A Phase II Study of Bevacizumab and Erlotinib in Subjects With Advanced Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) or Sporadic Papillary Renal Cell Cancer
Phase: PHASE2
Conditions: HLRCC, Sporadic Papillary Renal Cell Cancer
Sponsor: National Cancer Institute (NCI)

Abbreviated Title: Bev/Erlotinib in Papillary RCC
Version Date: 07/02/2021
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Abbreviated Title:  Bev/Erlotinib in Papillary RCC
NIH Protocol Number: 10-C-0114 
NCT Number: NCT01130519
Version Date: July 2, 2021
A Phase II Study of Bevacizumab and Erlotinib in Subjects with Advanced Hereditary 
Leiomyomatosis and Renal Cell Cancer (HLRCC) or Sporadic Papillary Renal Cell Cancer
NCI Principal Investigator:
Ramaprasad Srinivasan, M.D., Ph.D.
Staff Clinician, UOB, CCR, NCI
National Cancer Institute 
10 Center Drive, Room 2-5950
Tel: 240-760-6251
Email: ramasrin@mail.nih.gov 
Commercial Agents: Bevacizumab, Erlotinib

Abbreviated Title: Bev/Erlotinib in Papillary RCC
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PRÉCIS 
Background

Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) is a familial cancer 
syndrome characterized by a propensity for developing renal cancer, and uterine and 
cutaneous leiomyomas. The kidney cancer associated with HLRCC is clinically 
aggressive and is characterized by unique histopathologic features that are sometimes 
described as type 2 papillary RCC.

Germline mutations in the fumarate hydratase (FH) gene are the genetic hallmark of 
HLRCC. Mutational inactivation of FH has been shown to result in VHL-independent 
upregulation of hypoxia inducible factor (HIF) and its downstream transcriptional targets. 

The recognition that HIF upregulation may play an important role in the formation and 
propagation of renal cancer associated with HLRCC suggests that interventions directed 
against components of this pathway, such as VEGF and TGF-α/EGFR, may be of benefit 
in this patient population. 

We propose to test the hypothesis that dual VEGF/EGFR blockade with 
bevacizumab/erlotinib is likely to be clinically active in patients with HLRCC associated 
RCC as well as those with sporadic papillary sporadic RCC.
Objective
Primary Objective

To determine the overall response rate (RECIST) in patients with 1) metastatic RCC 
associated with HLRCC and 2) metastatic sporadic/non-HLRCC papillary renal cancer 
treated with a combination of bevacizumab and erlotinib 
Eligibility

Diagnosis of advanced RCC associated with HLRCC (cohorts 1 and 3) or sporadic/non-
HLRCC papillary RCC (cohort 2 and 4)

ECOG PS 0-2

Measurable disease, as outlined in RECIST 1.1

No history of major bleeding, recent or active myocardial ischemia, GI perforation, 
cerebrovascular accidents or other significant intercurrent illness

No coagulopathy or bleeding diathesis

No recent surgery (< 4 weeks or inadequately healed surgical scars)

Adequate organ function
o
Adequate liver function (total bilirubin ≤ 1.5 mg/dL or < 3 x upper limit of normal 
(ULN) in subjects with Gilbert’s disease, and AST (SGOT) / ALT (SGPT) ≤ 2.5 x 
ULN
o
Adequate renal function (creatinine ≤ 2.0 x ULN or creatinine clearance > 30 
mL/min 

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o
Neutrophils >1500/µL and platelets >100,000

No brain metastases

No more than 2 prior regimens containing a VEGF-pathway inhibitor; no prior therapy 
with bevacizumab

Ability to understand and sign informed consent
Design

Patients will receive a fixed starting dose of bevacizumab (10mg/kg IV every 2 weeks) 
and erlotinib (150mg/day p.o.). Dose reductions and drug interruptions for unacceptable 
toxicity will be allowed.

Patients will be evaluated for response every 8 weeks using RECIST criteria 

The study is based on an open label Simon two-stage minmax design in two cohorts, 1) 
cohort 1- patients with HLRCC, and 2) cohort 2- patients with sporadic papillary RCC. In 
each cohort, 13 patients will be accrued in the first stage and will accrue a maximum of 20 
patients. Accrual into and analysis of the two cohorts will be independent.

Following completion of accrual to cohorts 1 and 2, the study was expanded to include 
two additional cohorts- Cohort 3 (HLRCC patients and Cohort 4 (patients with 
sporadic/non HLRCC papillary RCC) to better estimate the overall response rate and to 
perform additional exploratory biomarker analyses. Up to 20 additional evaluable patients 
will be included in each of these cohorts. 

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TABLE OF CONTENTS
PRÉCIS......................................................................................................................................2
TABLE OF CONTENTS ..........................................................................................................4
STATEMENT OF COMPLIANCE ..........................................................................................7
1
INTRODUCTION .........................................................................................................7
1.1
Study Objectives........................................................................................................7
1.2
Background and Rationale.........................................................................................8
2
ELIGIBILITY ASSESSMENT AND ENROLLMENT .............................................30
2.1
Eligibility Criteria....................................................................................................30
2.2
Screening Evaluation...............................................................................................32
2.3
Patient Registration and Status Update Procedures.................................................32
3
STUDY IMPLEMENTATION ...................................................................................33
3.1
Study Design............................................................................................................33
3.2
Drug Administration................................................................................................33
3.3
Treatment Modifications .........................................................................................34
3.4
Correlative Studies for Research .............................................................................42
3.5
Study Evaluation......................................................................................................45
3.6
Concurrent, Restricted and Excluded Therapies .....................................................54
3.7
Surgical Guidelines..................................................................................................54
3.8
Radiation Therapy Guidelines .................................................................................54
3.9
Cost and Compensation ...........................................................................................55
3.10
Criteria for Removal from Protocol Therapy and Off Study Criteria .....................55
4
SUPPORTIVE CARE .................................................................................................56
5
DATA COLLECTION AND EVALUATION ...........................................................56
5.1
Data Collection ........................................................................................................56
5.2
Response Evaluation................................................................................................56
5.3
Overall survival (OS) is defined as the duration of time from the date of study 
enrolment until time of death. Patients without a death event will be censored at the date 
survival assessment was last evaluated (e.g., clinic visit, phone call).Toxicity Criteria.....64
6
STATISTICAL CONSIDERATIONS ........................................................................64
6.2
Accrual Ceiling........................................................................................................65
7
HUMAN SUBJECTS PROTECTION ........................................................................67
7.1
Rationale for Subject Selection ...............................................................................67

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7.2
Participation of Subjects Unable to Give Consent ..................................................67
7.3
Evaluation of Benefits and Risks/Discomforts........................................................67
7.4
Alternative Treatments ............................................................................................68
7.5
Risk/Benefit Analysis ..............................................................................................69
7.6
Consent Process and Documentation.......................................................................69
7.7
Patient Records and Quality Assurance...................................................................70
8
NIH REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING 
PLAN 70
8.1
Definitions ...............................................................................................................70
8.2
OHSRP Office and of Compliance and Training/IRB Reporting ...........................70
8.3
NCI Clinical Director Reporting .............................................................................70
9
MANUFACTURER SAFETY REPORTING.............................................................70
9.1
Adverse Event Reporting Period .............................................................................71
9.2
Definitions ...............................................................................................................71
9.3
Assessment of Adverse Events................................................................................73
9.4
Procedures for Eliciting, Recording, and Reporting Adverse Events .....................73
9.5
Adverse Event Reporting to Genentech ..................................................................75
9.6
Additional Reporting Requirements to Genentech..................................................77
9.7
Follow-up Information.............................................................................................78
9.8
Study Close-Out.......................................................................................................78
9.9
Queries......................................................................................................................78
9.10
Other Reports...........................................................................................................79
10
COLLABORATIVE AGREEMENTS........................................................................79
10.1
Cooperative Research and Development Agreement (CRADA) ............................79
11
REGULATORY AND OPERATIONAL CONSIDERATIONS................................80
11.1
STUDY DISCONTINUATION AND CLOSURE .................................................80
11.2
Quality Assurance and Quality Control...................................................................81
11.3
Conflict of Interest Policy........................................................................................81
11.4
Confidentiality and Privacy .....................................................................................82
12
PHARMACEUTICAL INFORMATION ...................................................................82
12.1
Bevacizumab............................................................................................................82
12.2
Erlotinib ...................................................................................................................84
REFERENCES ........................................................................................................................86

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APPENDIX A: ECOG PERFORMANCE STATUS..................................................92
14
APPENDIX B: NEW YORK HEART ASSOCIATION (NYHA) CARDIAC 
CLASSIFICATION.................................................................................................................93
15
APPENDIX C: LIST OF INTERACTING DRUGS...................................................94
16
APPENDIX D: CASE TRANSMISSION VERIFICATION FORM .........................96

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STATEMENT OF COMPLIANCE
The trial will be carried out in accordance with International Conference on Harmonisation 
Good Clinical Practice (ICH GCP) and the following: 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies 
(45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR 
Part 812) 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training.
The protocol, informed consent form(s), recruitment materials, and all participant materials 
will be submitted to the Institutional Review Board (IRB) for review and approval.  Approval 
of both the protocol and the consent form must be obtained before any participant is enrolled.  
Any amendment to the protocol will require review and approval by the IRB before the 
changes are implemented to the study.  In addition, all changes to the consent form will be 
IRB-approved; an IRB determination will be made regarding whether a new consent needs to 
be obtained from participants who provided consent, using a previously approved consent 
form.
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INTRODUCTION
1.1
Study Objectives
1.1.1
Primary Objective

To determine the overall response rate (RECIST) in patients with 1) metastatic RCC 
associated with HLRCC and 2) metastatic sporadic/non-HLRCC papillary RCC, treated 
with a combination of bevacizumab and erlotinib
1.1.2
Secondary Objective

To assess progression-free survival, duration of response and overall survival
1.1.3
Exploratory Objectives

To investigate the effect of bevacizumab/erlotinib on circulating endothelial cells and 
endothelial progenitor cells and to explore the utility of these markers as surrogates of 
angiogenesis inhibition

To investigate the effect of bevacizumab/erlotinib on potential biomarkers of 
angiogenesis in plasma such as VEGF and soluble VEGFR2

To evaluate the prevalence of somatic FH mutations/inactivation in patients with sporadic 
papillary RCC 

To determine the extent of TGF-α upregulation and/or EGFR expression/ pathway 
activation in leiomyomas/ RCC tumor tissue (when available)

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
To evaluate modulation of HIF, VEGF and EGFR pathways in cutaneous leiomyomas (in 
patients with HLRCC) and in renal tumors (when tumors are accessible for biopsy) 
following therapy

To assess the effect of therapy on HLRCC associated skin leiomyomas
1.2
Background and Rationale
1.2.1
HLRCC and Papillary RCC
Hereditary Leiomyomatosis and Renal Cell Cancer is a familial syndrome in which affected 
individuals are at increased risk for the development of papillary renal cell cancer as well as 
cutaneous leiomyomas. Linkage analysis studies have led to the identification of germline 
mutations in the Krebs’ cycle enzyme fumarate hydratase (FH) as the genetic event 
underlying this inherited syndrome.
The most common clinical features associated with this syndrome are cutaneous leiomyomas.  
Cutaneous leiomyomas are highly penetrant, and develop early (median age at presentation 
was 25 years in one study). Cutaneous leiomyomas most often occur on the trunk or 
extremities, and are often symptomatic. Wei et al. reported that 81% of HLRCC patients had 
cutaneous lesions, and 90% of these had sensitivity to light touch of the lesions.(1)  
Although renal cell cancer occurs less frequently than leiomyomas (approximately one third 
of patients with HLRCC seen at the National Cancer Institute had renal cell cancer), it is 
usually associated with an aggressive clinical course and poor outcome. Unlike other well 
described hereditary renal carcinoma syndromes where multiple bilateral renal tumors are the 
norm, most HLRCC patients tend to have solitary renal lesions; however, bilateral, 
multifocal lesions have been described in some patients. HLRCC patients also develop renal 
cysts.  Lehtonen et al. found that 42% of germline FH mutation-positive patients had renal 
cysts on radiologic review.(2)  The clinical significance of these cysts is unclear and their 
malignant potential remains to be determined.
Renal cell cancer associated with HLRCC is characterized by distinct histopathologic 
features and clinical course. These tumors are often clinically aggressive, and tend to 
metastasize early with a predilection for regional and distant lymph nodes, liver and bone. 
There are currently no standard treatment options available for patients with advanced or 
unresectable disease, with the majority of these patients dying due to metastatic disease. In 
the past, HLRCC-associated renal tumors have been histologically described as resembling 
papillary type II or collecting duct tumors. In a recent report, Merino et al. have described the 
distinctive histopathologic features of HLRCC-associated renal tumors based on a review of 
forty tumors.(3)  These tumors have characteristic large orangiophilic nuclei and a clear 
perinuclear halo, with a variety of architectural patterns such as papillary, tubulo-papillary, 
tubular, solid or mixed. There is currently no well described sporadic counterpart to HLRCC-
associated kidney cancer and no conclusive evidence that somatic FH mutations play a 
significant role in sporadic kidney cancer tumorigenesis. However, we (investigators in the 
UOB/NCI) have evaluated several patients with papillary histology whose tumors 
histologically resemble that of HLRCC-associated renal cancer, with no accompanying 
family history, germline FH mutation or other sequelae of this syndrome. Most pathologists 
currently offer vague descriptions of these tumors, often characterizing them as papillary 
type 2 RCC or collecting duct tumors. Evaluation of these non-familial cases of papillary 

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RCC variants for evidence of somatic inactivation of FH is ongoing.
Genetic and Biochemical Basis of Renal Oncogenesis in HLRCC
Patients with HLRCC have a germline mutation localized to the long arm of chromosome 1 
(1q42.3-q43).  The gene responsible for HLRCC was identified through linkage analysis, and 
encodes fumarate hydratase (FH), a Krebs cycle enzyme.  In addition to the germline 
loss/mutation of one FH allele, functional inactivation of the remaining copy of FH has also 
been found in most HLRCC associated renal tumors, cutaneous leiomyomas, and uterine 
leiomyomas. Correspondingly, tumors in HLRCC patients have been found to have 
extremely low or absent FH activity. Thus, the FH gene appears to act as a tumor suppressor 
gene, following Knudson’s “two hit” model of carcinogenesis.  Germline mutations are 
generally due to missense, frameshift, nonsense, or splice site mutations, and are distributed 
throughout the gene.  
While the exact biochemical mechanism by which loss of FH activity leads to tumorigenesis 
is still under investigation, several lines of evidence suggest that generation of a 
pseudohypoxic state may play a role. This is supported by the demonstration by Pollard et al. 
(by immunochemistry and immunoblotting) that there was strong hypoxia inducible factor-1 
(HIF-1) expression in kidney tumors from HLRCC patients.(4)  Similarly, Isaacs et al. 
demonstrated increased expression of both HIF-1  and HIF-2  in renal tumors from patients 
with HLRCC compared to normal, matched renal tissue from the same patient.(5) In 
addition, there is also evidence of increased expression of downstream tumorigenic and pro-
angiogenic transcriptional targets of HIF. For instance, the observed increase in microvessel 
density correlated with an increase in expression of VEGF mRNA. Furthermore, as described 
by Pollard et al., increased microvessel density is seen in leiomyomas from HLRCC patients, 
when compared to matched normal myometrium (6). 
A recent publication from our group elucidates one potential mechanism by which FH 
inactivation can lead to upregulation of HIF. FH is an essential cellular enzyme catalyzing 
the conversion of fumarate to malate in the mitochondrial tricarboxylic acid (TCA) or Krebs 
cycle, which is the primary eukaryotic cellular pathway for the aerobic metabolism of 
glucose. Loss of FH activity results in the overaccumulation of its substrate fumarate. Isaacs 
et al. demonstrated that inactivation of FH and consequent excess intracellular fumarate 
accumulation lead to inhibition of HIF propyl hydroxylase (HPH), a critical enzymatic 
regulator of intracellular HIF levels, through competitive inhibition.(5)  This interferes with 
hydroxylation of HIF at key proline residues and its subsequent recognition by the VHL 
complex, thus preventing VHL-dependent proteosomal degradation of HIFs. The resulting 
accumulation of HIF leads to transcriptional overexpression of proangiogenic factors such as 
VEGF as well as other genes such as transforming growth factor- α (TGF- α), platelet 
derived growth factor (PDGF) and GLUT-1. (Figure 1) Overexpression of VEGF (and 
PDGF) is likely responsible for enhanced tumor angiogenesis and the highly vascular renal 
tumors seen in HLRCC, while TGF- α overexpression may activate tumor growth pathways 
via its receptor (epidermal growth factor receptor, EGFR). Activation of components of the 
HIF pathway such as Glut-1 may also explain the avid FDG uptake of HLRCC-associated 
renal tumors demonstrated by PET imaging (Unpublished data).

