable

Adults unable to give consent are excluded from enrolling in the protocol. However, reconsent 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 7.5), all subjects ≥ age 18 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 (ACAT) for evaluation to assess ongoing capacity of the subjects and to identify an LAR, as needed. Please see section **7.6.1** for consent procedure.
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7.3 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 and/or outcome. 7.3.2 Potential risks 7.3.2.1 Study Drugs Potential risks of study drugs include the possible occurrence of any of a range of side effects that are listed in the consent document. The most common risks of bevacizumab include nose bleeds, hypertension, fatigue, skin rash, headache and soreness in mouth or throat. The most common risks of erlotinib include skin rash, diarrhea, appetite loss and fatigue. The procedure for protecting against or minimizing risks will be to medically evaluate patients on a regular basis as described in Section 3. 7.3.2.2 Blood Draws Side effects of blood draws include pain and bruising, lightheadedness, and rarely, fainting. 7.3.2.3 ECG/Echocardiogram Some skin irritation can occur where the ECG/EKG electrodes are placed. The test is completely painless, and generally takes less than a minute to perform. There is no physical risk involved with echocardiogram. Side effects of an echocardiogram are discomfort from the transducer being firmly placed against the chest.
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7.3.2.4 scans

The radiation risks of the CT/PET and bone scans are discussed in section **7.3.2.6**. In addition to radiation risks, scans that employ contrast may cause allergic reactions, injection site reactions abdominal discomfort and fainting. MRIs carry no radiation risks but are contraindicated in participants with metal in their bodies. In participants that receive gadolinium contrast with MRIs, allergic reactions, injection site reactions and kidney damage may occur.
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7.3.2.5 serial 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. Biopsies may be performed with CT guidance. If that is the case, then this research study involves exposure to radiation as outlined in section **7.3.2.6**. 7.3.2.6 Radiation In this research study, participants may have up to 2 CT-guided biopsies, 8 CT scans, 6 bone scans and up to 6 PET scans performed per year for disease assessment. Subjects undergoing scans will be exposed up to 13.68 rem annually. This level of exposure is associated with an increased risk of cancer.
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7.4 alternative treatments

Patients will be apprised of other therapeutic options, both experimental and those of standard care.
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7.5 risk/benefit analysis

There are currently no standard therapeutic options for patients with metastatic renal cell carcinoma associated with HLRCC or for patients with advanced sporadic papillary RCC, who have a poor prognosis with most dying from metastatic disease and its sequelae. Patients participating in this trial may derive a benefit from the treatment administered. Although the individual agents used in this trial are not experimental, use of the combination of bevacizumab and erlotinib has not yet been FDA approved. However, the combination has been administered safely in prior phase I and II trials, and the majority of the side effects have been mild to moderate. The mechanism of action of the drugs suggests that the drugs could potentially render benefit in patients with some types of papillary renal cancer.
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7.6 consent process and documentation

The informed consent document will be provided as a physical or electronic document to the participant or consent designee(s) as applicable for review prior to consenting. A designated study investigator will carefully explain the procedures and tests involved in this study, and the associated risks, discomforts and benefits. In order to minimize potential coercion, as much time as is needed to review the document will be given, including an opportunity to discuss it with friends, family members and/or other advisors, and to ask questions of any designated study investigator. A signed informed consent document will be obtained prior to entry onto the study. The initial consent process as well as re-consent, when required, may take place in person or remotely (e.g., via telephone or other NIH approved remote platforms used in compliance with policy, including HRPP Policy 303) per discretion of the designated study investigator and with the agreement of the participant/consent designee(s). Whether in person or remote, the privacy of the subject will be maintained. Consenting investigators (and participant/consent designee, when in person) will be located in a private area (e.g., clinic consult room). When consent is conducted remotely, the participant/consent designee will be informed of the private nature of the discussion and will be encouraged to relocate to a more private setting if needed. Note: When required, witness signature will be obtained similarly as described for the investigator and participant as described below. Consent will be documented with required signatures on the physical document (which includes the printout of an electronic document sent to participant). When required, witness signature will be obtained similarly as described for the investigator and participant. For the optional biopsy for research, 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. 7.6.1 Consent Process for Adults Who Lack Capacity to Consent to Research Participation For participants addressed in section 7.3, an LAR will be identified consistent with Policy 403 and informed consent obtained from the LAR, as described in Section 7.6.
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7.7 patient records and quality

Complete records must be maintained on each patient treated on the protocol. These records will include primary documentation to confirm that:
The patient met all eligibility criteria  
Signed informed consent was obtained prior to treatment Treatment was given according to protocol. Toxicity was assessed according to protocol. Response was assessed according to protocol.
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8 nih reporting requirements/data and

Please refer to definitions provided in Policy 801: Reporting Research Events found here.
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8.2 ohsrp office and of

8.2.1 Expedited Reporting Please refer to the reporting requirements in Policy 801: Reporting Research Events and Policy 802 Non-Compliance Human Subjects Research found here. 8.2.2 IRB Requirements for PI Reporting at Continuing Review Please refer to the reporting requirements in Policy 801: Reporting Research Events found here.
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8.3 nci clinical director reporting