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Figure 1: Normoxia: In the presence of oxygen, HIF is hydroxylated by HIF prolyl hydroxylase (HPH), 
which allows the VHL complex to recognize and target it for ubiquitin-mediated degradation in the 
proteosome.  HLRCC:  Loss of FH shunts the TCA cycle to produce excess fumarate.  Fumarate 
stabilizes HIF through competitive inhibition of HPH, preventing HIF hydroxylation and degradation.  
Elevated HIF drives transcription products involved with angiogenesis (VEGF), glucose transport 
(GLUT-1), and growth stimulation (TGF-α, PDGF).
1.2.2
Bevacizumab
1.2.2.1
Bevacizumab: Background
Bevacizumab is a recombinant humanized monoclonal IgG1 antibody that binds to and 
inhibits the biologic activity of human VEGF. Bevacizumab contains human framework 
regions and complementarity-determining regions of a murine antibody that binds to VEGF.  
Approximately 93% of the amino acid sequence, including most of the antibody framework, 
is derived from human IgG1, and approximately 7% of the sequence is derived from the 
murine antibody. Bevacizumab is approved by the Food and Drug Administration as first-
line treatment of patients with metastatic carcinoma of the colon and rectum in combination 
with intravenous 5-fluorouracil-based chemotherapy, with oxaliplatin based chemotherapy 
for metastatic colon and rectal cancers, and with carboplatin and paclitaxel for non-small cell 
cancers of the lung. Bevacizumab binds VEGF and prevents its binding to cognate receptors 
(Flt-1 and KDR) on the surface of endothelial cells.
1.2.2.2
Bevacizumab: Preclinical Data
In cynomolgus monkeys, twice weekly IV treatments with bevacizumab (2, 10, and 50 
mg/kg) for 4, 13, or 26 weeks were well tolerated, with no overt signs of acute toxicity.8, 9 
Animals with open growth plates showed physeal dysplasia, as well as focal to diffuse 

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chondroid necrosis and linear fissuring of the cartilaginous growth plate. Females treated 
with 10-50 mg/kg twice weekly had decreased ovarian and uterine weights, which were 
associated with the absence of corpora lutea. These findings were expected considering the 
role of VEGF in the formation of the corpora lutea and the growing bone.10 In a further 
study using a similar treatment regimen, the recovery period of the physeal dysplasia and the 
ovarian and uterine changes induced by bevacizumab VEGF were partially reversible. No 
antibodies against bevacizumab were detected.
1.2.2.3
Bevacizumab:  Phase I Clinical Studies
Two phase I studies have been performed. Study AVF0737g was a dose escalation trial of 
single and multiple intravenous (IV) administration of rhuMAb in patients with advanced 
malignancies. Five dose levels were evaluated (0.1, 0.3, 1.0, 3.0, and 10 mg/kg). rhuMAb 
VEGF was administered as a 90-minute infusion on days 0, 28, 35 and 42.(7) The second 
study, AVF0761g, evaluated multiple doses of rhuMAb VEGF 3 mg/kg weekly for up to 8 
weeks in combination with one of three cytotoxic chemotherapy regimens (5-
fluorouracil/leucovorin, carboplatin/paclitaxel, or doxorubicin) in subjects with advanced 
solid malignancies.(8) rhuMAb VEGF was administered weekly at 3 mg/kg for eight doses. 
In both studies, rhuMAb VEGF appeared to be well tolerated. In AVF0737g, 3 of 25 patients 
treated experienced tumor-related hemorrhagic events, possibly related to the administration 
of rhuMAb VEGF. In two cases the event was considered serious: an intracranial hemorrhage 
(at an occult cerebral metastasis) in a patient with hepatocellular carcinoma and bleeding at 
the tumor site in a 38-year-old woman with a slowly progressing sarcoma of the thigh. No 
patient in AVF0761g reported serious bleeding. No dose limiting toxicity was reached in 
either study. No antibodies to rhuMAb VEGF were detected after therapy in either study.
1.2.2.4
Bevacizumab: Pharmacokinetics
The PK profile of bevacizumab was assessed using an assay that measures the total serum 
concentrations (i.e., the assay did not distinguish between freely circulating molecules of 
bevacizumab and those bound to a VEGF ligand). Based on a population PK analysis of 491 
patients receiving bevacizumab 1−20 mg/kg weekly, every 2 or 3 weeks, the estimated half-
life of bevacizumab was approximately 20 days (range, 11-50 days). The predicted time to 
reach a steady state was 100 days. The accumulation ratio following bevacizumab (10 
mg/kg) every 2 weeks was 2.8. The clearance rate for bevacizumab varied according to body 
weight, gender, and tumor burden. After correcting for body weight, males had a higher 
clearance rate (0.262 L/day vs. 0.207 L/day) and a larger volume of the central compartment 
(Vc; 3.25 L vs. 2.66 L) than females. Patients with higher tumor burden (at or above median 
value of tumor surface area) had a higher bevacizumab clearance rate (0.249 L/day vs. 0.199 
L/day) than patients with tumor burdens below the median. However, in a randomized study 
of 813 patients, there was no evidence of lesser efficacy (HR for overall survival) in males or 
patients with a higher tumor burden treated with bevacizumab compared with females and 
patients with a low tumor burden.
1.2.2.5
Bevacizumab: Phase II/III Clinical Studies
1.2.2.5.1 Phase II Clinical Studies:
Bevacizumab has been shown to be effective in the therapy of metastatic renal cell 
carcinoma. Yang et al.(9) completed a randomized, double-blind, phase 2 trial comparing 

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placebo to bevacizumab at doses of 3 and 10 mg/kg given every 2 weeks. There was a 
statistically significant increase in time to progression with the high-dose group compared to 
placebo.
1.2.2.5.2 Phase III Clinical Studies
In a clinical trial conducted by Hurwitz et al (10), the addition of bevacizumab- to 
fluorouracil-based combination chemotherapy (irinotecan, bolus fluorouracil, and leucovorin 
[IFL]) resulted in statistically significant and clinically meaningful improvement in survival 
among patients with metastatic colorectal cancer. The median duration of survival was 20.3 
months in the group given IFL plus bevacizumab, as compared with 15.6 months in the 
group given IFL plus placebo, corresponding to a hazard ratio for death of 0.66 (p < 0.001). 
The median duration of progression-free survival was 10.6 months in the group given IFL 
plus bevacizumab, as compared with 6.2 months in the group given IFL plus placebo (hazard 
ratio for disease progression, 0.54; p < 0.001). The corresponding rates of response were 
44.8% and 34.8% (p = 0.004). In a recent phase III study, the addition of bevacizumab to 
conventional chemotherapy (paclitaxel plus carboplatin) in the treatment of selected patients 
with advanced non-small cell lung cancer resulted in a significant survival benefit (hazard 
ratio for death, 0.79; p = 0.003) with the risk of increased treatment-related deaths.(11) Rates 
of clinically significant bleeding were 4.4% (bevacizumab arm) vs 0.7% (control arm; p < 
0.001). There were 15 treatment-related deaths in the chemotherapy-plus bevacizumab 
group, including 5 from pulmonary hemorrhage.
The most recent report to be added in metastatic renal cell carcinoma (mRCC) is that of 
Escudier and colleagues, who randomized patients between bevacizumab plus interferon and 
interferon alone. This trail was conducted in first-line treatment for mRCC.  This study 
demonstrated improved progression free survival from 5.4 months to 10.2 months with the 
addition of bevacizumab; data for overall survival have not yet been reported.(12)
1.2.2.6
Bevacizumab: Toxicities/Adverse Events
Based on clinical trials with bevacizumab as monotherapy or in combination with 
chemotherapy, the most common adverse events of any severity include asthenia, pain, 
headache, hypertension, diarrhea, stomatitis, constipation, epistaxis, dyspnea, dermatitis and 
proteinuria. The most common Grade 3-4 adverse events were asthenia, pain, hypertension, 
diarrhea, and leukopenia. The most serious AEs include life-threatening or fatal hemorrhage, 
arterial thromboembolic events, gastrointestinal perforation, congestive heart failure, 
primarily in breast cancer patients and wound dehiscence; these events were uncommon but 
occurred at an increased frequency compared to placebo or chemotherapy controls in 
randomized studies. Increased rates of severe neutropenia have been observed in patients 
treated with some chemotherapy regimens plus bevacizumab. Other SAEs observed with 
bevacizumab therapy include hypertensive crisis, nephrotic syndrome and reversible 
posterior leukoencephalopathy syndrome. 
The following is a description of major adverse events associated with bevacizumab therapy.  

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1.2.2.7
Hemorrhage 
An increased incidence of bleeding events was observed in patients treated with bevacizumab 
as compared to control treatment arms. In the bevacizumab-containing treatment arms of 
clinical trials (across all indications), the incidence rate of NCI-CTC Grade ≥ 3 bleeding 
events ranged from 0.4-5%, compared to 0-2.9% in control treatment arms. The hemorrhagic 
events that have been observed in bevacizumab clinical studies were predominantly tumor-
associated hemorrhage and minor mucocutaneous hemorrhage.
Life threatening hemorrhage was seen in a Phase I trial (AVF0737g) in the form of an 
intracranial hemorrhage (at an occult cerebral metastasis) in a patient with hepatocellular 
carcinoma and in the Phase II study (AVF0757g) in the form of massive hemoptysis or 
hematemesis. 
Tumor-associated hemorrhage - Major or massive pulmonary hemorrhage/hemoptysis has 
been observed primarily in patients with NSCLC. In a Phase II study in NSCLC, 6 cases of 
life-threatening (4 fatal) hemoptysis were reported among 66 patients treated with 
bevacizumab and chemotherapy;(13)  squamous cell histology was identified as the risk 
factor. In the Phase III trial in non-squamous NSCLC (E4599), the rate of Grade ≥ 3 
pulmonary hemorrhage was <1% in the control arm (carboplatin/paclitaxel) versus 2.3% in 
the chemotherapy plus bevacizumab arm (10/427 patients, including 7 deaths).
Of patients experiencing pulmonary hemorrhages requiring medical intervention, 
many had cavitation and/or necrosis of the tumor, either pre-existing or developing during 
bevacizumab therapy. Patients developing lung cavitation on treatment should be assessed by 
the treating physician for risk-benefit.
Gastrointestinal hemorrhages, including rectal bleeding and melena have been 
reported in patients with colorectal cancer, and have been assessed as tumor-associated 
hemorrhages. In the pivotal Phase III trial in advanced colorectal cancer, the rate of GI 
hemorrhage (all grades) was 24% in the IFL/bevacizumab arm compared to 6% in the IFL 
arm; Grade 3-4 hemorrhage was 3.1% for IFL/bevacizumab and 2.5% for IFL. Serious tumor 
associated bleedings have also been observed in patients with pancreatic cancer, gastric 
cancer, CNS metastases, hepatoma, or varices treated with bevacizumab.
Tumor-associated hemorrhages were also seen rarely in other tumor types and 
locations, and included a case of central nervous system (CNS) bleeding in a patient with 
hepatoma with occult CNS metastases, and another patient who developed continuous oozing 
of blood from a thigh sarcoma with necrosis.
Mucocutaneous hemorrhage - Across all bevacizumab clinical trials, mucocutaneous 
hemorrhage has been seen in 20%-40% of patients treated with bevacizumab. These were 
most commonly NCI-CTC Grade 1 epistaxis that lasted less than 5 minutes, resolved without 
medical intervention, and did not require any changes in bevacizumab treatment regimen. 
There have also been less common events of minor mucocutaneous hemorrhage in other 
locations, such as gingival bleeding and vaginal bleeding.
1.2.2.8
Thrombosis 
In Study AVF0780g in metastatic colorectal cancer, venous and arterial thrombosis were 
seen more frequently in patients treated with rhuMAb VEGF plus 5-FU/leucovorin than in 

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patients treated with 5-FU/leucovorin alone: 3 of 35 patients in the control arm, 9 of 35 
patients in the 5 mg/kg rhuMAb VEGF arm and 4 of 32 patients in the 10 mg/kg rhuMAb 
VEGF arm. One event was fatal (a pulmonary embolism in the 10 mg/kg arm) and three 
events required study discontinuation (a pulmonary embolism and a superior mesenteric vein 
occlusion in the 5 mg/kg arm and a cerebrovascular event in the 10 mg/kg arm). 
Cancer patients are known to be at high risk for thromboembolism owing to a number of 
factors including intrinsic tumor pro-coagulant activity, immobilization, indwelling catheters 
and the pro-thrombotic effects of chemotherapy. The incidence of thrombosis among patients 
with breast cancer receiving chemotherapy is approximately 5-10% being higher in patients 
on tamoxifen and in patients with metastatic disease. 
In the first 59 patients with metastatic breast cancer treated with rhuMAb VEGF 
monotherapy, two patients have developed a subclavian/axillary deep venous thrombosis on 
the side of the indwelling central line. In the AVF2107 study, there was a 1% incidence of 
arterial thromboembolic (TE) events (which include myocardial infarction, transient ischemic 
attack, cerebrovascular accident/stroke, and angina/unstable angina) in the IFL + placebo arm 
versus 3% in the ILF + bevacizumab arm. A pooled analysis of the rate of arterial TE events 
from 5 randomized studies showed that treatment with bevacizumab increased the risk of 
these events two- to three-fold (up to 5%). Furthermore, certain baseline characteristics, 
specifically age > 65 years and prior arterial TE event, conferred additional risk.
Arterial Thromboembolic Events (ATE): The risk of arterial thromboembolic events is 
increased with bevacizumab therapy; such events included cerebral infarction, transient 
ischemic attack (TIA), myocardial infarction (MI) and other peripheral or visceral arterial 
thrombosis. A pooled analysis of five randomized studies showed a twofold increase in these 
events (3.8% vs. 1.7%). ATE led to a fatal outcome in 0.8% patients with bevacizumab (vs. 
0.5% without bevacizumab). The rate of cerebrovascular accidents (including TIA) was 2.3% 
vs. 0.5%, and the rates of MI 1.7% vs. 0.7%. Certain baseline characteristics, such as age and 
prior arterial ischemic events, appear to confer additional risk.(14) 
In patients > 65 years treated with bevacizumab and chemotherapy, the rate of ATE was 
approximately 8.5%. Aspirin is a standard therapy for primary and secondary prophylaxis of 
ATE in patients at high risk of such events, and the use of aspirin ≤ 325 mg daily was 
allowed in the five randomized studies discussed above, though safety analyses specifically 
regarding aspirin use were not preplanned. Due to the relatively small numbers of aspirin 
users and ATE events, retrospective analyses of the ability of aspirin to affect the risk of 
ATE were inconclusive. Further analyses of the effects of concomitant use of bevacizumab 
and aspirin are ongoing.
Venous thromboembolism (VTE) (including deep venous thrombosis, pulmonary embolism 
and thrombophlebitis): In the Phase III pivotal trial in metastatic CRC, there was a slightly 
higher rate of VTE in patients treated with chemotherapy + bevacizumab compared with 
chemotherapy alone (19% vs. 16%). The incidence of NCI-CTC Grade≥ 3 VTEs in one 
NSCLC trial (E4599) was higher in the bevacizumab-containing arm compared to the 
chemotherapy control arm (5.6% vs. 3.2%).
In clinical trials across all indications the overall incidence of VTEs ranged from 2.8% to 
17.3% in the bevacizumab-containing arms compared to 3.2% to 15.6% in the chemotherapy 
control arms. The use of bevacizumab with chemotherapy does not substantially increase the 