Problems expeditiously reported to the OHSRP in iRIS will also be reported to the NCI Clinical Director. A separate submission is not necessary as reports in iRIS will be available to the Clinical Director. In addition to those reports, all deaths that occur within 30 days after receiving a research intervention should be reported via email to the Clinical Director unless they are due to progressive disease. To report these deaths, please send an email describing the circumstances of the death to Dr. Dahut at NCICCRQA@mail.nih.gov within one business day of learning of the death.
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9 manufacturer safety reporting

Safety assessments will consist of monitoring and reporting adverse events (AEs) and serious adverse events (SAEs) per protocol. This includes all events of death, and any study specific issue of concern. The investigator is responsible for ensuring that all AEs and SAEs that are observed or reported during the study are collected and reported to the FDA, appropriate IRB(s), and Genentech, Inc. in accordance with CFR 312.32 (IND Safety Reports).
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9.1 adverse event reporting period

The study period during which all AEs and SAEs must be reported begins after informed consent is obtained and initiation of study treatment and ends 30 days following the last administration of study treatment or study discontinuation/termination, whichever is earlier. After this period, investigators should only report SAEs that are attributed to prior study treatment.
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9.2 definitions 9.2.1 adverse event

An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. This includes the following:
AEs not previously observed in the subject that emerge during the protocol-specified AE reporting period, including signs or symptoms associated with HLRCC or Sporadic Papillary Renal Cell Cancer that were not present prior to the AE reporting period.  
Complications that occur as a result of protocol-mandated interventions (e.g.,
invasive procedures such as cardiac catheterizations).  
If applicable, AEs that occur prior to assignment of study treatment associated with medication washout, no treatment run-in, or other protocol-mandated intervention.  
Preexisting medical conditions (other than the condition being studied) judged by the investigator to have worsened in severity or frequency or changed in character during the protocol-specified AE reporting period.  
Protocol-mandated interventions (e.g., invasive procedures such as cardiac catheterizations).  
9.2.2 Serious Adverse Event (SAE)
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:
Death,  
A life-threatening adverse event Inpatient hospitalization or prolongation of existing hospitalization (see elaboration in 9.4.2)
Persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions A congenital anomaly/birth defect 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.  
9.2.3 Adverse Events of Special Interest (AESIs) AESIs are a subset of Events to Monitor (EtMs) of scientific and medical concern specific to the product, for which ongoing monitoring and rapid communication by the Investigator to the manufacturer is required. Such an event might require further investigation in order to characterize and understand it. Adverse events of special interest for this study include the following:  
Cases of potential drug-induced liver injury that include an elevated ALT or AST in combination with either an elevated bilirubin or clinical jaundice, as defined by Hy's law:
o Treatment-emergent ALT or AST  3  ULN in combination with total bilirubin 2  ULN
o Treatment-emergent ALT or AST  3  ULN in combination with clinical jaundice Data related to a suspected transmission of an infectious agent by the study drug
(STIAMP), as defined below:
Any organism, virus, or infectious particle (e.g., prion protein transmitting transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is considered an infectious agent. A transmission of an infectious agent may be suspected from clinical symptoms or laboratory findings that indicate an infection in a patient exposed to a medicinal product. This term applies only when a contamination of the study drug is suspected 9.2.3.1 Bevacizumab Events of Special Interest  
Hypertension ≥ grade 3 Proteinuria ≥ grade 3
GI perforation, abscesses and fistulae (any grade)  
Wound healing complications ≥ grade 3
Hemorrhage ≥ grade 3 (any grade CNS bleeding; ≥ grade 2 hemoptysis)  
Arterial thromboembolic events (any grade)
Venous thromboembolic events ≥ grade 3 PRES (any grade)
CHF ≥ grade 3 Non-GI fistula or abscess ≥ grade 2 9.2.3.2 Erlotinib Event of Special Interest Interstitial Lung Disease (ILD)
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9.2.4 severity

The severity of each Adverse Event will be assessed utilizing the CTCAE version 4.0. 9.2.5 Relationship to Study Product Expected adverse events are those adverse events that are listed or characterized in the Package Insert (P.I) or current Investigator Brochure (I.B). Unexpected adverse events are those not listed in the P.I or current I.B or not identified. This includes adverse events for which the specificity or severity is not consistent with the description in the P.I. or I.B. For example, under this definition, hepatic necrosis would be unexpected if the P.I. or I.B. only referred to elevated hepatic enzymes or hepatitis. For patients receiving combination therapy, causality will be assessed individually for each protocol-mandated therapy.
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9.3 assessment of adverse events

All AEs and SAEs whether volunteered by the subject, discovered by study personnel during questioning, or detected through physical examination, laboratory test, or other means will be reported appropriately. Each reported AE or SAE will be described by its duration (i.e., start and end dates), regulatory seriousness criteria if applicable, suspected relationship to either bevacizumab or erlotinib (see following guidance), and actions taken. To ensure consistency of AE and SAE causality assessments, investigators should apply the following general guideline:
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yes

There is a plausible temporal relationship between the onset of the AE and administration of bevacizumab or erlotinib, and the AE cannot be readily explained by the subject's clinical state, intercurrent illness, or concomitant therapies; and/or the AE follows a known pattern of response to bevacizumab or erlotinib; and/or the AE abates or resolves upon discontinuation of bevacizumab or erlotinib or dose reduction and, if applicable, reappears upon re-challenge.  
No Evidence exists that the AE has an etiology other than bevacizumab or erlotinib (e.g., preexisting medical condition, underlying disease, intercurrent illness, or concomitant medication); and/or the AE has no plausible temporal relationship to bevacizumab or erlotinib administration (e.g., cancer diagnosed 2 days after first dose of study drug).
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9.4 procedures for eliciting recording

A consistent methodology for eliciting AEs at all subject evaluation time points should be adopted. Examples of non-directive questions include:
"How have you felt since your last clinical visit?"  
"Have you had any new or changed health problems since you were last here?"
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9.4.2 specific instructions for recording

Investigators should use correct medical terminology/concepts when reporting AEs or SAEs. Avoid colloquialisms and abbreviations. a. Diagnosis vs. Signs and Symptoms If known at the time of reporting, a diagnosis should be reported rather than individual signs and symptoms (e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and elevated transaminases). However, if a constellation of signs and/or symptoms cannot be medically characterized as a single diagnosis or syndrome at the time of reporting, it is ok to report the information that is currently available. If a diagnosis is subsequently established, it should be reported as follow-up information.
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b. deaths

All deaths that occur during the protocol-specified AE reporting period (see section 9), regardless of attribution, will be reported to the appropriate parties. When recording a death, the event or condition that caused or contributed to the fatal outcome should be reported as the single medical concept. If the cause of death is unknown and cannot be ascertained at the time of reporting, report "Unexplained Death".
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c. preexisting medical conditions

A preexisting medical condition is one that is present at the start of the study. Such conditions should be reported as medical and surgical history. A preexisting medical condition should be re-assessed throughout the trial and reported as an AE or SAE only if the frequency, severity, or character of the condition worsens during the study. When reporting such events, it is important to convey the concept that the preexisting condition has changed by including applicable descriptors (e.g., "more frequent headaches").
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d. hospitalizations for medical or

Any AE that results in hospitalization or prolonged hospitalization should be documented and reported as an SAE. If a subject is hospitalized to undergo a medical or surgical procedure as a result of an AE, the event responsible for the procedure, not the procedure itself, should be reported as the SAE. For example, if a subject is hospitalized to undergo coronary bypass surgery, record the heart condition that necessitated the bypass as the SAE. Hospitalizations for the following reasons do not require reporting:  
Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures for preexisting conditions Hospitalization or prolonged hospitalization required to allow efficacy measurement for the study or Hospitalization or prolonged hospitalization for scheduled therapy of the target disease of the study.
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e. pregnancy

If a female subject becomes pregnant while receiving investigational therapy or within 6 months after the last dose of study drug, or if the female partner of a male study subject becomes pregnant while the study subject is receiving the study drug or within 6 months after the last dose of study drug, a report should be completed and expeditiously submitted to the Genentech, Inc. Follow-up to obtain the outcome of the pregnancy should also occur. Abortion, whether accidental, therapeutic, or spontaneous, should always be classified as serious, and expeditiously reported as an SAE. Similarly, any congenital anomaly/birth defect in a child born to a female subject exposed to bevacizumab and erlotinib should be reported as an SAE.
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f. post-study adverse events

The investigator should expeditiously report any SAE occurring after a subject has completed or discontinued study participation if attributed to prior bevacizumab or erlotinib exposure. If the investigator should become aware of the development of cancer or a congenital anomaly in a subsequently conceived offspring of a female subject who participated in the study, this should be reported as an SAE adequately to Genentech Drug Safety during follow up period. g. Reconciliation (Case Transmission Verification of Single Case Reports) The Investigator agrees to conduct reconciliation for the product. The Investigator will ensure that all single case reports have been received by Genentech. The Investigator agrees to conduct the Case Transmission verification to ensure that all single case reports have been adequately received by Genentech via the Investigator emailing Genentech a Quarterly line-listing documenting single case reports sent by the investigator to Genentech in the preceding time period. The periodic line-listing will be exchanged within seven (7) calendar days of the end of the agreed time period. Confirmation of receipt should be received within the time period mutually agreed upon. If discrepancies are identified, the Investigator and Genentech will cooperate in resolving the discrepancies. The responsible individuals for each party shall handle the matter on a caseby-case basis until satisfactory resolution. The Investigator shall receive reconciliation guidance documents within the 'Activation Package'. Following Case Transmission Verification, single case reports which have not been received by Genentech shall be forwarded by Investigator to Genentech within five (5) calendar days from request by Genentech. At the end of the study, a final cumulative Case Transmission Verification report will be sent to Genentech by Investigator.
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9.5 adverse event reporting to

All non-serious adverse events will be reported to Genentech both quarterly and at the conclusion of the study in a concatenated format using the Case Transmission Verification (CTV) form (see **APPENDIX D**). Please email the completed CTV form to CTVIST_Drugsafety@gene.com.  
All non-serious adverse events for Genentech quarterly and at conclusion of study include the following:
All non-serious Grade 2 unexpected events that are possibly, probably or definitely related to the research and All non-serious Grade 3 that are possibly, probably or definitely related to the research.  
Non-serious adverse events and SAEs will be collected from the time consent is given, throughout the treatment period and up to 30 days following the last dose of the trial drug.  
9.5.2 Exchange of Single Case Reports
The investigator will be responsible for collecting all protocol-defined Adverse Events (AEs)/Serious Adverse Events (SAEs), AEs of Special Interest (AESIs), Special Situation Reports (including pregnancy reports) and Product Complaints (with or without an AE) originating from the Study for the Product. Investigators must report all the above-mentioned single case reports adequately to Genentech within the timelines described below. The completed MedWatch or CIOMS I form or Genentech approved reporting forms should be faxed/emailed immediately upon completion to Genentech at the following contacts: All protocol-defined AEs, SAEs, AESIs, Special Situation Reports (including pregnancy reports) and Product Complaints *with* an AE should be sent to:
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fax 650-238-6067 email usdsaereporting-d@gene.com