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risk of VTE compared with chemotherapy alone. However, patients with mCRC who receive 
bevacizumab and experienced VTE may be at higher risk for recurrence of VTE.
1.2.2.9
Hypertension 
Hypertension has been seen in all rhuMAb VEGF clinical trials to date. Hypertension is 
common in patients treated with bevacizumab, with an incidence of 20-30% (all grades) 
across trials, with a mean increase of +5.5mmHg to +8.4mmHg for systolic pressure, or 
+4.1mmHg to +5.4mmHg for diastolic pressure. Incidence of Grade 3 (hypertension 
requiring initiation of or increase in hypertensive medications) ranges from 7.8 to 17.9%. 
Grade 4 hypertension (hypertensive crisis) occurred in up to 0.5% of bevacizumab-treated 
patients. Hypertension associated with bevacizumab can generally be controlled with routine 
oral drugs while the treatment is continued. Monitoring of blood pressure is recommended 
during bevacizumab therapy.  Optimal control of blood pressure according to standard public 
health guidelines is recommended for patients on treatment with or without bevacizumab. 
Temporary interruption of bevacizumab therapy is recommended in patients with 
hypertension requiring medical therapy until adequate control is achieved.  If hypertension 
cannot be controlled with medical therapy, bevacizumab therapy should be permanently 
discontinued.  Bevacizumab should be permanently discontinued in patients who develop 
hypertensive crisis or hypertensive encephalopathy.
There has been one reported case of hypertensive encephalopathy in a patient receiving 3 
mg/kg of rhuMAb VEGF on study AVF0776g. In addition, there are 2 reports of reversible 
posterior leukoencephalopathy syndrome (RPLS) (Ozcan et al., 2006; Glusker et al., 2006). 
In study 0776g 12 other patients developed either new hypertension (7 patients) or worsening 
existing hypertension (5 patients) and 10 of these patients required medical therapy (3 
patients in the 3 mg/kg rhuMAb arm (n = 18) and 7 in the 10 mg/kg (n = 41), no data 
available from the 20 mg/kg arm). After 10 weeks of treatment, the mean change in blood 
pressure for all subjects compared with baseline was as follows (mean systolic change/mean 
diastolic change): 3 mg/kg rhuMAb VEGF + 10.5 mmHg/+8.5 mmHg and 10 mg/kg 
rhuMAb VEGF +18.5 mmHg/+8.2 mmHg. In Study AVF0780g (colorectal cancer), using 
NCICTC Grade 3 or 4 events, there were four events in the control arm (n = 35), four events 
between 2 patients in the 5 mg/kg rhuMAb VEGF (n = 35) and nine events among 5 subjects 
in the 10 mg/kg rhuMAb VEGF (n = 32). The most commonly used therapies to treat this 
hypertension have been angiotensin converting enzyme inhibitors and calcium channel 
blockers. VEGF has been shown to induce nitric oxide-mediated vasodilatation and 
hypotension.(15) In a recent study, VEGF has been shown to govern endothelial nitric oxide 
synthase expression via a KDR/flk-1 receptor and protein kinase C signaling pathway, which 
suggests a possible mechanism for rhuMAb VEGFs induction of hypertension.(16) 
1.2.2.10
Proteinuria 
Proteinuria by dipstick analysis has been seen in all rhuMAb VEGF clinical trials and has 
ranged in severity from mild asymptomatic increase in urine protein (incidence of about 
38%) to rare instances of Grade 3 proteinuria (> 3.5 g/24 hour urine) (3%), or nephrotic 
syndrome (1.4%). Pathologic findings on renal biopsies in two patients showed proliferative 
glomerulonephritis. The risk of proteinuria may be higher in patients with advanced RCC or 
history of hypertension. There is also evidence that the rate of proteinuria may be dose 
related.

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In study AVF0776g, 8 of 59 (12%) subjects treated with 3 mg/kg or 10 mg/kg have 
developed some degree of proteinuria (detected by dipstick) during the study. Three of these 
patients also developed hypertension. Two patients were discontinued from study because of 
proteinuria; one patient (10 mg/kg arm) had > 2.5g/24hr which decreased to 0.7 mg/24hr 
within 4 weeks with a normal serum creatinine and a second patient in the 20 mg/kg arm who 
developed > 5g/24hr. Another patient (3 mg/kg arm) developed hypertensive 
encephalopathy, which was followed by the development of nephrotic syndrome (5 g/24hr). 
This patient died of progressive disease soon thereafter and renal biopsy was not performed. 
A recent study has shown that VEGF mediates glomerular repair, which suggested a possible 
mechanism for rhuMAb VEGF-associated proteinuria.(17)
1.2.2.11
Congestive Heart Failure 
The risk of left ventricular dysfunction may be increased in patients with prior or concurrent 
anthracycline treatment. In Phase III controlled clinical trials in metastatic breast cancer 
(AVF 2119g) in which all patients had received prior anthracyclines, congestive heart failure 
(CHF) or cardiomyopathy were reported in 7 patients (3%) in the bevacizumab+capecitabine 
arm compared to 2 (1%) in the capecitabine-only arm. A recently published Phase II study in 
subjects with refractory acute myelogenous leukemia reported 5 cases of cardiac dysfunction 
(CHF or decreases to <40% in left ventricular ejection fraction) of 48 subjects treated with 
sequential cytarabine, mitoxantrone, and bevacizumab. All but one of these subjects had 
significant prior exposure to anthracyclines as well. Other studies are ongoing in this patient 
population. Patients receiving anthracyclines or with prior exposure to anthracyclines should 
have a baseline MUGA or ECHO with a normal ejection fraction.
Two patients with metastatic breast cancer in study AVF0776g who had been treated 
previously with doxorubicin developed congestive heart failure while on rhuMAb VEGF, 
one patient after one year at 10 mg/kg and the second patient after two doses at 20 mg/kg.  
1.2.2.12
Perforation 
GI perforations/fistula were rare but occurred at an increased rate in bevacizumab-containing 
therapies. The majority of such events required surgical intervention and some were 
associated with a fatal outcome. In the pivotal Phase III trial in CRC (AVF2107), the 
incidence of bowel perforation was 2% in patients receiving IFL/bevacizumab and 4% in 
patients receiving 5-FU/bevacizumab compared to 0.3% in patients receiving IFL alone. GI 
perforation has also been reported in patients with gastric/esophageal cancer, pancreatic 
cancer, ovarian cancer or co-morbid GI conditions such as diverticulitis and gastric ulcer. GI 
perforation should be included in the differential diagnosis of patients on bevacizumab 
therapy presenting with abdominal pain or rectal/abdominal abscess.
A Genentech sponsored trial of bevacizumab in recurrent ovarian cancer was terminated 
early due to a greater than expected incidence of bowel perforations (11%). Patients were 
dosed at 15 mg/kg q3wks as compared to our planned dosing of 10 mg/kg q2wks. Previous 
studies of bevacizumab in colon cancer had an incidence of bowel perforation of between 4 - 
6%. At the recent January 2006 GOG meeting, an analysis of all ovarian cancer patients 
receiving bevacizumab in CTEP sponsored trials, approximately 150 patients, had only a 
4.8% perforation/ fistula rate, approximating much closer the incidence seen in colon cancer. 
Further analysis is ongoing to ascertain the true risk of bowel perforation in ovarian cancer 
patients receiving bevacizumab.(18)

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1.2.2.13
Fistula 
Fistula formations, including events resulting in death, have been observed in patients 
receiving bevacizumab in clinical studies and postmarketing reports. Fistulae in the GI tract 
are common (1-10% incidence) in patients with metastatic colorectal cancer, but uncommon 
(0.1-1%) or rare (0.01-0.1%) in other indications. In addition, fistulae that involve areas other 
than the GI tract have also been observed (e.g., tracheoesophageal, bronchopleural, 
urogenital, biliary). For example, life-threatening or fatal tracheoesophageal fistula has been 
reported in patients with small cell lung cancer treated with concurrent chemoradiation and 
bevacizumab. In a Phase II trial of irinotecan + carboplatin + RT and bevacizumab followed 
by maintenance bevacizumab that accrued 25 patients, there have been two confirmed cases 
of tracheoesophageal (TE) fistula (one fatal) and a third case of fatal upper aerodigestive tract 
hemorrhage, with TE fistula suspected but not confirmed. All three events occurred during 
the bevacizumab maintenance phase (1.5 to 4 months after completion of chemoradiation). 
While pulmonary fistula (including TE fistula) has also been observed in advanced NSCLC 
or SCLC patients receiving bevacizumab and chemotherapy (without radiation), the 
incidence was extremely low.
1.2.2.14
Wound Healing Complications 
Bevacizumab delays wound healing in rabbits, and it may also compromise or delay wound 
healing in patients. Bowel anastomotic dehiscence and skin wound dehiscence have been 
reported in clinical trials with bevacizumab. The appropriate interval between surgery and 
initiation of bevacizumab required to avoid the risk of impaired wound healing has not been 
determined. Across metastatic CRC trials, at least 28 days must have elapsed following 
major surgery before bevacizumab could be initiated; data suggested initiation of 
bevacizumab 29-60 days following surgery did not appear to increase the risk of wound 
healing complications compared to those treated with chemotherapy alone. The optimal 
interval between termination of bevacizumab and subsequent elective surgery has not been 
determined, although at least 4 weeks should be required between the last dose of 
bevacizumab and elective surgery. In the pivotal study in CRC, among patients who 
underwent major surgery while on study therapy, there was an increased rate of significant 
postoperative bleeding or wound healing complications in the IFL + bevacizumab arms vs. 
IFL alone [10% (4/40) vs. 0% (0/25)].(19)  Decisions on the timing of elective surgery 
should take into consideration the half life of bevacizumab (average 21 days, range 11-50 
days). If patients receiving treatment with bevacizumab require elective major surgery, it is 
recommended that bevacizumab be held for 4–8 weeks prior to the surgical procedure. 
Patients undergoing a major surgical procedure should not begin/restart bevacizumab until 4 
weeks after that procedure (in the case of high-risk procedures such as liver resection, 
thoracotomy, or neurosurgery, it is recommended that chemotherapy be restarted no earlier 
than 6 weeks and bevacizumab no earlier than 8 weeks after surgery).
1.2.2.15
Reversible Posterior Leukoencephalopathy Syndrome (RPLS) or similar 
leukoencephalopathy syndrome 
RPLS or clinical syndromes related to vasogenic edema of the white matter have rarely been 
reported with bevacizumab therapy (< 1%). Clinical presentations are variable and may 
include altered mental status, seizure, and cortical visual deficit. HTN is a common risk 
factor and was present in most (though not all) patients on bevacizumab who developed 

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RPLS. MRI scans are key to diagnosis and typically demonstrate vasogenic edema (hyper-
intensity in T2 and FLAIR images and hypo-intensity in T1 images) predominantly in the 
white matter of the posterior parietal and occipital lobes; less frequently, the anterior 
distributions and the gray matter may also be involved. RPLS should be in the differential 
diagnosis in patients presenting with unexplained altered mental status change, visual 
disturbances, seizure or other CNS findings. RPLS is potentially reversible, but timely 
correction of the underlying causes, including control of blood pressure and interruption of 
the offending drug, is important in order to prevent progression to irreversible tissue damage.
1.2.2.16
Infusion-Related Reactions  
Infusion reactions with bevacizumab were uncommon (<3%) and rarely severe (0.2%). 
Infusion reactions may include rash, urticaria, fever, rigors, hypertension, hypotension, 
wheezing, or hypoxia. Currently, there is no adequate information on the safety of 
retreatment with bevacizumab in patients who have experienced severe infusion-related 
reactions.
1.2.2.17
Fertility and Pregnancy 
Clinical data are lacking regarding the immediate or long-term effect of bevacizumab on 
fertility and pregnancy. Ovarian failure, which is defined as amenorrhea lasting 3 or more 
months, FSH level greater than or equal to 30 mIU/mL and a negative serum β-HCG 
pregnancy test, was prospectively evaluated in a subset study of 179 women receiving 
mFOLFOX alone (N= 84) or mFOLFOX with bevacizumab (N=95) as part of the NSABP C-
08 trial for adjuvant stage II and III colorectal cancer, a use for which bevacizumab is not 
approved.  New cases of ovarian failure were identified in 34% (32/95) of women receiving 
bevacizumab in combination with chemotherapy compared with 2% (2/84) of women 
receiving chemotherapy alone [relative risk of 14 (95% CI 4, 53)].  After discontinuation of 
bevacizumab treatment, recovery of ovarian function was demonstrated in 22% (7/32) of 
these women.   Additionally, bevacizumab is known to be teratogenic and detrimental to fetal 
development in animal models. Bevacizumab may alter corpus luteum development and 
endometrial proliferation, thereby having a negative effect on fertility. As an IgG1, it may 
also be secreted in human milk. Therefore, fertile men and women on bevacizumab studies 
must use adequate contraceptive measures (hormonal or barrier method of birth control; 
abstinence) and women should avoid breast feeding.
1.2.2.18
Immunogenicity
As a therapeutic protein, there is a potential for immunogenicity with bevacizumab. With the 
currently available assay with limited sensitivity, high titer human anti-bevacizumab 
antibodies have not been detected in approximately 500 patients treated with bevacizumab.
1.2.2.19
Neutropenia
Increased rates of severe neutropenia, febrile neutropenia, or infection with severe 
neutropenia (including some fatalities) have been observed in patients treated with some 
myelotoxic chemotherapy regimens plus bevacizumab in comparison to chemotherapy alone 
(Sandler et al. 2006).
1.2.2.20
Osteonecrosis of the Jaw
Osteonecrosis of the jaw (ONJ) has been reported in patients receiving bevacizumab, but not 

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bisphosphonates, in the postmarketing setting.  The pathogenesis of the osteonecrosis is 
unclear.
1.2.2.21
Changes in Blood Chemistries
Hypophosphatemia and hypoalbuminemia have been seen in patients taking bevacizumab.
1.2.2.22
Changes in Thyroid Hormone Levels
Hypothryoidism has been seen in patients taking bevacizumab
1.2.3
Erlotinib
1.2.3.1
Erlotinib: Background
Epidermal Growth Factor Receptor Expression and Significance in Cancer
The control of cell growth is mediated by a complex network of signaling pathways 
responsive to external influences, such as growth factors, as well as to internal controls and 
checks.  Epidermal growth factor (EGF) was one of the first growth factors to be described.  
It was shown to be mitogenic, an effect mediated by the binding of EGF (or other ligands) to 
the cell surface EGF receptor (EGFR), stimulating autophosphorylation of the intracellular 
tyrosine kinase domain of the receptor.  Subsequent investigations revealed EGFR to be one 
of a family of closely related receptors that includes EGFR (HER1), HER2, HER3, and 
HER4.  
EGFR and other HER family members are considered to be important in the development, 
progression, and aggressive behavior of human epithelial malignancies and to be relevant 
therapeutic targets.  A number of human malignancies are associated with aberrant or 
over-expression of EGFR.(20)  Stimulation of tumor cells via the EGFR is important for both 
tumor growth and tumor survival in vivo.  Over-expression of EGFR in certain human 
tumors, including non–small cell lung carcinoma (NSCLC), has been correlated with both 
chemo-resistance and poor prognosis. (21-32)  Inhibitors of EGFR tyrosine kinase activity 
have been in development for a number of years, and although earlier compounds lacked 
specificity and potency, newer compounds have proven active in nonclinical and clinical 
studies.
Erlotinib (previously known as OSI-774) is an orally active, potent, selective inhibitor of the 
EGFR tyrosine kinase.  Early clinical data with erlotinib indicate that the compound is 
generally safe and well tolerated at doses that provide the targeted effective concentration 
based on nonclinical experiments.  A recently completed, randomized, double-blind, placebo-
controlled trial has shown that erlotinib as a single agent significantly improves the survival 
of patients with incurable Stage IIIb/IV NSCLC who have failed standard therapy for 
advanced or metastatic disease.(33)
1.2.3.2
Erlotinib: Preclinical Data – Toxicology
Toxicology studies have been performed in mice, rats (up to 6 months), dogs (up to 1 year), 
and monkeys (1 week).  Treatment-related effects observed in at least one species or study 
included effects on the cornea (atrophy, ulceration), skin (follicular degeneration and 
inflammation, redness, and alopecia), ovary (atrophy), liver (necrosis), kidney (papillary 
necrosis and tubular dilatation), lacrimal glands (atrophy), salivary glands (atrophy), 

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mandibular lymph nodes (inflammation), spleen (hematopoiesis), gastrointestinal tract 
(delayed gastric emptying and diarrhea), and embryo-fetal toxicity.  Red blood cell 
parameters were decreased, and white blood cells (primarily neutrophils) were increased.  
There were treatment-related increases in ALT, AST, triglyceride and bilirubin and decreases 
in albumin; increases in bilirubin were likely caused by a treatment-related impairment of 
bilirubin metabolism.
1.2.3.3
Erlotinib: Phase I Clinical Studies
Phase I trials of erlotinib explored both schedule and dose to evaluate the safety, tolerability, 
and pharmacokinetic profile of the compound given as a single agent.  A number of 
pharmacokinetic trials in healthy subjects have been conducted, along with three classic 
Phase I trials in patients with advanced cancer.  The single-agent maximum tolerated dose 
(MTD) was estimated to be 150 mg administered once daily.  
Cigarette smoking has been shown to reduce erlotinib exposure by 50-60%.  The MTD of 
erlotinib in NSCLC patients who currently smoke cigarettes was 300mg.  Efficacy and long 
term safety of a dose higher than the recommended starting doses have not been established 
in patients who continue to smoke cigarettes.  Smokers should be advised to stop smoking.
The primary toxicities of single-agent erlotinib consisted of rash (dermatosis), diarrhea, 
nausea, fatigue, stomatitis, vomiting, and headache.  When given daily, dose-limiting toxicity 
(diarrhea) was observed at 200 mg/day.  At 150 mg/day, diarrhea was manageable with the 
addition of loperamide therapy; this dose was considered the maximal tolerated dose. 
Rash (variously referred to as dermatitis, acneiform rash, or maculopapular rash) has been 
variable in onset, duration, and severity, but typically appears on the face, neck, scalp, chest, 
and back starting after ~1 week of treatment.  The mechanistic basis of the rash remains 
uncertain; histopathologic examination of biopsies of the rash demonstrated inflammatory 
cell infiltrate and mild epidermal hyperproliferation.  In some cases, the rash gradually 
improved despite continued dosing and, in general, resolved without sequelae following 
erlotinib discontinuation.  The rash did not result in study discontinuation in patients with 
cancer in the Phase I trials.  Laboratory abnormalities observed infrequently with single-
agent erlotinib involved primarily liver function tests, including elevation of ALT, AST, 
and/or bilirubin.
Selection of the 150 mg/day dose of erlotinib for subsequent single-agent studies was 
based on pharmacokinetic parameters, as well as the safety and tolerability profile of 
this dose in Phase I trials in heavily pretreated patients with advanced cancer.  Drug 
levels seen in patients with cancer receiving the 150 mg/day dose were consistently 
above the average plasma concentration of 500 ng/mL targeted for clinical efficacy.
1.2.3.4
Erlotinib: Pharmacokinetic Studies and metabolism
Erlotinib, a quinazoline, directly and reversibly inhibits the human EGFR tyrosine kinase 
with an IC50 of 2 nM (0.79 ng/mL) in an in vitro enzyme assay and reduces EGFR 
autophosphorylation in intact tumor cells with an IC50 of 20 nM (7.9 ng/mL).  This potent 
inhibition is selective for the EGFR tyrosine kinase both in assays assessing the effects of 

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erlotinib on a variety of other isolated tyrosine kinases and in cellular bioassays designed to 
isolate this functional pathway.  Erlotinib is designed to inhibit EGF dependent proliferation 
of cells at submicromolar concentrations and blocks cell cycle progression in the G1 phase. 
Data on drug exposure and anti-tumor responses in human tumor xenograft models (HN5 and 
A431) were analyzed in order to estimate the plasma concentration of erlotinib associated 
with anti-tumor activity.  Based on these efficacy models, the minimum steady-state plasma 
concentration targeted for clinical activity in humans is projected to be 500 ng/mL.
Oral erlotinib is well absorbed and has an extended absorption phase, with mean peak plasma 
levels occurring at 3 hours after oral dosing of 150 mg/dL at steady state.  A study in healthy 
subjects provided an estimate of bioavailability of 59% (95% CI:  55%, 63%).  The time to 
reach steady-state plasma concentration was ~5 days.  The accumulation ratio with daily 
dosing of erlotinib was estimated to be 2.0.  From a population pharmacokinetic analysis of 
708 patients, the median trough concentration (Cmin) 24 hours following the previous dose 
was 1041 (697) ng/mL.  Median AUC achieved during the dosing interval at steady state 
was 19,801 ng  hr/mL.  Exposure after an oral dose is increased by food.  
There is extensive binding of erlotinib and metabolites to both serum albumin and AAG 
(alpha-1-acid glycoprotein), with total plasma protein binding for erlotinib and OSI-420 of 
~95% and 91%, respectively.  Erlotinib is extensively metabolized in the liver by the hepatic 
cytochromes in humans–primarily by CYP3A4 and to a lesser extent by CYP1A2.  The 
primary metabolite of erlotinib, OSI-420, has potency comparable to that of erlotinib, but is 
present at levels that are  10% of erlotinib levels.  Erlotinib is excreted predominantly via 
the feces ( 90%).  The elimination half-life after a 150-mg oral dose is ~30 hours.  In 
population-based data analyses, no relationships were identified between predicted steady-
state trough concentration and patient age, body weight, sex, ethnicity, or creatinine 
clearance.
1.2.3.4.1 Erlotinib Drug Interactions
Erlotinib is both protein bound (92%–95%) and metabolized by hepatic cytochromes 
CYP3A4 and CYP3A5 and pulmonary cytochrome CYP1A1.  Therefore, a potential for 
drug–drug interaction exists when erlotinib is co-administered with drugs that are highly 
protein bound or that are CYP3A4 inhibitors/inducers.  Co-administration of erlotinib with 
omeprazole, a proton pump inhibitor, decreased the exposure of erlotinib (AUC) by 46% and 
the maximum concentration (Cmax) by 61%. There was no change to Tmax or half-life.  
Therefore, drugs that alter the pH of the GI tract may alter the solubility of erlotinib and 
hence its bioavailability.
The exposure to erlotinib (AUC) increased to a moderate extent, by 39%, and the maximum 
concentration (Cmax) by 17%, when erlotinib was co-administered with ciprofloxacin, an 
inhibitor of both CYP3A4 and CYP1A2.
Co-administration of erlotinib with an inhibitor of CYP3A4 metabolism (ketoconazole, 200 
mg po BID for 5 days) resulted in increased exposure to erlotinib as measured by an 86% 
increase in median erlotinib AUC and a 69% increase Cmax, compared with administration 
of erlotinib alone.
Induction of CYP3A4 metabolism by a known enzyme inducer (rifampin, 600 mg po QD for 
7 days) resulted in a 69% decrease in the median erlotinib AUC, compared with 

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administration of erlotinib alone.  However, the effect of rifampin on Cmax was negligible.  In 
another study, rifampicin pretreatment followed by co-administration of rifampicin with a 
single 150 mg dose of erlotinib resulted in a mean erlotinib exposure (AUC) that was 57.6% 
of that observed following a single 150 mg erlotinib dose in the absence of rifampicin 
treatment.  Therefore, a potential for drug-drug interaction exists when erlotinib is co-
administered with drugs that are highly protein bound or that are potent CYP3A4 inhibitors 
or inducers.
International normalized ratio (INR) elevations and/or bleeding events have been reported in 
some cancer patients while on erlotinib alone and in combination with other 
chemotherapeutic agents, and concomitant NSAIDS or anticoagulants, including warfarin.
 Please refer to Appendix C for a listing of interacting drugs.
1.2.3.4.2 Erlotinib Use in Hepatic and Renal Impairment
The influence of hepatic metastases and/or hepatic dysfunction on the pharmacokinetics of 
erlotinib is not yet known.  However, erlotinib is cleared predominately by the liver, and 
caution should be used when administering erlotinib to patients with hepatic dysfunction. 
Erlotinib is also a strong inhibitor of the UDP-glucuronosyltransferase UGT1A1 enzyme 
responsible for the glucuronidation of bilirubin.  Hyperbilirubinemia appears most often to be 
a side effect related to genetic polymorphisms of UGT1A1.  Rare cases of hepatic failure 
(including fatalities) have been reported during the postmarketing use of erlotinib.  
Confounding factors for severe hepatic dysfunction have included pre-existing liver disease 
such as cirrhosis, viral hepatitis, hepatocellular carcinoma, hepatic metastases, or 
concomitant treatment with potentially hepatotoxic drugs.
A study comparing the pharmacokinetics of erlotinib in patients with moderately impaired 
hepatic function with patients with normal hepatic function showed no significant difference 
in exposure suggesting that no dose modification is necessary for moderately hepatic-
impaired patients.  Caution, however, may need to be exercised in these patients as authors of 
an independent study performed by a collaborative group recommended an erlotinib dose of 
75 mg daily in patients with hepatic dysfunction. 
Rare cases of myocardial infarction (including fatalities) have been reported during the 
postmarketing use of erlotinib. No clinical studies have been conducted in patients with 
compromised renal function since erlotinib and its metabolites are not significantly excreted 
by the kidneys.
1.2.3.5
Erlotinib: Phase II / III Clinical Studies
Multiple Phase II trials evaluating the safety, tolerability, and antitumor activity of erlotinib 
have been conducted in patients with advanced, refractory malignancies including cancer of 
the head and neck, lung, aerodigestive tract, ovary, breast, central nervous system (glioma), 
and others. Erlotinib has been evaluated both as a single agent and administered concurrently 
with conventional chemotherapy agents using various doses and schedules.    
Evidence of activity has been observed in squamous cell carcinoma of the head and neck, 
ovarian, breast and pancreatic carcinoma, non–small cell lung cancer (NSCLC), and 

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glioblastoma multiforme (GBM).  Patients received 150 mg/day of erlotinib in all of these 
studies except the GBM study where dose escalation was allowed until limited by rash and 
where a higher starting dose was tested in subjects receiving concomitant enzyme inducing 
anti-epileptic drugs.  Dose reduction was allowed in all studies in the case of intolerance.  
Diarrhea was treated with loperamide therapy and/or dose reduction.  Rash was treated with a 
variety of agents, including oral and topical antibiotics, corticosteroids, and other agents.  
Patients receiving erlotinib in combination with various chemotherapy agents have generally 
experienced the same type of adverse events (AEs) as with either agent alone.  
The first randomized placebo controlled trial to demonstrate a survival advantage for an 
EGFR inhibitor was the Phase III study, BR21.  This international trial, conducted by the 
National Cancer Institute of Canada Clinical Trial Group (NCIC CTG), included 731 patients 
with incurable Stage IIIb/IV NSCLC who have failed standard therapy for advanced or 
metastatic disease.  Patients randomized in a 2:1 ratio to single-agent erlotinib 150 mg/day 
obtained a 42.5% improvement in median survival over placebo, from 4.7 to 6.7 months.  
The one-year survival increased significantly (from 22% to 31%) as did the median and 6 
month PFS, response rate, and the time to deterioration of tumor related symptoms of pain, 
cough, and dyspnea.(33)  
In BR-21, of the 727 patients evaluable for safety (485 erlotinib, 242 placebo), the most 
common AEs in the erlotinib arm were rash (75% erlotinib, 17% placebo), diarrhea (54% 
erlotinib, 18% placebo) and stomatitis (17% erlotinib, 18% placebo) events.  The majority of 
these events were mild to moderate in severity.  The incidence of interstitial lung disease 
(ILD) reported was the same in the placebo and erlotinib groups at 0.8% in each arm.
Two large, Phase III, randomized studies in first-line NSCLC patients evaluated erlotinib in 
combination with platinum-based two-drug combination chemotherapy.  A total of 1079 
previously untreated patients received carboplatin/paclitaxel with either erlotinib or placebo 
in the TRIBUTE trial (OSI2298g) conducted in the United States.  An additional 1172 
patients received cisplatin/gemcitabine plus either erlotinib or placebo in the TALENT trial 
(BO16411) conducted in 27 countries in Europe and other ex-U.S. locations.  Neither study 
met its primary endpoint of improved overall survival or a secondary endpoint of improved 
time to disease progression or overall response rate.  Overall, the number of adverse events 
and serious adverse events were well balanced between the two arms of each study, with two 
exceptions.  As expected, rash and diarrhea occurred more frequently in the erlotinib arms.  
In the TRIBUTE study, more serious adverse events resulting in death were seen in the 
erlotinib arm compared with the placebo arm (53 vs. 27).  Most of the apparent imbalance 
was due to events reported as pneumonia or progression of underlying cancer.(34, 35)
The efficacy of erlotinib as a single agent in previously untreated NSCLC patients with 
somatic EGFR mutations was evaluated in a randomized study in Europe. Patients were 
randomized to receive either erlotinb (N=86) or a standard chemotherapy doublet (n=88). 
Patients treated with erlotinib had a significantly better PFS (10.4 vs 5.2 months, HR= 0.34, 
CI0.23-0.49) and higher overall response rate (65% vs 16%). Based on these data, erlotinib 
has been approved by the US FDA for first line treatment of NSCLC bearing EGFR 
mutations (Del exon 19, or L858R mutations).

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1.2.3.6
Erlotinib: Toxicities/Adverse Events
Common adverse events associated with erlotinib administration include rash and diarrhea.  
Other common adverse events include nausea/vomiting, mucositis/ stomatitis, headache, and 
fatigue. 
a) Rash: A rash occurred in 75% of erlotinib-treated NSCLC patients enrolled in BR.21.  
Similar incidences of rash have occurred when erlotinib was administered 
concurrently with chemotherapy including gemcitabine, paclitaxel/carboplatin, and 
gemcitabine/cisplatin. A papular, pustular rash manifesting most often on the face and 
upper trunk was common across all studies, but rash was rarely the cause of study 
drug discontinuation. Other dermatologic manifestations reported in clinical studies 
or postmarketing use of erlotinib include nail changes, paronychia, painful fissures or 
cracking of the skin on the hands and feet, and hair growth abnormalities (alopecia, 
thinning hair, eyelash/eyebrow changes, hirsutism). Bullous and exfoliative skin 
disorders, including fatalities, have been reported, albeit rarely.
b) Although the rash may resemble acne, it is histopathologically different.  The skin 
reaction commonly occurs on the face, upper chest and back, but may be more 
generalized with desquamation.  Associated symptoms may include itching, 
tenderness and/or burning, or dry skin.  The following agents have been used to treat 
rash:  alcohol-free emollient cream, diphenhydramine, topical or oral corticosteroids, 
and topical (clindamycin) or oral antibiotics (tetracycline, minocycline, doxycycline) 
with anti-inflammatory properties.  The median time to onset of skin rash was 8 days.
c) Ocular: Contact lens use while receiving erlotinib therapy is not recommended due to 
potential ocular effects such as conjunctivitis, keratoconjunctivitis sicca, corneal 
ulceration and perforation.  
d) Diarrhea: The incidence of diarrhea in BR.21 was 54% of erlotinib-treated NSCLC 
patients.  The median time to occurrence of first diarrheal symptom was 9 days. 
e) Pulmonary: There have been infrequent reports of serious (including fatal) interstitial 
lung disease (ILD) in patients receiving erlotinib for treatment of NSCLC or other 
advanced solid tumors.  In Study BR.21, the incidence of ILD (0.8%) was the same in 
the placebo and erlotinib groups.  The overall incidence in erlotinib-treated patients 
from all studies (including uncontrolled studies and studies with concurrent 
chemotherapy) is approximately 0.6%.  Included in this rate of ILD are reported 
diagnoses of pneumonitis, radiation pneumonitis, hypersensitivity pneumonitis, 
interstitial pneumonia, interstitial lung disease, obliterative bronchiolitis, pulmonary 
fibrosis, acute respiratory distress syndrome, alveolitis, and lung infiltration, 
irrespective of investigator assessed causality.  Most of the cases were associated with 
confounding or contributing factors such as concomitant/prior chemotherapy, prior 
radiotherapy, preexisting parenchymal lung disease, metastatic lung disease, or 
pulmonary infections.
f)
Renal: Rare cases of acute renal failure or renal insufficiency have been reported 
(including fatalities).  Many of these cases have been associated with dehydration 
associated with nausea, vomiting, diarrhea, and/or anorexia.  There have been rare 
reports of renal failure in patients receiving erlotinib in combination with platinum-