All Product Complaints *without* an AE should be sent to:
Email: **kaiseraugst.global_impcomplaint_management@roche.com**
It is understood and agreed that the Sponsor will be responsible for the evaluation of AEs/SAEs, AESIs, Special Situation Reports (including pregnancy reports) and Product Complaints (with or without an AE) originating from the study. These single case reports will be exchanged between the parties as outlined below so that regulatory obligations are met.  
Serious adverse events (SAEs), AEs of Special Interest (AESIs), pregnancy reports (including pregnancy occurring in the partner of a male study subject), other Special Situation Reports and Product Complaints (with or without an AE), where the patient has been exposed to the Genentech Product, will be sent on a MedWatch form or CIOMS I form or on Genentech approved reporting forms to Genentech Drug Safety. Transmission of these reports (initial and follow-up) will be either electronically or by fax and within the timelines specified below:
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sadrs

Serious AE reports that are related to the Product shall be transmitted to Genentech within fifteen (15) calendar days of the awareness date.
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other saes

Serious AE reports that are unrelated to the Product shall be transmitted to Genentech within thirty (30) calendar days of the awareness date.
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aesis

AESIs shall be forwarded to Genentech within fifteen (15) calendar days of the awareness date.
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9.6 additional reporting requirements to

While such reports are not serious AEs or Adverse Drug Reactions (ADRs) per se, as defined herein, any reports of pregnancy (including pregnancy occurring in the partner of a male study subject), where the fetus may have been exposed to the bevacizumab or erlotinib, shall be transmitted to Genentech within thirty (30) calendar days of the awareness date. Pregnancies will be followed up until the outcome of the pregnancy is known, whenever possible, based upon due diligence taken to obtain the follow-up information.
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pregnancies in female partners of

Male patients will be instructed through the Informed Consent Form to immediately inform the investigator if their partner becomes pregnant during the study or within 6 months after the last dose of bevacizumab and erlotinib. A Clinical Trial Pregnancy Reporting Form should be completed and submitted to Genentech within thirty (30) calendar days of the awareness date.
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other special situation reports

In addition to all SAEs, pregnancy reports and AESIs, the following other Special Situations Reports should be collected even in the absence of an Adverse Event and transmitted to Genentech within thirty (30) calendar days:
Data related to the Product usage during breastfeeding Data related to overdose, abuse, misuse or medication error (including potentially exposed or intercepted medication errors)
In addition, reasonable attempts should be made to obtain and submit the age or age group of the patient, in order to be able to identify potential safety signals specific to a particular population.  
9.6.1.2 Product Complaints All Product Complaints (with or without an AE) shall be forwarded to Genentech within fifteen (15) calendar days of the awareness date. A Product Complaint is defined as any written or oral information received from a complainant that alleges deficiencies related to identity, quality, safety, strength, purity, reliability, durability, effectiveness, or performance of a product after it has been released and distributed to the commercial market or clinical trial.  
Note: Investigators should also report events to their IRB as noted in section 8.2.
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medwatch 3500a reporting guidelines

In addition to completing appropriate patient demographic (Section A) and suspect medication information (Sections C&D), the report should include the following information within the Event Description (section B.5) of the MedWatch 3500A form:
Protocol number and title description  
Description of event, severity, treatment, and outcome if known Supportive laboratory results and diagnostics Investigator's assessment of the relationship of the adverse event to each investigational product and suspect medication
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9.7 follow-up information

Additional information may be added to a previously submitted report by any of the following methods:
Adding to the original MedWatch 3500A report and submitting it as follow-up  
Adding supplemental summary information and submitting it as follow-up with the original MedWatch 3500A form Summarizing new information and faxing it with a cover letter including patient identifiers (i.e. D.O.B. initial, patient number), protocol description and number, if assigned, brief adverse event description, and notation that additional or follow-up information is being submitted (The patient identifiers are important so that the new information is added to the correct initial report)
MedWatch 3500A (Mandatory Reporting) form is available at: https://www.fda.gov/media/69876/download
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9.8 study close-out

Any study report submitted to the FDA by the Investigator should be copied to Genentech. This includes the final study report. Additionally, any literature articles that are a result of the study should be sent to Genentech. Copies of such reports should be sent to the assigned Clinical Operations contact for the study at Avastin-gsur@gene.com and to Genentech Drug Safety CTV oversight mailbox at: ctvist_drugsafety@gene.com.
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9.9 queries

Queries related to the study will be answered by the investigator. However, responses to all safety queries from regulatory authorities or for publications will be discussed and coordinated between the investigator and Genentech. The investigator agrees that Genentech shall have the final say and control over safety queries relating to the Bevacizumab and Erlotinib (while supplied by Genentech). The investigator agrees not to answer such queries from regulatory authorities and other sources relating to the Bevacizumab independently but shall redirect such queries to Genentech. The PI and Genentech will use all reasonable effort to ensure that deadlines for responses to urgent requests for information or review of data are met. The PI and Genentech will clearly indicate on the request the reason for urgency and the date by which a response is required.
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9.10 safety crisis management