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containing chemotherapy regimens.
g) Other side effects: Other side effects noted in studies with erlotinib (with or without 
chemotherapy) include:
h) Events occurring in >10% of subjects-Fatigue, anorexia, nausea, vomiting, 
dehydration, stomatitis, infections, pruritus, dry skin, abdominal pain, weight loss, 
edema, constipation, fever, myalgia, depression, anxiety, dyspepsia, dizziness, 
headache, insomnia, neuropathy, alopecia, elevations in AST, ALT and bilirubin 
decreases in phosphate and albumin.
i)
Hepatic failure and hepatorenal syndrome, GI perforation, cerebrovascular accidents, 
myocardial infarction and microangiopathic hemolytic anemia have also been 
reported in patients taking erlotinib.
1.2.4
Erlotinib and Bevacizumab Combination
1.2.4.1
Erlotinib and Bevacizumab Combination: Background
EGFR and VEGF are both involved with downstream angiogenic pathways, both directly and 
indirectly affect tumor cells.  VEGF is downregulated by EGFR inhibition, and VEGF has 
been shown to inhibit EGFR autocrine signaling.(36, 37)  Preclinical data in xenograft 
models using combinations of various EGFR and VEGF inhibitors demonstrate much greater 
anti-tumor activity than inhibitors of either alone.(38-41)
1.2.4.2
Erlotinib and Bevacizumab Combination: Phase I Clinical Trials/ Dosing 
Rationale/ Pharmacokinetics
A phase I/II clinical trial with combination bevacizumab and erlotinib in NSCLC by Herbst 
et al.(35) in non-small cell lung cancer patients determined the phase II doses to be erlotinib 
150mg/day orally plus bevacizumab 15mg/kg intravenously every 21 days.  Doses 
considered the highest single-agent dose of both agents were able to be used, since no dose-
limiting toxicities or serious adverse events were observed in the phase I cohort of 12 
patients.  No pharmacokinetic interaction was observed between bevacizumab and erlotinib. 
All PK parameters estimated for erlotinib were similar to those reported by Hidalgo et al., 
and erlotinib exposure in the presence of bevacizumab after a single dose was similar to 
single-agent erlotinib for both 100mg and 150mg.(35, 42) 
In the phase I cohort, 7 of 12 patients developed grade 1 or 2 proteinuria, and 2 of 12 had 
grade 1 epistaxis.  No treatment related grade 3 or 4 toxicities were reported, and no 
maximum tolerated dose was reached.  In the phase II portion cohort of 34 patients, the most 
common adverse events, regardless of attribution to the drugs, were: rash (85%), diarrhea 
(65%), hematuria (32%), infection (29%), proteinuria (9%), and epistaxis (6%).  There were 
several serious adverse events: two patients had grade 3 hypertension, managed with 
antihypertensives; one patient’s grade 3 hypertension resolved when bevacizumab was 
discontinued (erlotinib was maintained); one grade 3 rash, which resolved to grade 1 with 
dose reduction of erlotinib (bevacizumab was maintained); one grade 3 pruritus, which 
resolved to grade 2 with 2 days of treatment; three cases of grade 3 or 4 pneumonia.(35) 
An second phase I/II trial by Vokes et al.(43) in squamous cell  head and neck cancer patients 
confirmed the tolerability of fixed doses of erlotinib at 150mg orally daily and bevacizumab 

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15mg/kg every 3 weeks intravenously, with no dose limiting toxicities seen in the phase I 
cohort.  However, serious hemorrhage events occurred in 3 patients; 1 patient with grade 4 
bleed at a tumor site during a later cycle of phase I cohort, 1 patient with grade 3 at a known 
tumor site in phase II, and 1 grade 5 fatal bleed at a laryngeal vessel (not known to have 
tumor involvement) during phase II.  No other grade 4 or 5 toxicities were seen.  Other grade 
2-3 toxicities seen in the 48 patients enrolled in both phase I and II were: rash (42%), 
diarrhea (19%), fatigue (24%), bleeding (4%, including the grade 3 mentioned above but not 
the grade 4 and 5), infection (20%), grade 2 only stomatitis (4%), and grade 2 only nausea 
(4%). 
1.2.4.3
Erlotinib and Bevacizumab Combination: Phase II Clinical Trials
Several phase II clinical trials have demonstrated encouraging data with good PR rates and 
stable disease rates in otherwise refractory patients.  Herbst et al. (44) in a randomized three-
arm Phase II trial in second line treatment of recurrent NSCLC patients using the 
combination bevacizumab plus erlotinib vs. bevacizumab plus chemotherapy vs. 
chemotherapy alone, found that CR/PR responses were 17.9%, 12.5%, and 12.2% 
respectively.  However, although there was no significant difference in PFS and OS between 
bevacizumab-erlotinib and bevacizumab-chemotherapy, the median OS times were 13.7, 
12.6, and 8.6 months respectively.(44)
1.2.4.3.1 Current Study
As of December, 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 65% (13/20 confirmed PRs) and that in cohort 2 was 29% (6/21 
confirmed PRs). Additionally, there was one unconfirmed partial responder in cohort 2.  The 
median PFS in cohort 1 was 24.2 months [95% CI 12.8 - ], while that in cohort 2 was 7.4 
months [95% CI 3.73 – 10.2]. 
Additional response and PFS data (interim) are summarized in the table below.
Summary of Results
Best Response by RECIST 
Cohort 1 
[HLRCC] (%)
Cohort 2 [Non-
HLRCC] (%)
Total (%)
Complete response (CR)
0
0
0
Confirmed Partial response 
(PR)
13 (65%)
6 (29%)
18 (44%)

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Summary of Results
Overall Response Rate
65%
29%
44%
Stable disease (SD)
7 (35%)
12 (57%)
20 (49%)
Progressive disease (PD)
0
3 (14%)
3 (7%)
Disease Control Rate 
(SD+PR)
100%
86%
93%
Median Progression Free 
Survival –Months [95%CI]
24.2
[95% CI 12.8 - 
]
7.4
[95% CI 3.73 – 10.2]
12.8
[95% CI 7.47 – 
26.3]
The regimen was well tolerated with an adverse event profile largely consistent with that 
previously described with this combination. The most commonly seen grade 3-4 adverse 
events included hypertension (24%) and proteinuria (12%). One patient died from 
complications arising from an upper gastrointestinal hemorrhage deemed possibly related to 
bevacizumab. 
1.2.4.4
Erlotinib and Bevacizumab Combination: Toxicities
The simultaneous blockade of the EGFR pathway with a RTK inhibitor and an anti-VEGF 
antibody with the combination of bevacizumab and erlotinib may provide a potentially 
synergistic therapeutic effect.  However, this has not shown to result in increased toxicity. 
Several phase II clinical trials have now been reported using the combination at the highest 
single-agent doses with tolerable toxicity profiles, and toxicities correspond directly with 
those seen in either agent alone.
The most common adverse events have been rash, diarrhea, infection, hematuria, and 
proteinuria.  Rash has been attributed as a class-effect toxicity seen in erlotinib, similar to 
other EGFR-targeted agents.  Bevacizumab has been associated with tumor bleeding (which 
can be life-threatening, especially in squamous cell histology), hypertension, proteinuria, 
asthenia, headache and nausea.  
Phase II clinical trials have consistently reported similar toxicity profiles to those seen in 
both agents alone.  Hainsworth et al.(45) reported in a Phase II trial of bevacizumab and 

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erlotinib in carcinomas of unknown primary that the most common toxicities were acneiform 
rash, diarrhea, and fatigue.  Treatment related toxicities in 50 patients were as follows: grade 
3 fatigue (16%), grade 3 and 4 rash (10%), grade 3 diarrhea (8%), grade 3 nausea and 
vomiting (8%), grade 3 and 4 proteinuria (6%), grade 3 bleeding (2%), grade 3 
thrombocytopenia (2%), grade 3 pruritus (2%), grade 3 and 4 stomatitis (4%), grade 1 and 2 
edema (10%), grade 1 and 2 neutropenia (12%), grade 1 and 2 hypertension (6%), and grade 
1 and 2 hypersensitivity reaction (2%).  One patient had grade 5 exfoliative dermatitis and 
mucositis leading to septicemia and death.
By organ system, toxicities for both erlotinib and bevacizumab, either as single agents or in 
combination, include:

Neurologic – Headache, asthenia, pain, reversible posterior leukoencephalopathy 
syndrome

Cardiovascular – hypertension (including hypertensive crisis), hypotension, 
congestive heart failure, supraventricular arrhythmias, ventricular fibrillation, 
myocardial ischemia/infarction, left ventricular dysfunction 

Gastrointestinal – diarrhea, nausea, vomiting, constipation, gastrointestinal 
perforation, fistulae formation, mucositis and stomatitis, liver function test 
abnormalities, anorexia, colitis, dyspepsia, ileus, anastamosis leak, peptic ulcer

Hematological – bleeding (including life-threatening and fatal hemorrhage, especially 
tumor-associated bleeding, including intracranial bleeding, pulmonary hemorrhage, 
and gastrointestinal bleeding), arterial thromboembolic events (including 
cerebrovascular accidents, transient ischemic attacks, myocardial infarctions, and 
visceral arterial ischemia), venous thrombotic events (including pulmonary emboli, 
deep venous thromboses, and thrombophlebitis), epistaxis, mucocutanous bleeding, 
leucopenia, neutropenia, thrombocytopenia, anemia

Renal/GU – proteinuria (including nephritic syndrome), acute renal failure, fistula

Dermatological –rash (most often acneiform), dermatitis (including exfoliative 
dermatitis/exfoliation), wound dehiscence and wound healing complications, 
ulceration, alopecia

Pulmonary – dyspnea, interstitial lung disease, bronchospasm, cough, fistula, voice 
changes 

ENT- allergic rhinitis, paranasal sinus reactions (including septal perforation), dry 
mouth/xerostomia, dysgeusia

Ocular – episcleritis and other ocular surface disease, dry eyes

General – fatigue, hypersensitivity and infusion reaction, dehydration, edema, 
pruritus, infection, fever, chills, weight loss, pain

Metabolic/Laboratory – elevations in alkaline phosphatase, tansaminases, bilirubin, 
creatinine, and proteinuria

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1.2.5
Rationale for proposed clinical trial
The recognition that HIF upregulation may play an important role in the formation and 
propagation of renal cancer associated with HLRCC suggests that interventions directed 
against components of this pathway, such as VEGF and TGF-α/EGFR, may be of benefit in 
this patient population. 
In pre-clinical studies, Isaacs, et al. noted that when the HLRCC gene (fumarate hydratase) is 
inactivated in cells, fumarate over-accumulates and competes with 2-oxyglutarate, the co-
enzyme for the HIF prolyl hydroxylase.(5) This results in a VHL-independent mechanism for 
HIF accumulation.  Furthermore, oxidative phosphorylation is severely compromised in these 
tumors due to the mutation of both copies of a critical Krebs’ cycle enzyme.  Therefore, for 
survival, these tumor cells are totally dependent on glycolysis for energy production and are 
exquisitely sensitive to ambient glucose concentration.  We hypothesize that in addition to 
inhibiting angiogenesis, bevacizumab/anti-VEGF- based regimens might permit us to exploit 
the dependence of these tumors on glucose by impairing delivery of this critical metabolic 
substrate. We have also developed an HLRCC kidney cancer cell line (UOK262), derived 
from a primary renal tumor in an HLRCC patient. This cell line requires a high ambient 
glucose concentration for survival, a feature that is consistent with impairment of aerobic 
metabolism. 
These preclinical data suggest that simultaneous targeting of vascular (VEGF, with 
bevacizumab) as well as autocrine growth (EGFR, erlotinib) pathways downstream from HIF 
provides an opportunity to affect tumor growth in kidney cancer associated with this rare 
hereditary cancer syndrome. 
Additionally, the UOB/NCI follows several patients with metastatic RCC associated with 
HLRCC. These patients have generally proven to be refractory to a variety of interventions 
including cytokines and standard cytotoxic chemotherapy. On the other hand, we have 
observed evidence of antitumor activity with combined VEGF/EGFR blockade in these 
patients. We recently undertook a retrospective review of fifteen metastatic HLRCC patients 
followed on UOB diagnostic/natural history protocols (unpublished data). Five of these 
patients had received bevacizumab in combination with an EGFR antagonist (erlotinib in 
four patients and gefitinib in one). Of these, one patient had a complete response (CR) and 
continues to be disease free over 2 years following initiation of therapy; two patients had a 
partial response (including regression of large liver mets and adenopathy) lasting 18-24 
months, while two other patients have had stable disease (15+ and 21+ months respectively), 
including one who had previously failed single agent erlotinib, several chemotherapeutic and 
an anti-VEGF TKI regimen. In contrast, no responses were seen in patients receiving a 
variety of ‘conventional’ agents including interferon, interleukin and cytotoxic 
chemotherapy. 
The combination of bevacizumab and erlotinib has been studied in patients with clear cell 
RCC and appears to be associated with manageable toxicity at doses proposed in this LOI. In 
a single arm phase II study, Hainsworth et al. demonstrated a 25% objective response rate in 
patients with metastatic clear cell RCC receiving this combination, which is significantly 
higher than the response rate expected with either agent alone.(46) However, a subsequent 
randomized placebo-controlled Phase II clinical trial failed to demonstrate superiority of the 
combination over bevacizumab alone (no significant differences in PFS, RR or OS) in 

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metastatic clear cell RCC.(47)  While this latter study has dampened enthusiasm for 
combined VEGF/EGFR blockade in clear cell RCC, its relevance to patients with non-clear 
cell histology as well as in molecularly well defined clear cell RCC subsets (i.e those with 
VHL inactivation vs those without) remains to be determined. Clear cell and 
papillary/HLRCC-associated RCC are clinically and histologically distinct entities and are 
driven by disparate genetic/molecular defects. Hence, although HIF upregulation occurs as a 
consequence of both VHL (clear cell RCC) and FH inactivation (HLRCC), there are 
doubtless other, as yet incompletely understood mechanisms/pathways that contribute to the 
differences observed in these two subtypes of RCC. The NCI clinical experience with dual 
VEGF/EGFR blockade in HLRCC (outlined above), combined with preclinical evidence 
suggesting upregulation of both VEGF and TGF- α /EGFR pathways provides a sufficiently 
compelling argument for the evaluation of bevacizumab/erlotinib in this patient population. 
While we have considered comparing bevacizumab alone or in combination with erlotinib in 
consecutive single arm trials or in a randomized phase II trial as appealing alternatives, the 
relative rarity of this disease makes the proposed dual agent single arm study the most 
feasible study. 
As part of this study, we also propose to evaluate the activity of this regimen in patients with 
sporadic papillary RCC, in whom there is no evidence of a heritable germline FH defect. 
There are currently no standard treatment options for patients with unresectable papillary 
RCC; single agent anti-VEGFR or anti-EGFR tyrosine kinase inhibitors appear to have 
modest single agent activity. Given the relatively recent recognition of this entity, we 
propose to explore the possibility that some variants of sporadic papillary RCC may share 
common clinical/molecular features with HLRCC-associated renal tumors that may render 
them amenable to treatment with this regimen. As part of this trial, an attempt will be made 
to further characterize these sporadic tumors, particularly with regard to the prevalence of 
somatic FH inactivation and VEGF/EGFR pathway activation.
2
ELIGIBILITY ASSESSMENT AND ENROLLMENT 
2.1
Eligibility Criteria 
2.1.1
Inclusion Criteria
Patients must meet all the following criteria to be eligible for study enrolment:

Diagnosis of advanced RCC associated with HLRCC (cohorts 1 & 3) or sporadic/non-
HLRCC papillary RCC (cohort 2 & 4) 

Measurable disease, as outlined in RECIST 1.1 

No more than two prior regimens targeting the VEGF pathway; no prior bevacizumab 
therapy

Age  18 years. 

Performance status ECOG 0-2

Patients must have normal organ and marrow function as defined below: WBC count  
3,000/uL, absolute neutrophil count  1,500/uL, platelet count 100,000/uL, serum 
creatinine ≤ 2x  upper limit of reference range or creatinine clearance ≥ 30 ml/min, AST 

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and ALT <2.5 x upper limit of reference range, total bilirubin < 1.5x upper limit of 
reference range ( <3 x upper limit of reference range in patients with Gilbert’s disease), 
alkaline phosphatase ≤ 2.5 x upper limit of reference range (or ≤ 5 x upper limit of 
reference range if considered to be related to liver or bone metastases by the PI)

Recovery from acute toxicity of prior treatment for RCC (to ≤ grade 1 the active version 
of CTCAE or to a level permitted under other sections of Inclusion/ Exclusion criteria).  

At least 4 weeks from completion of major surgery and a healed surgical incision

Negative pregnancy test (within 7 days of enrolment) in women of childbearing potential

No myocardial infarction, GI perforation/fistula, intraabdominal abscess, cerebrovascular 
accidents within six months prior to study entry

No coagulopathy or bleeding diathesis

Ability to understand and the willingness to sign a written informed consent document.

Archival tissue block or unstained tumor tissue available for correlative studies
2.1.2
Exclusion Criteria

Prior invasive malignancy of other histology, with the exception of adequately treated 
basal or squamous cell carcinoma of the skin, or any other malignancy for which the 
patient does not currently require treatment and/or has no evidence of disease for >= 2 
years. 

Patients with known brain metastases unless treated with an appropriate modality with no 
evidence of progression/recurrence for >3months

Hypertension not controlled by medical therapy (resting systolic blood pressure greater 
than 140 mmHg or diastolic blood pressure greater than 90 mmHg on at least two 
occasions over a 24 hour period despite optimal medical management).

Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection 
requiring intravenous antibiotics, symptomatic congestive heart failure (New York Heart 
Association grade III or greater, Appendix B), unstable angina pectoris, or psychiatric 
illness/social situations that would limit compliance with study requirements. 

Serious, non-healing wound or ulcer; bone fracture within 3 months prior to study entry

Patient known to be HIV-positive and requiring antiretroviral therapy (due to the risk of 
potential drug interactions)

Concomitant therapy with potent inhibitors of CYP450 3A4 (e.g. ketoconazole, 
verapamil etc., see  Appendix C) or with potent CYP450 1A2 inhibitors 
(fluoroquinolone antibiotics including ciprofloxacin, levofloxacin, and norfloxacin; 
ticlodipine, cimetidine, amiodarone, etc. see Appendix C)

Pregnant women are excluded from this study because bevacizumab and erlotinib are 
anti-cancer agents with the potential for teratogenic or abortifacient effects.  Because 
there is an unknown but potential risk for adverse events in nursing infants secondary to 

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treatment of the mother with these agents, breastfeeding should be discontinued if the 
mother is treated on this study

All men and women of childbearing potential must be willing to use effective 
contraception as determined by the principal investigator (including but not limited to 
abstinence, hormonal contraceptives (birth control pills, injections, or implants), 
intrauterine device (IUD), tubal ligation, vasectomy) from the time of enrollment to at 
least six months following the last dose of drug

Any known hypersensitivity to bevacizumab, erlotinib or other excipients of these drugs

Documented baseline proteinuria >1000mg/day on 24 hour urine collection. Only 
patients with 1+ or greater proteinuria on UA and a spot urine protein:creatinine ratio of 
> 0.5 will undergo a 24 hour urine collection for quantitation of proteinuria.

Left ventricular ejection fraction <40% as measured on transthoracic echocardiogram.
2.1.3
Inclusion of Women and Minorities

Both men and women and members of all races and ethnic groups are eligible for this 
trial.
2.1.4
Recruitment Strategies
Participants in this study will be recruited through internal referral, our local physician 
referral base, through Cancer Hotline information, listing on cancer trial websites, and 
through a variety of other IRB-approved recruitment material sent to oncologists. This 
protocol may also be abstracted into a plain language announcement posted on NIH websites 
and on NIH social media forums.  
2.2
Screening Evaluation
Screening evaluation testing/procedures are conducted under the separate screening protocol, 
01C0129.
Subjects will be screened per Study Calendar.
2.3
Patient Registration and Status Update Procedures
Registration and status updates (e.g. when a participant is taken off protocol therapy and 
when a participant is taken off-study) will take place per CCR SOP ADCR-2, CCR 
Participant Registration & Status Updates found here.
2.3.1
Treatment Assignment Procedures
Cohorts
Number
Name
Description
1
Cohort 1
Patients with HLRCC

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2
Cohort 2
Patients with sporadic papillary RCC
3
Cohort 3
Patients with HLRCC (opened after cohorts 1 & 2 
closed)
4
Cohort 4
Patients with sporadic/non HLRCC papillary RCC 
(opened after cohorts 1 & 2 closed)
Arms
Number
Name
Description
1
Bevacizumab+ Erlotinib
All patients will be receiving fixed starting dose of 
bevacizumab (10 mg/kg IV every 2 weeks) and 
erlotinib (150 mg/day PO)
Subjects in cohorts 1, 2, 3 and 4 will be directly assigned to arm 1.
3
STUDY IMPLEMENTATION
3.1
Study Design
This is an open label, single arm phase II study utilizing a fixed starting dose of bevacizumab 
(10 mg/kg IV every 2 weeks) and erlotinib (150 mg/day PO). 
Treatment cycles will consist of 28 days; erlotinib will be administered daily on days 1-28, 
and bevacizumab every 2 weeks IV. There will be no break between 2 consecutive cycles 
(i.e., erlotinib administration will be continuous). 
The patient will return to the NIH Clinical Center to undergo clinical and laboratory 
evaluation prior to the start of each cycle. 
Patients will be evaluated radiologically for evidence of response or progression 
approximately 8 weeks after initiation of therapy, every 8 weeks thereafter for the first 32 
weeks, and then every 12 weeks while on treatment. Patients with evidence of disease 
response or stable disease will continue to receive therapy in the absence of serious toxicity.
In the event of a complete response, treatment will continue for 2 cycles beyond CR at which 
point consideration will be given to discontinuing both agents. Patients may be retreated at 
the discretion of the PI in the event of disease recurrence.
3.2
Drug Administration
3.2.1
Bevacizumab Administration
Patients will receive treatment with bevacizumab 10mg/kg, administered by intravenous 
infusion on days 1 and 15 of each 28 day cycle (+/- 3 days).  The initial dose of bevacizumab 
will be infused over 90 minutes +/- 15 minutes.  If well tolerated, the second infusion will be 

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over 60 +/- 10 minutes, and if tolerated, all subsequent infusions are to be administered over 
30 +/- 10 minutes. 
In the event of an infusion-related event, the infusion of bevacizumab should be stopped and 
held until resolution of acute symptoms. The PI or AI will be notified of the infusion-related 
event at the time of the occurrence. Upon resolution, the infusion may be restarted (as 
outlined in section 3.3.2) at a rate that will increase the total infusion time by 30 minutes 
beyond the current time. 
3.2.2
Erlotinib Administration
Erlotinib is to be administered orally at a daily dose of 150 mg initially. Patients are to take 
erlotinib at least 1 hour before or 2 hours after meals.
3.3
Treatment Modifications
3.3.1
General Plan to Manage Safety 
a) 
Bevacizumab-Specific
A number of measures will be taken to ensure the safety of patients participating in this trial.  
These measures will be addressed through exclusion criteria (see Section 2.1.2) and routine 
monitoring as follows.
Patients enrolled in this study will be evaluated clinically and with standard laboratory tests 
before enrolment on trial and at regular intervals during their participation in this study.  
Safety evaluations will consist of medical interviews, recording of adverse events, physical 
examinations, daily blood pressure monitoring, and laboratory measurements.  Patients will 
be evaluated for adverse events (all grades), serious adverse events, and adverse events 
requiring study drug interruption or discontinuation at each study visit for the duration of 
their participation in the study. Patients discontinued from the treatment phase of the study 
for any reason other than progression will be evaluated approximately three months after the 
decision to discontinue treatment as outlined under Off Study Criteria. (see Section 3.10.3).  
Specific monitoring procedures are as follows:

Hypertension will be monitored through routine evaluation of blood pressure prior to 
each bevacizumab treatment as well as by patient self-monitoring.  Optimal control of 
blood pressure according to standard public health guidelines is recommended for 
patients on treatment with or without bevacizumab.
Proteinuria will be monitored by urine protein:creatinine (UPC) ratio or dipstick at least 
every 2 weeks. 

If patients on treatment with bevacizumab require elective major surgery, it is 
recommended that bevacizumab be held for 4-8 weeks prior to the surgical procedure. 
Patients undergoing a major surgical procedure should not begin/restart bevacizumab 
until 4 weeks after that procedure (in the case of high risk procedures such as liver 
resection, thoracotomy, or neurosurgery, it is recommended that chemotherapy be 
restarted no earlier than 6 wk and bevacizumab no earlier than 8 wk after surgery). 

Women of childbearing potential should have a negative pregnancy test prior to starting 
therapy with bevacizumab and should use adequate contraceptive methods during and for 

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at least 6 months after bevacizumab therapy.    Women who become pregnant while on 
bevacizumab will discontinue the drug.
b) 
Erlotinib specific
Skin toxicities will be monitored by routine physical examination and managed 
symptomatically.    The following agents may be used to treat rash:  alcohol-free emollient 
cream, diphenhydramine, topical or oral corticosteroids, and topical (clindamycin) or oral 
antibiotics (tetracycline, minocycline, doxycycline).  Topical drying agents are not 
recommended.  
Diarrhea will be monitored and managed symptomatically.  Guidelines for management 
include administration of loperamide and Erlotinib dose reduction/interruption as described in 
Section 3.3.3.
Although quite rare, ILD can be life threatening.  Therefore, patients will be monitored closely 
for symptoms consistent with ILD, such as new onset dyspnea without an obvious cause.  In 
the event that ILD is suspected, Erlotinib treatment should be discontinued and the patient 
should receive appropriate medical management.  Although there is no proven therapy, 
systemic corticosteroids are often used empirically.  Erlotinib should not be restarted in those 
patients suspected of having drug-related ILD.  See Section 3.3.3 for management guidelines, 
including Erlotinib dose interruption.
Liver function abnormalities, including elevated serum ALT, AST, and/or bilirubin, have been 
observed infrequently with single-agent Erlotinib and occasionally with Erlotinib in 
combination with concomitant chemotherapy.  Periodic monitoring of liver function is 
recommended.  Erlotinib dosing should be interrupted if changes in liver function are severe 
(as outlined in section 3.3.3).
Women of childbearing potential should have a negative pregnancy test prior to starting 
therapy with Erlotinib and should use adequate contraceptive methods during and for at least 3 
months after Erlotinib therapy is discontinued.    Women who become pregnant while on 
erlotinib will be taken off the drug.
It is not known whether Erlotinib is excreted in human milk.  Because many drugs are excreted 
in human milk and because the effects of Erlotinib on infants have not been studied, women 
should be advised against breast-feeding while receiving Erlotinib therapy.
3.3.2
Dose Modifications
Patients will be asked to record side effects/symptoms developing or worsening on therapy 
on a Side Effect Diary which will be reviewed by the research nurse/PI/associate investigator 
during clinic visits. Treatment modifications will be made in the event of toxicities (graded 
based on NCI Common Toxicity Criteria for Adverse Events, version 4.0) related to either 
bevacizumab or erlotinib according to the guidelines below. Dose modifications for 
laboratory abnormalities will be required only if these abnormalities are clinically significant 
(regardless of grade). There will be no dose modifications for electrolyte abnormalities 
(potassium, sodium, calcium, magnesium, phosphorus) that can be corrected (to ≤ grade 1 or 
baseline) within 48 hours. In the event one of the agents is discontinued permanently, the 
patient can continue to receive the second agent in the absence of an indication requiring 
permanent discontinuation of that agent. Sections 3.3.3 and 3.3.4 outline toxicities 

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mandating withholding of dose modification; however, bevacizumab and/or erlotinib may 
be placed on hold temporarily for less severe AEs or for other reasons if it is felt to be in the 
best interests of the patients. 
3.3.3
Dose Modifications for Toxicities Related to Bevacizumab
There will be no reductions in the bevacizumab dose. If adverse events occur that require 
holding bevacizumab, the dose will remain the same once treatment resumes. If bevacizumab 
needs to be held for >16 weeks due to dose-limiting toxicity as outlined below, the agent will 
be permanently discontinued. This limit does not apply to patients in whom bevacizumab has 
been temporarily discontinued to enable performance of major elective surgery; these 
patients can restart bevacizumab once the surgical scars have healed adequately regardless of 
the duration for which the agent has been discontinued. The following guidelines will be 
used to guide bevacizumab dosing in the event of toxicity related to the drug. 
1. Hypertension: Hypertension is one of the most common toxicities experienced with 
bevacizumab. Subjects will be asked to monitor their blood pressure at home at least once a 
day and contact the UOB team for elevated readings. Elevated BP readings should be 
confirmed by a qualified health care professional when possible and decisions regarding 
grading of hypertension and initiation/intensification of antihypertensive therapy will 
generally be driven by BP measurements performed by a health care professional. Table 
3.3.2.1 outlines the management plan for patients developing hypertension on therapy. 
Although the active version of CTCAE criteria will be used to grade hypertension, the 
scheme outlined in the table below will be used to guide dose modifications. Early treatment 
of grades 1-2 hypertension to prevent or minimize the risk of developing more persistent or 
clinically significant hypertension is allowed and is not considered a grade 3 event.
The choice of agents and dosage used may vary based on individual circumstances. 
Calcium channel blockers, beta blockers, diuretics, ACE inhibitors, and angiotensin receptor 
blockers are examples of classes of antihypertensicve agents that may be used.

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Hypertension will be managed in accordance with the guidelines outlined in the table 
below:
BP Measurements - Systolic/Diastolic
Treatment/Dose Modification
A
>140 mmHg (systolic) 
OR
>90 mmHg (diastolic) 

Add new or additional antihypertensive 
medications or increase dose of existing 
medications.

Maintain dose of bevacizumab and erlotinib.

If unable to control BP to <140/90 in two 
weeks, hold bevacizumab and follow 
guidelines under row C
B
>160 mmHg (systolic)
OR
>100 mmHg (diastolic)
OR
Symptomatic

Hold bevacizumab.

Add new or additional antihypertensive 
medications or increase dose of existing 
medications.

Resume treatment at same dose level when 
BP falls to <140/90 or baseline.
C
>140 mmHg (systolic)
OR
>90 mmHg (diastolic)
Despite therapy for at least 2 weeks 

Hold bevacizumab.

Maintain or intensify antihypertensive therapy

Resume treatment at same dose level when 
BP falls to <140/90 or baseline
D
CTCAE Grade 4 

Discontinue bevacizumab 

No further treatment with bevacizumab 
allowed except in patients benefiting from 
therapy in whom treatment may be restarted if  
BP is controlled to <140/90 within 3 weeks 
and there are no permanent sequelae. Patient 
will be removed from study if a second 
episode of grade 4 hypertension occurs

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2. Hemorrhage/Bleeding: The following scheme will be used
Grade 1/2 non-
pulmonary and non-CNS 
events
No dose modification
  Grade 3  
  Non-pulmonary and
    non-CNS hemorrhage
Subjects who are also receiving full-dose anticoagulation will be 
discontinued from receiving bevacizumab.  
All other subjects will have bevacizumab held until all of the 
following criteria are met:

The bleeding has resolved and hemoglobin is stable.

There is no bleeding diathesis that would increase the risk 
of therapy.

There is no anatomic or pathologic condition that 
significantly increases the risk of hemorrhage recurrence.
Subjects who experience a repeat Grade 3 hemorrhagic event will be 
discontinued from receiving bevacizumab.
  Grade 4 
     non-pulmonary or 
    non-CNS hemorrhage
Discontinue bevacizumab.
   Grade 1 pulmonary 
Subjects who are also receiving full-dose anticoagulation will be 
discontinued from receiving bevacizumab.  
All other subjects will have bevacizumab held until all of the 
following criteria are met:

The bleeding has resolved and hemoglobin is stable.

There is no bleeding diathesis that would increase the risk 
of therapy.