In case of a safety crisis, e.g., where safety issues have a potential impact on the indication(s), on the conduct of the study, may lead to labeling changes or regulatory actions that limit or restrict the way in which Bevacizumab and Erlotinib (while supplied by Genentech) is used, or where there is media involvement, the party where the crisis originates will contact the other party as soon as possible. The investigator agrees that Genentech shall have the final say and control over safety crisis management issues relating to the Bevacizumab and Erlotinib (while supplied by Genentech). The investigator agrees not to answer such queries from regulatory authorities and other sources relating to the Bevacizumab independently but shall redirect such queries to Genentech.
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9.11 reporting to regulatory authorities

Genentech as the Marketing Authorization Holder will be responsible for the reporting of individual case safety reports from the study to the regulatory authority in compliance with applicable regulations. The PI will be responsible for the expedited reporting of safety reports originating from the study to the Institutional Review Boards (IRB) as noted in Section **8.2.1**. The PI will be responsible for the distribution of safety information to its own investigators, where relevant, in accordance with local regulations.
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9.10 other reports

The investigator will forward a copy of the Final Study Report to Genentech upon completion of the Study.
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10 collaborative agreements 10.1 cooperative

The agents supplied by Genentech used in this protocol is provided to the NCI CCR under a Cooperative Research and Development Agreement (CRADA) between Genentech [hereinafter referred to as Collaborator], CRADA \#02407. 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. Clinical Trial Data and Results and Raw Data developed under a collaborative agreement will be made available exclusively to Collaborator(s), the NCI, and the FDA, as appropriate. All data made available will comply with HIPAA regulations When a Collaborator wishes to initiate a data request, the request should first be sent to the NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group studies, or PI for other studies) of Collaborator's wish to contact them. Any data provided to Collaborator(s) for phase 3 studies must be in accordance with the guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a DMC for this clinical trial Any manuscripts reporting the results of this clinical trial must be provided to Genentech for advisory review and comment prior to submission for publication. Collaborator(s) will have 30 days from the date of receipt for review. Collaborator shall have the right to request that publication be delayed for up to an additional 30 days in order to ensure that Collaborator's confidential and proprietary data, in addition to Collaborator(s)'s intellectual property rights, are protected. Copies of abstracts must be provided to Collaborator(s) for courtesy review as soon as possible and preferably at least three (3) days prior to submission, but in any case, prior to presentation at the meeting or publication in the proceedings. Press releases and other media presentations must also be forwarded to Genentech prior to release. Copies of any manuscript, abstract, and/or press release/ media presentation should be sent to Genentech. No publication, manuscript or other form of public disclosure shall contain any of Collaborator's confidential/proprietary information.
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11 regulatory and operational considerations

This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable cause. Written notification, documenting the reason for study suspension or termination, will be provided by the suspending or terminating party to study participants, investigator, funding agency and regulatory authorities. If the study is prematurely terminated or suspended, the Principal Investigator (PI) will promptly inform study participants, the Institutional Review Board (IRB), and Genentech and will provide the reason(s) for the termination or suspension. Study participants will be contacted, as applicable, and be informed of changes to study visit schedule. Circumstances that may warrant termination or suspension include, but are not limited to:
Determination of unexpected, significant, or unacceptable risk to participants  
Demonstration of efficacy that would warrant stopping Insufficient compliance to protocol requirements Data that are not sufficiently complete and/or evaluable Determination that the primary endpoint has been met Determination of futility
Study may resume once concerns about safety, protocol compliance, and data quality are addressed, and satisfy the sponsor, IRB and as applicable, Food and Drug Administration (FDA).
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11.2 quality assurance and quality

Each clinical site will perform internal quality management of study conduct, data and biological specimen collection, documentation and completion. An individualized quality management plan will be developed to describe a site's quality management. Quality control (QC) procedures will be implemented beginning with the data entry system and data QC checks that will be run on the database will be generated. Any missing data or data anomalies will be communicated to the site(s) for clarification/resolution. Following written Standard Operating Procedures (SOPs), the monitors will verify that the clinical trial is conducted and data are generated and biological specimens are collected, documented (recorded), and reported in compliance with the protocol, International Conference on Harmonisation Good Clinical Practice (ICH GCP), and applicable regulatory requirements (e.g., Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP)). The investigational site will provide direct access to all trial related sites, source data/documents, and reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and regulatory authorities.
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11.3 conflict of interest policy

The independence of this study from any actual or perceived influence, such as by the pharmaceutical industry, is critical. Therefore, any actual conflict of interest of persons who have a role in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, persons who have a perceived conflict of interest will be required to have such conflicts managed in a way that is appropriate to their participation in the design and conduct of this trial. The study leadership in conjunction with the National Cancer Institute has established policies and procedures for all study group members to disclose all conflicts of interest and will establish a mechanism for the management of all reported dualities of interest.
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11.4 confidentiality and privacy

Participant confidentiality and privacy is strictly held in trust by the participating investigators, their staff, and the sponsor(s). This confidentiality is extended to cover testing of biological samples and genetic tests in addition to the clinical information relating to participants. Therefore, the study protocol, documentation, data, and all other information generated will be held in strict confidence. No information concerning the study or the data will be released to any unauthorized third party without prior written approval of the sponsor. All research activities will be conducted in as private a setting as possible. The study monitor, other authorized representatives of the sponsor, representatives of the Institutional Review Board (IRB), and/or regulatory agencies may inspect all documents and records required to be maintained by the investigator, including but not limited to, medical records (office, clinic, or hospital) and pharmacy records for the participants in this study. The clinical study site will permit access to such records. The study participant's contact information will be securely stored at the/each clinical site for internal use during the study. At the end of the study, all records will continue to be kept in a secure location for as long a period as dictated by the reviewing IRB, Institutional policies, or sponsor requirements. Study participant research data, which is for purposes of statistical analysis and scientific reporting, will be transmitted to and stored at the NCI CCR. This will not include the participant's contact or identifying information. Rather, individual participants and their research data will be identified by a unique study identification number. The study data entry and study management systems used by the clinical site(s) and by NCI CCR research staff will be secured and password protected. At the end of the study, all study databases will be archived at the NIH. To further protect the privacy of study participants, a Certificate of Confidentiality has been issued by the National Institutes of Health (NIH). This certificate protects identifiable research information from forced disclosure. It allows the investigator and others who have access to research records to refuse to disclose identifying information on research participation in any civil, criminal, administrative, legislative, or other proceeding, whether at the federal, state, or local level. By protecting researchers and institutions from being compelled to disclose information that would identify research participants, Certificates of Confidentiality help achieve the research objectives and promote participation in studies by helping assure confidentiality and privacy to participants.
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12 pharmaceutical information 12.1 bevacizumab

Source: Bevacizumab is commercially available. Bevacizumab will be supplied by Genentech. How Supplied: Bevacizumab is supplied as a clear to slightly opalescent, sterile liquid ready for parenteral administration in two vial sizes:
- Each 100 mg (25 mg/mL - 4 mL fill) glass vial contains bevacizumab with phosphate, trehalose, polysorbate 20, and Sterile Water for Injection, USP. - Each 400 mg (25mg/ml - 40 mL fill) glass vial contains bevacizumab with phosphate, trehalose, polysorbate 20, and Sterile Water for Injection, USP.  
12.1.2 Physiochemical Properties Classification: Bevacizumab is a recombinant humanized anti-VEGF monoclonal antibody composed of human IgG1 framework regions and antigenbinding complementaritydetermining regions from a murine monoclonal antibody (muMAb VEGF A.4.6.1).  
Approximately 93% of the amino acid sequence, including most of the antibody framework, is derived from the human IgG1, and approximately7% of the sequence is derived from the murine antibody Other Names: Recombinant humanized monoclonal anti-VEGF antibody (rhuMAB VEGF, Avastin®) Code Number: rhuMAb VEGF, RO4876646 12.1.3 Molecular characterization Chemical Structure: human IgG1 framework regions and antigenbinding complementaritydetermining regions from a murine monoclonal antibody Molecular Weight: ~149,000 daltons Description: Clear to slightly opalescent, colorless to pale brown, sterile liquid concentrate for solution of IV infusion Mechanism of Action: Inhibition of vascular endothelial growth factor (VEGF) resulting in inhibition of angiogenesis. 12.1.4 Toxicity Please refer to package insert 12.1.5 Formulation and Preparation Preparation: Vials contain no preservatives and are intended for single use only. Place the calculated dose in 100 mL of 0.9% sodium chloride for injection.
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12.1.6 stability and storage

Upon receipt of the study drug, vials are to be refrigerated at 2C–8C (36F–46F) and should remain refrigerated until just prior to use. DO NOT FREEZE. DO NOT SHAKE. Vials should be protected from light. Opened vials must be used within 8 hours. VIALS ARE FOR SINGLE USE ONLY. Vials used for 1 subject may not be used for any other subject. Once study drug has been added to a bag of sterile saline, the solution must be administered within 8 hours. 12.1.7 Administration Procedures
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12.2 erlotinib

12.2.1 Source Source: Erlotinib is commercially available. Erlotinib will be initially supplied by Genentech. Once Genentech is no longer able to supply erlotinib for this study, erlotinib will be purchased from commercial sources by the NIH Pharmacy. How Supplied: Erlotinib is supplied as white film-coated tablets for daily oral administration, available in tablets of 25 mg, 100mg, and 150 mg each. 12.2.2 Physiochemical Properties Classification: Erlotinib is a Human Epidermal Growth Factor Receptor Type 1/Epidermal Growth Facot Receptor (Her1/EGFR) tyrosine kinase inhibitor. Other Names: OSI-774; Tarceva 12.2.3 Molecular characterization: Chemical Structure: Erlotinib is a quinazolinamine with the chemical name N- (3ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine. Erlotinib hydrochloride has the molecular formula C22H23N3O4-HCl Molecular Weight: 429.90 Description: Off-white to pale yellow powder. Mechanism of Action: Highly selective EGFR tyrosine kinase inhibitor. 12.2.4 Toxicity Please refer to package insert 12.2.5 Formulation and Preparation Formulation: Erlotinib tablets are available in three dosage strengths containing erlotinib hydrochloride (27.3 mg, 109.3 mg, and 163.9 mg) equivalent to 25 mg, 100 mg, and 150 mg erlotinib and the following inactive ingredients: lactose monohydrate, hypromellose, hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, sodium starch glycolate, sodium lauryl sulfate, and titanium dioxide. The tablets also contain trace amounts of color additives, including FD&C Yellow \#6 (25 mg only) for product identification. 12.2.6 Solubility and Storage Storage: Tablets should be stored at 25º C (77º F); excursions permitted to 15-30º C (59-86º C) Solubility: Erlotinib hydrochloride is very slightly soluble in water, slightly soluble in methanol, and practically insoluble in acetonitrile, acetone, ethyl acetate, and hexane. Aqueous solubility of erlotinib hydrochloride is dependent on pH, with increased solubility at a pH of less than 5 due to protonation of the secondary amine. Over the pH range of 1.4 to 9.6, maximal solubility of approximately 0.4mg/mL occurs at a pH of approximately 2.
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12.2.7 administration procedures route of