There is no anatomic or pathologic condition that 
significantly increases the risk of hemorrhage recurrence.
Grade 2, 3, or 4 
pulmonary or any grade 
CNS hemorrhage 
Discontinue bevacizumab
3. Proteinuria: 
If random protein:creatinine ratio performed prior to bevacizumab administration 
demonstrates the spot urine protein:creatinine ratio is >3.5, bevacizumab should be held 
until a 24 hour urine protein can be obtained. Bevacizumab can continue as long as 24 
hour urine protein remains less than 3.5g/24 hours.  If proteinuria is greater than 3.5g/24 
hours, bevacizumab is to be held and 24 hour urine remeasured in 1-2 weeks.  
Bevacizumab can be restarted when proteinuria decreases to less than 3.5 g/24 hours. 
4. Surgical or periodontal procedures: If there is a need for an elective major surgical or 
periodontal procedure, bevacizumab should be held for 4-8 weeks prior to the procedure 
and must not be resumed until 4 weeks after the surgical procedure (in the case of high 
risk procedures such as liver resection, thoracotomy, or neurosurgery, it is recommended 
that bevacizumab be restarted no earlier than 8 wk after surgery). Longer delays may be 

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necessary if clinically indicated in order to ensure that adequate healing has taken place 
prior to bevacizumab resumption. Minor oral or periodontal procedures or surgical 
procedures may be done with no delay/discontinuation of bevacizumab at the discretion 
of the PI.
5. Thrombosis
Arterial Thrombosis: Patients will be taken off study in the event of arterial thrombosis. 
Arterial thrombosis includes angina, myocardial infarction, transient ischemic attack, 
cerebrovascular accident, any visceral or peripheral artery thrombosis.
Venous Thrombosis: For venous thrombosis requiring systemic anticoagulation, the 
patient may continue with bevacizumab while on systemic anticoagulation per the 
following guidelines. 
Venous Thrombosis 
Grade 1 or 2 
Grade 3
OR
Asymptomatic 
Grade 4
No intervention/dose modification
Hold bevacizumab treatment. If the planned duration of full-dose 
anticoagulation is < 2 weeks, bevacizumab should be held until the full-
dose anticoagulation period is over.
If the planned duration of full-dose anticoagulation is >2 weeks, 
bevacizumab may be resumed during the period of full-dose anticoagulation 
IF all of the criteria below are met:
- Subjects on heparin must have a stable dose of heparin prior to restarting 
bevacizumab.
- The subject must not have pathological conditions that carry high risk of 
bleeding (e.g. tumor involving major vessels or other conditions)
- The subject must not have had grade 2 or greater hemorrhagic events 
while on study
If thromboemboli worsen/recur upon resumption of study therapy, 
discontinue bevacizumab
Symptomatic 
Grade 4 
Discontinue bevacizumab
6. Allergic reactions and cytokine release syndrome (acute infusion reaction):
Patients with grade 1/2 events can have their infusion interrupted until resolution of acute 
symptoms, and then restarted at 50% of the rate at which the reaction occurred. The 
infusion rate may be increased by 50% every 30 minutes if well tolerated. Infusions may 
be started at the original rate during the next dose of bevacizumab. Patients who develop 
grade 3/4 allergic/infusional reactions should have bevacizumab discontinued. 

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7. Reversible posterior leukoencephalopathy syndrome (RPLS): Bevacizumab should be 
held in patients with signs and symptoms suggestive of reversible posterior 
leukoencephalopathy syndrome (RPLS), pending work-up and management, including 
control of blood pressure. Bevacizumab should be discontinued upon diagnosis of RPLS.
8. Bowel perforation: Patients who develop a bowel perforation will discontinue 
bevacizumab permanently.
9. For other grade 3 toxicities related to bevacizumab, the agent will be held until resolution 
to ≤ grade 1 or baseline and then resumed at the same dose. For grade 4 toxicities, 
bevacizumab will be discontinued; resumption of bevacizumab may be considered if a 
patient is benefiting from therapy, and the grade 4 toxicity is transient, has recovered to < 
grade 1 and unlikely to recur with retreatment.
10. Fistula formation: For any grade tracheo-esophageal fistula, Bevacizumab will be 
permanently discontinued. For any fistula other than TE- that is grade 1 or 2, 
bevacizumab will be held until resolution. For grade 3-4 non tracheo-esophageal fistulae, 
bevacizumab will be permanently discontinued.
3.3.4
Dose Modifications for Toxicities Related to Erlotinib
Erlotinib Dose Reduction Scheme: The following scheme of dose reduction will be followed 
when erlotinib-related toxicities necessitate dose modification.
Starting Dose: 150 mg/d
First Dose Reduction: 100mg/d
Second Dose Reduction: 50mg/d
The following guidelines will be used to guide erlotinib dosing in the event of toxicity 
related to the drug. 
1.
Skin Rash: 
Skin toxicities will be monitored by routine physical examination and managed 
symptomatically. If a patient develops a skin rash, the following actions will be taken for the 
management of this reaction:

The rash should be graded/assessed by a physician as soon as possible according to the 
CTCAE cutaneous toxicity criteria and documented accordingly

If a rash of CTCAE grade 2 or lower is detected, symptomatic treatment should be 
provided and erlotinib continued at the current dose.  If grade 2 skin rash is considered 
intolerable by the patient, a dose reduction should be considered.  When skin toxicity 
improves by at least one grade level, the dose may be re escalated as tolerated at PI 
discretion.  

A variety of agents can be used to manage skin rashes.  These include mild to moderate 
strength steroid creams or oral corticosteroids, topical or systemic antibiotics, topical or 
systemic antihistamines, emollients and occasionally retinoid creams.

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
If a rash of CTCAE grade 3 is detected, erlotinib should be withheld until recovery to 
grade 1 or below, at which point erlotinib may be restarted at one dose level lower

Patients with CTCAE grade 4 rash will discontinue erlotinib permanently.

If erlotinib must be withheld for >4 weeks due to cutaneous toxicity, the patient will be 
taken off the agent permanently
2. Management of gastrointestinal (GI) Toxicities
Nausea and/or vomiting
In subjects who have emesis and are unable to retain study treatment, every attempt should 
be made to obtain control of nausea and vomiting.  The dose of erlotinib may be repeated if 
emesis occurs within 30 minutes of taking the tablets or all the tablets are seen in the emesis.  
Nausea, vomiting, or both may be controlled with antiemetic therapy. Patients developing 
grade 3 or 4 nausea/vomiting despite optimal antiemetic therapy should have erlotinib 
withheld until resolution to grade 1 or below, at which point erlotinib may be restarted at one 
dose level lower.
Diarrhea
Diarrhea should be treated with standard medications (such as loperamide) to avoid dose 
modification or interruption, if possible.  Diarrhea related to erlotinib has been successfully 
managed with anti-diarrheal agents such as loperamide. Once diarrhea is determined to be 
related to erlotinib, an acceptable strategy for symptomatic management is initiation of 
loperamide 2mg orally administered following the first episode, which can be repeated as 
frequently as every 2 hours while awake (or administered at a dose of 4mg every 4 hours 
during sleeping hours) (not to exceed a total of 16mg/24 hours) until the patient is diarrhea-
free for 4-6 hours. 
No dose modifications will be necessary for CTCAE grade 1 or 2 diarrhea.  If CTCAE grade 
3 diarrhea develops despite adequate prophylaxis, erlotinib should be withheld until diarrhea 
resolves to ≤ grade 1.  Once the diarrhea resolves to less than or equal to grade 1, treatment 
with erlotinib may recommence with a dose reduction of one level. Patients should be 
maintained at the reduced dose of erlotinib without attempt at dose re-escalation.  Patients 
experiencing Grade 4 diarrhea should be discontinued from erlotinib treatment.
3.
Interstitial Lung Disease:
Although relatively rare, ILD can be life threatening.  Therefore, patients should be 
monitored closely for symptoms consistent with ILD, such as new onset dyspnea without an 
obvious cause.  In the event that ILD is suspected, erlotinib treatment should be discontinued 
and the patient should receive appropriate medical management.  Although there is no proven 
therapy, systemic corticosteroids are often used.  Erlotinib should not be restarted in those 
patients suspected of having drug-related ILD.  

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4. Patients who develop other grade 3 or 4 toxicities related to erlotinib will have their 
treatment withheld until resolution to ≤ grade 1, at which point erlotinib may be restarted 
with a dose reduction of one level.
3.3.5
Management of Female Study Subjects
Women of childbearing potential should have a negative pregnancy test prior to starting 
therapy with erlotinib and bevacizumab and should use adequate contraceptive methods 
during and for at least 6 months after discontinuation of therapy. It is not known whether 
erlotinib or bevacizumab are excreted in human milk.  Because many drugs are excreted in 
human milk and because the effects of erlotinib and bevacizumab on infants have not been 
studied, women should be advised against breast-feeding while receiving therapy.
3.4
Correlative Studies for Research
3.4.1
Planned Research Studies
3.4.1.1
Tumor Biopsy
Tumor biopsies (renal primary or metastases or cutaneous leiomyomas) may be obtained 
from patients who have easily accessible lesions. Core or excisional biopsy of an easily 
accessible sentinel lesion (such as cutaneous/subcutaneous lesions, percutaneously accessible 
hepatic lesions, lymph nodes etc.) may be performed at study entry and again at 
approximately at 8 weeks following initiation of therapy. Biopsies that are to be used solely 
for research purposes will be obtained only if they can be performed with minimal risk of 
complications from the procedure and only after the procedure has been explained to the 
patient and informed consent obtained. Kidney or liver biopsies will not be performed solely 
for research purposes in patients while on bevacizumab. Major surgical procedures such as 
laparotomy or laparoscopic procedures will not be performed solely to obtain biopsies for 
research purposes. The biopsies will be performed by members of the interventional 
radiology, dermatology or surgical staff. A portion of the biopsies will be frozen in liquid 
nitrogen immediately and transferred to the UOB laboratory (Contact for receiving and 
processing specimen: Robert Worell/ Cathy Vocke, Ph.D. - Tel: 301-496-6353). Prior to 
freezing and depending on tissue availability, a small portion of the biopsy specimen may be 
transferred under sterile conditions to the UOB laboratory to be used to establish a tumor cell 
line.
In addition, attempts will be made to obtain any available archived tumor tissue on all 
patients to help evaluate FH status and/or relevant components of the VEGF/EGFR 
pathways.
3.4.1.2
Sample Processing
Collection of blood samples for research analysis may be obtained at periodic intervals which 
meet the NIH Guidelines for Blood Draw Limit (MAS - M95-9).  No more than 10.5 mL/kg 
or over 550mL will be obtained from adults over an eight week period of time.   
Samples will be processed for the following planned studies. In the event of limited sample 
availability, we plan to prioritize studies in the order listed below:

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3.4.1.2.1 Analysis of somatic FH mutation, CGH and c-MET mutation to attempt to 
correlate clinical effects of bevacizumab and erlotinib with molecular 
abnormalities (may be performed on archived tumor tissue when available).  
Sequencing of EGFR to identify mutations sensitive to EGFR TKIs may also be 
performed.
3.4.1.2.2 Immunohistochemistry-To evaluate the effect of bevacizumab and erlotinib on 
tumor microvessel density, proliferation and apoptosis 
3.4.1.2.3 HIF expression, EGFR expression and VEGFR2 expression, and evaluation of 
components of the EGF and VEGF pathways may be performed to explore the 
correlation between these biomarkers and clinical response.  Evaluation of the 
components of the FH and Keap1/Cul3/NRF2 pathway by IHC and other 
techniques may also be performed when possible.
3.4.1.2.4 Analysis by RT- PCR of transcriptional targets affected by EGFR and VEGF 
signaling pathways, including but not limited to p27 KIP1, E-cadherin, b-catenin 
etc.
3.4.1.2.5 cDNA arrays to compare gene expression profiles in tumor cells before and during 
treatment with bevacizumab and erlotinib. Blood samples for evaluation of basal 
plasma levels of angiogenesis biomarkers such as VEGF and to assess the effect of 
bevacizumab and erlotinib on these biomarkers, 10cc lavender top tube, will be 
obtained prior to first dose, at end of 8, 16, 24 and 32 weeks.   And at the time of 
disease progression, 5-10 cc of venous blood will be collected into CPT tubes 
containing sodium citrate and thoroughly mixed.
3.4.1.2.6       1. Circulating Tumor Cells:
Peripheral blood will be collected to correlate changes in circulating tumor 
cells with clinical response.  CTCs will be assessed using ferrofluidic 
enrichment and multi-parameter flow cytometric detection. CTCs are 
identified by positive expression of epithelial markers and a viability marker 
and negative expression of hematopoietic markers.
Draw blood into one 10-cc lavender top tubes at (1) baseline, just prior to 
beginning therapy, (2) C2D1, prior to therapy and (3) C3D1, prior to therapy. 
Contact the Trepel Lab, Developmental Therapeutics Branch, NCI by email 
(Jane Trepel- trepel@helix.nih.gov; and Sunmin Lee- lees@pop.nci.nih.gov) 
when the patient is scheduled and by phone as soon as the blood is drawn at 
240-760-6330. Keep blood at ambient temperature.  A member of the Trepel 
Lab will pick up the sample.
2. Circulating Endothelial Cells (CEP and CEC):
Peripheral blood will be obtained pre-treatment and post-treatment with 
bevacizumab and erlotinib and coded samples will be used for analysis of 
angiogenesis markers such as circulating endothelial cells (CEC) and 
circulating endothelial progenitor cells (CEP). CEP and CEC will be assessed 
by multiparameter flow cytometry. Cells will be analyzed for forward and side 

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scatter, and cells expressing hematopoietic markers will be excluded.  
Endothelial cells will be identified using co-expression of markers, such as 
CD31, CD146 and CD133. The cell populations will also be analyzed for 
viability using scatter profiles and a vital stain, such as Hoechst 33258. 
Multiparameter flow analysis will be performed with a Miltenyi Quant 
equipped with FlowJo software. The outcome measures will be the number of 
CEC and CEP per 106 mononuclear cells or per microliter of peripheral blood, 
analyzed in samples taken before and after treatment.  These numbers will 
then be examined for correlations with various parameters to assess their 
potential utility as surrogate biomarkers for drug activity, for establishing the 
optimal biologic dose, for patient stratification, and monitoring of therapy-
related side effects. 
Draw blood into two 8-cc CPT citrate (BD) tubes at (1) baseline, just prior to 
beginning therapy, (2) C2D1, prior to therapy and (3) C3D1, prior to therapy. 
Contact the Trepel Lab, Developmental Therapeutics Branch, NCI by email 
(Jane Trepel- trepel@helix.nih.gov; and Sunmin Lee- lees@pop.nci.nih.gov) 
when the patient is scheduled and by phone as soon as the blood is drawn at 
240-760-6330. Keep blood at ambient temperature.  A member of the Trepel 
Lab will pick up the sample.
3. Immune Subsets:
Peripheral blood mononuclear cells (PBMC) will be assessed using 
multiparameter flow cytometry for immune subsets including but not 
necessarily limited to Tregs, MDSC, effector and exhausted CD8+ T-cells, 
and CD14+ monocytes.  Assessment will include functional markers, i.e. PD-
1, Tim-3, CTLA-4 CD40, HLA-DR and/or PD-L1. Draw blood into one 8-cc 
CPT citrate (BD) tubes at (1) baseline, just prior to beginning therapy, (2) 
C2D1, prior to therapy and (3) C3D1, prior to therapy.  Contact the Trepel 
Lab, Developmental Therapeutics Branch, NCI by email (Jane Trepel- 
trepel@helix.nih.gov; and Sunmin Lee- lees@pop.nci.nih.gov) when the 
patient is scheduled and by phone as soon as the blood is drawn at 240-760-
6330. Keep blood at ambient temperature.  A member of the Trepel Lab will 
pick up the sample.
3.4.1.2.7 Correlative laboratory studies will be performed by investigators in the Urologic 
Oncology Branch (under the direction of Drs Linehan, Srinivasan, Bottaro) and/or 
Jane Trepel’s laboratory and may involve collaboration with other NIH intramural 
investigators. Studies listed will be performed wherever possible and as permitted 
or dictated by clinical outcome and/or sample and resource availability.
3.4.2
Collection, Storage, Use and Disposition of Human Specimens
Samples will be ordered in CRIS and tracked through a Clinical Trial Data Management 
system.  Should a CRIS screen not be available, the CRIS downtime procedures will be 
followed.  Samples will not be sent outside NIH without appropriate approvals and/or 
agreements, if required. 