12.2.8 Incompatibilities Erlotinib is metabolized predominantly by CYP3A4, and potent inhibitors of CYP3A4 increase exposure while potent CYP3A4 inducers increase clearance of erlotinib. Please refer to package insert for further information and a partial list of interacting agents.
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42. Hidalgo M, Siu LL, Nemunaitis J, Rizzo J, Hammond LA, Takimoto C, Eckhardt SG, Tolcher A, Britten CD, Denis L, Ferrante K, Von Hoff DD, Silberman S, Rowinsky EK. Phase I and pharmacologic study of OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies. J Clin Oncol. 2001;19(13):3267-79. Epub 2001/07/04. PubMed PMID: 11432895. 43. Vokes E, Cohen A, Mauer A. A phase I study of erlotinib and bevacizumab for recurrent or metastatic squamous cell carcinoma of the head and neck. . Journal of Clinical Oncology, 2005 ASCO Annual Meeting Proceedings. 2005;23(16S):Abstract 5504. 44. Herbst RS, O'Neill VJ, Fehrenbacher L, Belani CP, Bonomi PD, Hart L, Melnyk O, Ramies D, Lin M, Sandler A. Phase II study of efficacy and safety of bevacizumab in combination with chemotherapy or erlotinib compared with chemotherapy alone for treatment of recurrent or refractory non small-cell lung cancer. J Clin Oncol. 2007;25(30):4743-50. Epub 2007/10/03. doi: JCO.2007.12.3026 [pii] 10.1200/JCO.2007.12.3026. PubMed PMID: 17909199. 45. Hainsworth JD, Spigel DR, Farley C, Thompson DS, Shipley DL, Greco FA. Phase II trial of bevacizumab and erlotinib in carcinomas of unknown primary site: the Minnie Pearl Cancer Research Network. J Clin Oncol. 2007;25(13):1747-52. Epub 2007/05/02. doi: 25/13/1747 [pii] 10.1200/JCO.2006.09.3047. PubMed PMID: 17470864. 46. Hainsworth JD, Sosman JA, Spigel DR, Edwards DL, Baughman C, Greco A. Treatment of metastatic renal cell carcinoma with a combination of bevacizumab and erlotinib. J Clin Oncol. 2005;23(31):7889-96. PubMed PMID: 16204015. 47. Bukowski R, Kabbinavar F, Figlin R, Flaherty K, Srinivas S, Vaishampayan U, Drabkin H, Dutcher J, Scappaticci F, McDermott D. Bevacizumab with or without erlotinib in metastatic renal cell cancer (RCC). Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. 2006;24(18S):4523. 48. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-47. Epub 2008/12/23. doi: 10.1016/j.ejca.2008.10.026. PubMed PMID: 19097774. 49. Scher HI, Halabi S, Tannock I, Morris M, Sternberg CN, Carducci MA, Eisenberger MA, Higano C, Bubley GJ, Dreicer R, Petrylak D, Kantoff P, Basch E, Kelly WK, Figg WD, Small EJ, Beer TM, Wilding G, Martin A, Hussain M, Prostate Cancer Clinical Trials Working G. Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group. J Clin Oncol. 2008;26(7):1148-59. doi: 10.1200/JCO.2007.12.4487. PubMed PMID: 18309951; PMCID: PMC4010133. 50. Rustin GJ, Quinn M, Thigpen T, du Bois A, Pujade-Lauraine E, Jakobsen A, Eisenhauer E, Sagae S, Greven K, Vergote I, Cervantes A, Vermorken J. Re: New guidelines to evaluate the response to treatment in solid tumors (ovarian cancer). J Natl Cancer Inst. 2004;96(6):487-8. PubMed PMID: 15026475. 51. Bubley GJ, Carducci M, Dahut W, Dawson N, Daliani D, Eisenberger M, Figg WD, Freidlin B, Halabi S, Hudes G, Hussain M, Kaplan R, Myers C, Oh W, Petrylak DP, Reed E, Roth B, Sartor O, Scher H, Simons J, Sinibaldi V, Small EJ, Smith MR, Trump DL, Wilding G, et al. Eligibility and response guidelines for phase II clinical trials in androgenindependent prostate cancer: recommendations from the Prostate-Specific Antigen Working Group. J Clin Oncol. 1999;17(11):3461-7. doi: 10.1200/JCO.1999.17.11.3461. PubMed PMID: 10550143. 52. Vergote I, Rustin GJ, Eisenhauer EA, Kristensen GB, Pujade-Lauraine E, Parmar MK, Friedlander M, Jakobsen A, Vermorken JB. Re: new guidelines to evaluate the response to treatment in solid tumors [ovarian cancer]. Gynecologic Cancer Intergroup. J Natl Cancer Inst. 2000;92(18):1534-5. PubMed PMID: 10995813. 53. Ooi A, Dykema K, Ansari A, Petillo D, Snider J, Kahnoski R, Anema J, Craig D, Carpten J, Teh BT, Furge KA. CUL3 and NRF2 mutations confer an NRF2 activation phenotype in a sporadic form of papillary renal cell carcinoma. Cancer Res. 2013;73(7):2044-51. doi: 10.1158/0008-5472.CAN-12-3227. PubMed PMID: 23365135. 54. Ooi A, Wong JC, Petillo D, Roossien D, Perrier-Trudova V, Whitten D, Min BW, Tan MH, Zhang Z, Yang XJ, Zhou M, Gardie B, Molinie V, Richard S, Tan PH, Teh BT, Furge KA. An antioxidant response phenotype shared between hereditary and sporadic type 2 papillary renal cell carcinoma. Cancer cell. 2011;20(4):511-23. doi: 10.1016/j.ccr.2011.08.024. PubMed PMID: 22014576. 55. Tsai WY, Chi Y, Chen CM. Interval estimation of binomial proportion in clinical trials with a two-stage design. Statistics in medicine. 2008;27(1):15-35. doi: 10.1002/sim.2930. PubMed PMID: 17566141.
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13 appendix a ecog performance

Grade Scale 0 Fully active, able to carry on all pre-disease performance without restriction.  
1 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.  
2 Ambulatory and capable of all self care but unable to carry out any work activities. Up and about more than 50% of waking hours.  
3 Capable of only limited self-care, confined to bed or chair more than 50% of waking hours.  
4 Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair.  
5 Dead
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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 list of

The following lists are not exhaustive and are only intended as a guide. Potent inhibitors of CYP450 3A4- Prohibited at study entry and concomitantly while on erlotinib Amprenavir Atovaquone Clarithromycin Clotrimazole Cyclosporine Diltiazem Erythromycin Fluconazole Gemfibrozil Grapefruit, Grapefruit juice Indinavir Isoniazid Itraconazole, Ketoconazole Nefazodone Nelfinavir Posaconazole Ritonavir Saquinavir Telithromycin Troleandomycin Verapamil St.John' Wort Inhibitors of CYP450 3A4-To be avoided when possible; use only when considered necessary after discussion with PI/medically responsible investigator Aprepitant Metronidazole Potent inhibitors of CYP450 1A2 (with or without additional inhibioton of CYP450 3A4- Prohibited at study entry and concomitantly while on erlotinib Fluoroquinolone antibiotics such as ciprofloxacin, levofloxacin, and norfloxacin Amiodarone Cimetidine Fluvoxamine Mibefradil Ticlopidine Potential inducers of CYP450 1A2-To be avoided when possible; use only when considered necessary after discussion with PI/medically responsible investigator Albendazole Modafinil Omeprazole Phenobarbital Phenytoin Quinine Rabeprazole Rifampin
supported study case transmission verification
16 appendix d case transmission

| Principle Investigator Name Genentech Study Number: Sponsor Study Number: Country of Occurrence: Reporting Period:   | From:          | To:       |
|----------------------------------------------------------------------------------------------------------------------|----------------|-----------|
| Periodic or Final Case  Transmission Verification (CTV):                                                             | Periodic CTV   | Final CTV |
| Details of Person Completing the Form: Name: Date:  Telephone Number:                                                | Email address: |           |
| No Adverse Events (AEs), Adverse Events of Special Interest (AESIs) or Special Situation Events per                  |                |           |  
No Adverse Events (AEs), Adverse Events of Special Interest (AESIs) or Special Situation Events per study were submitted to the company's drug safety department in the reporting period listed above  
The following is a list of AEs, AESIs and other Special Situation Events per study submitted to the company's drug safety department in the reporting period listed above:  
| company's drug safety department in the reporting period listed above: Date AE sent  to  US Drug  Safety   |           |             |                  |            |            |         |           |
|------------------------------------------------------------------------------------------------------------|-----------|-------------|------------------|------------|------------|---------|-----------|
| Case  Number  (Company  Use Only)                                                                          | Date of   |             |                  |            |            |         |           |
| Awareness  of AE  (Day-Mon-Year)                                                                           | Patient's | Patient's   | Suspect  Drug(s) | Event Term | Serious or | Outcome | Causality |
| Study ID                                                                                                   | Initials  | Non Serious |                  |            |            |         |           |  
For any additional events continue on an additional form.  
Please email the completed CTV form to CTVIST_Drugsafety@gene.com For any additional events continue on an additional form.  
If any AEs, AESIs or other Special Situation Events per study have been identified that were not reported to the company, report them immediately and contact the company's drug safety department.  
| For Company Use Only:  Date CTV form was reviewed: Name of reviewer: Signature of reviewer:   |
|-----------------------------------------------------------------------------------------------|  
Case Transmission Verification Section A All Adverse Events, Adverse Events of Special Interest and other Special Situation Events per study have been received by the drug safety department?  
Yes No (If no, complete **Section** B)
No Adverse Event(s), Adverse Event(s) of Special Interest or other Special Situation Events per study reported: Section B  
| Provide a list of Adverse Event(s), Adverse  Event(s) of Special Interest or other Special  Situation Events per study not received by the  drug safety department: Date CTV form sender was contacted: Date Adverse Event(s), Adverse Event(s) of  Special Interest or other Special Situation  Events per study were received by the drug  safety department:   |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|