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3.4.2.1
Clinical Samples
Blood and urine samples for clinically relevant, non-research hematology, serum chemistry, 
urinalysis, and skin biopsy tissue will be prepared using standard procedures.  Routine 
clinical analyses will be performed by the NIH clinical center central laboratories or NCI 
Pathology department.  Samples will be processed and disposed according to standard 
laboratory procedure.
3.4.2.2
Storage and research use of research human specimens
Sample Collection and Planned Research Studies: Research samples will be collected with a 
view to performing a variety of correlative/biomarker studies (as indicated in section 3.4.1.1).
Sample Processing and Storage:  Each patient research sample will be assigned a unique 
patient identifier and relevant sample characteristics (such as timing of sample collection, 
treatment cycle and day identifiers) will be recorded. The location of all samples will be 
carefully tracked in the secure UOB database.  All stored samples will be coded and no 
identifying patient information will be on placed on sample containers. Stored samples will 
be kept in freezers / refrigerators or secure containers located in the Urologic Oncology 
Branch research laboratories or in the laboratories of collaborators.  
Timeframe for research studies: Samples will be stored until requested by an authorized 
researcher(s).  All researchers are required to use the samples for research purposes 
associated with this trial (as per the NCI IRB approved protocol). Subjects will be given the 
option of consenting to future use of their research samples per the informed consent process 
with their option declared in the consent document.  Samples from those patients who 
consent to this will be stored permanently. However, these samples will be used only for 
research studies on active NCI IRB approved protocols covered by a valid informed consent 
document. Samples will be destroyed at the completion of the study from those subjects who 
decline future use of their samples. Once primary research objectives for the protocol are 
achieved, intramural researchers can request access to remaining samples provided they have 
an IRB approved protocol and patient consent. Any unused samples must be returned to the 
UOB laboratories as appropriate.  The PI will record any loss or unanticipated destruction of 
samples as a deviation. Reporting will be per the requirements of section 7.2. 
3.5
Study Evaluation
3.5.1
Baseline Evaluation
Studies required at baseline which were also performed at screening do not need to be 
repeated if collected in a baseline appropriate timeframe. The following baseline studies must 
be performed within 4 weeks prior to initiation of study therapy.  

A complete history and physical with documentation of measurable disease and 
performance status

Imaging studies: CT of the chest abdomen and pelvis (or MRI scans when appropriate)

MRI (or CT with contrast) of the brain

PET scan

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
Bone Scan

12 lead ECG

ECHO

Photographic evaluation of skin leiomyoma (only in patients with HLRCC associated 
cutaneous leiomyomas)

TSH, and if elevated, T3; free T4; anti-TPO and TSI; and lipid panel.  

Anti-Mullerian Hormone, FSH, LH, estradiol, progesterone in pre-menopausal women

Serum Lactic Acid
The following must be performed within 7 days prior to initiation of study therapy

Targeted history and physical examination focusing on any salient changes from baseline 

CBC with differential, PT/PTT, urinalysis, spot urine protein:creatinine ratio (patients 
with 1+ or greater proteinuria on UA and a spot urine protein:creatinine ratio of > 0.5 will 
undergo a 24 hour urine collection for quantitation of proteinuria)

Acute Care Panel (Na, K, Cl, CO2, Creatinine, Glucose, and Urea Nitrogen)

Mineral Panel (Phosphorus, Magnesium, Albumin, and Calcium)

Hepatic Panel (Alk Phosphatase, ALT, AST, Total Bilirubin, and Direct Bilirubin)

Total Protein, CK, Uric Acid, and LD

Urine or serum pregnancy test in women of childbearing potential
3.5.2
Before every cycle
a.
Limited History and physical focusing on relevant changes from initial H&P
b. CBC with differential, Urinalysis, spot urine protein:creatinine ratio
c.
Acute Care Panel (Na, K, Cl, CO2, Creatinine, Glucose, and Urea Nitrogen)
d. Mineral Panel (Phosphorus, Magnesium, Albumin, and Calcium)
e.
Hepatic Panel (Alk Phosphatase, ALT, AST, Total Bilirubin, and Direct 
Bilirubin)
f.
Total Protein, CK, Uric Acid, and LD
g. Pregnancy test in women of childbearing potential
Labs can be completed +/- 5 days of scheduled visit
Circumstances may arise beyond our control where subject may not be able to complete 
required lab work, required visit, and/or bevacizumab at the scheduled time.  Although every 
effort will be made to avoid scheduling conflicts, it is possible that the clinic visits and/or lab 
evaluations may be missed at times.

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3.5.3
Restaging cycles: 
Every two cycles (every 8 weeks) during first 8 cycles (first 32 weeks), then every three 
cycles (every 12 weeks) thereafter.
a.
Limited History and physical focusing on relevant changes from initial H&P
b. CBC with differential
c.
Acute Care Panel (Na, K, Cl, CO2, Creatinine, Glucose, and Urea Nitrogen)
d. Mineral Panel (Phosphorus, Magnesium, Albumin, and Calcium)
e.
Hepatic Panel (Alk Phosphatase, ALT, AST, Total Bilirubin, and Direct 
Bilirubin)
f.
Total Protein, CK, Uric Acid, and LD
g. Imaging studies: CT/MRI evaluation of known/suspected disease sites, bone 
scan (if positive for metastatic bony disease at baseline)
h. PET scan (if required clinically) 
i.
Dermatology Consult with photographic evaluation of skin leiomyoma (only in 
patients with HLRCC associated cutaneous leiomyomas)
j.
TSH  
k. Anti-Mullerian Hormone, FSH, LH, estradiol, progesterone in pre-menopausal 
women
l.
Serum Lactic Acid
Due to holidays, Clinical Center closures or other special circumstances might necessitate 
performance of restaging scans outside the protocol specified window, and in these 
circumstances, restaging studies may be performed the week before or after the start of the 
restaging cycle and the reason documented in the patient chart. 
3.5.4
Every 2 weeks Monitoring
a.
Urinalysis and spot urine protein:creatinine ratio prior to every dose of 
bevacizumab.  If random protein:creatinine ratio performed prior to 
bevacizumab administration demonstrates the spot urine protein:creatinine 
ratio is >3.5, bevacizumab should be held until a 24 hour urine protein can be 
obtained.
Labs can be completed +/- 5 days of scheduled visit
Circumstances may arise beyond our control where subject may not be able to complete 
required lab work, required visit, and/or bevacizumab at the scheduled time.  Although every 
effort will be made to avoid scheduling conflicts, it is possible that the clinic visits and/or lab 
evaluations may be missed at times.

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3.5.5
Daily Monitoring
Blood Pressure- Patient will be asked to measure and record his/her blood pressure at least 
once a day and will be provided with a BP monitor. Patients will be instructed to record BP 
readings on a BP monitoring diary which will be provided and will be reviewed by the 
research nurse/PI/AI at each clinic visit. In addition, patients will call the UOB research team 
for readings above 140/90 mmHg and may be instructed to have elevated readings confirmed 
by a local health care provider.
Patient will be instructed take their own BP daily with recognition that there will be 
occasions where there are missed BP readings due to unforeseen circumstances or patient 
oversight.

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3.5.6
Study Calendar 
Cycle
Screening
Baseline
1
2
3
Every 2 
weeks
Every 
Cycle 
Restaging
cyclesl (End of 
Cycle 2 onward)
Disease 
Progression / End of 
Therapy m 
Day (D) of Cycle 
(+/- 5 days)
1
15
1
15
1
1
Informed consent
X
Complete Medical 
history and 
physical exam 
Xa
Xb
Study Eligibility 
incl availability of 
tissue and 
confirmation of 
dx
X
Targeted History & 
Focused Physical o
Xd
X
X
X
X
Vital signs/weight o
Xa, j
X
X
X
X
X
X
X
X
ECHO
Xa
Xb
12-lead ECG
Xa
Xb

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Cycle
Screening
Baseline
1
2
3
Every 2 
weeks
Every 
Cycle 
Restaging
cyclesl (End of 
Cycle 2 onward)
Disease 
Progression / End of 
Therapy m 
Day (D) of Cycle 
(+/- 5 days)
1
15
1
15
1
1
Acute Care Panel, 
Mineral Panel. 
Hepatic Panel, 
Total Protein, CK, 
Uric Acid, LD, 
CBC with 
differentialp
Xd
Xd
X
X
X
X
Urinalysis and spot 
protein/creatp
Xd
Xd
X
X
X
X
X
X
Pregnancy test
Xd
Xd
X
X
X
ECOG PSm
Xa
Xb
X
X
X
X
Scans for 
Radiological and 
Clinical Tumor 
Assessment 
(RECIST)q
Xa
Xb
X
X
MRI/CT Brain
Xa
Xb

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Cycle
Screening
Baseline
1
2
3
Every 2 
weeks
Every 
Cycle 
Restaging
cyclesl (End of 
Cycle 2 onward)
Disease 
Progression / End of 
Therapy m 
Day (D) of Cycle 
(+/- 5 days)
1
15
1
15
1
1
PET Scanq
Xa
Xb
Xf
Bone Scanq
Xa
Xb
Xe
Sample for 
Biomarkers
X
X
X
Xg
X
Tumor biopsy 
(optional)
X
X
Review of Patient 
Side Effect 
Diary/Pill Count 
Form
X
X
X
X
Tolerability/
AE reportingn
X
X
X
X
Concurrent 
treatment
Xa
X
X
X
X
X
Dermatology 
Consult
Xh

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Cycle
Screening
Baseline
1
2
3
Every 2 
weeks
Every 
Cycle 
Restaging
cyclesl (End of 
Cycle 2 onward)
Disease 
Progression / End of 
Therapy m 
Day (D) of Cycle 
(+/- 5 days)
1
15
1
15
1
1
Photography of skin 
lesions
Xa, h
Xb, h
Xh
TSH 
Xa,i
Xb, i
X
X
X
Anti-Mullerian 
Hormone, FSH, 
LH, estradiol, 
progesteronek
Xa
Xb
X
Serum Lactic Acid
Xa
Xb
X
Free T4; anti-TPO 
and TSI; and lipid 
panel
Xa
Xb
a.
Should be performed within 4 weeks prior to enrollment on study
b.
Should be performed within 4 weeks prior to initiation of study therapy.  Does not need to be repeated if performed within this 
timeframe at screening. 
c.
May be performed within 7 days prior to the initiation of study therapy.  Does not need to be repeated if performed previously 
within this timeframe.
d.
Should be performed within 7 days prior to enrollment on study
e.
To be repeated at restaging if abnormal initially

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f.
If required clinically
g.
Following cycles 2, 4, 6, and 8 for VEGF; and prior to therapy, C2D1, and C3D1 for CEC/CEP
h.
Only in patients with HLRCC associated cutaneous leiomyomas
i.
if elevated, T3
j.
Vital signs will be done when clinically indicated by prescriber
k.
In premenopausal women
l.
Restaging cycles occur every 8 weeks during the 1st 8 cycles (32 weeks), then every 3 cycles (12 weeks) thereafter
m.
Approximately 30 days following the last dose of study therapy 
n.
May be completed by remote visit with a member of the study team (e.g., if the patient is not able to return to the NIH CC). 
Remote visits will be conducted in compliance with NIH guidelines and FDA regulations.  A patient may be referred to their local 
provider or asked to come to the NIH CC for an in-person assessment, if clinically indicated, and at the discretion of the PI.  In the 
case of any visits with participants’ local providers, records will be obtained.  
o.
Full physical exams and vital signs may be omitted during follow up visits if a patient is unable to return at the NIH Clinical 
Center and if the clinical evaluation does not indicate a need for collection.
p.
As results are comparable across laboratories, if the patient is not able to return to the NIH Clinical center, laboratory tests may be 
obtained locally. 
q.
In the event that the patient is unable to return to the NIH Clinical Center during a follow up visit, imaging may be delayed, but 
will be completed as soon as feasible. Collection of research blood or urine will be omitted or collected in a delayed fashion.

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3.6
Concurrent, Restricted and Excluded Therapies
Co-administration of erlotinib and drugs with potent CYP3A4 inhibitor effects is not allowed 
nor is the use of ciprofloxacin. Agents with potent inducer 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 (see 
3.6.1). 
Use of anti-neoplastic or anti-tumor agents not part of the study therapy, including 
chemotherapy, radiation therapy, immunotherapy, and hormonal anticancer therapy, is not 
permitted while participating in this study. 
Use of concurrent investigational agents to treat RCC is not permitted.
Grapefruit juice is a CYP3A4 inhibitor, therefore, consumption of grapefruit or grapefruit 
juice should be avoided during erlotinib treatment.
The solubility of erlotinib is pH dependent.  Erlotinib solubility decreases as pH increases. 
Co-administration of erlotinib with omeprazole, a proton pump inhibitor, decreased the 
exposure of erlotinib (AUC) by 46% and the maximum concentration (Cmax) by 61%.  
There was no change to Tmax or half-life.  Therefore, drugs that alter the pH of the GI tract 
may alter the solubility of erlotinib and hence its bioavailability and should be avoided when 
possible.
In a single-dose study in healthy volunteers, the AUC was reduced by 64% in smokers when 
compared with nonsmokers.  In BR.21, current smokers achieved erlotinib trough plasma 
concentrations that were approximately 2-fold lower than never smokers.  Smokers should be 
advised to stop smoking while taking erlotinib as plasma concentrations of erlotinib are 
reduced due to the effect of cigarette smoking.
3.6.1
Restrictions

Warfarin is allowed in therapeutic and low-doses and these patients should be monitored 
regularly for changes in their International Normalized Ratio (INR).

The following agents that affect metabolism by the CYP450 3A4 or CYP450 1A2 
systems will be avoided when possible and used only when considered necessary, after 
discussion with the PI or a responsible associate investigator- metronidazole, aprepitant, 
albendazole, phenobarbitol, modafinil, phenytoin, quinine, omeprazole, rabeprazole, 
rifampin (Appendix C).
3.7
Surgical Guidelines
Major elective surgical procedures should not be scheduled during protocol treatment or 
within 4 weeks of the last dose of bevacizumab. Patients undergoing unexpected major 
surgical procedures should have bevacizumab and erlotinib withheld. Treatment may be 
resumed at a later date at the discretion of the PI (bevacizumab should not be resumed earlier 
than 4 weeks post-operatively, with adequately healed incisions).
3.8
Radiation Therapy Guidelines
Patients requiring radiation therapy for RCC will discontinue study treatment.

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3.9
Cost and Compensation 
3.9.1
Costs
NIH does not bill health insurance companies or participants for any research or related 
clinical care that participants receive at the NIH Clinical Center.  If some tests and 
procedures performed outside the NIH Clinical Center, participants may have to pay for these 
costs if they are not covered by insurance company.  Medicines that are not part of the study 
treatment will not be provided or paid for by the NIH Clinical Center.   
3.9.2
Compensation 
Participants will not be compensated on this study.
3.9.3
Reimbursement 
The NCI will cover the costs of some expenses associated with protocol participation.  Some 
of these costs may be paid directly by the NIH and some may be reimbursed to the 
participant/guardian as appropriate.  The amount and form of these payments are determined 
by the NCI Travel and Lodging Reimbursement Policy.   
3.10 Criteria for Removal from Protocol Therapy and Off Study Criteria
Prior to removal from study, effort must be made to have all subjects complete a safety visit 
approximately 30 days following the last dose of study therapy.  
3.10.1 Off Treatment Criteria
Treatment may continue until one of the following criteria applies:

Disease progression

Intercurrent illness that prevents further administration of treatment

Unacceptable adverse event(s) (as outlined in Section 3.3)

Patient decides to withdraw from the study

General or specific changes in the patient’s condition render the patient 
unacceptable for further treatment in the judgment of the investigator

Positive pregnancy test

Investigator discretion
3.10.2 Follow Up
Patients with unresolved toxicities will be followed per section 5.1. 
Patients who stop treatment for reasons other than progression will be followed when 
possible in order to determine time to progression and overall survival. Follow-up will be 
performed either through visits to/evaluations at the NIH CC or at their local physician’s 
office with records forwarded to us. Scans will be obtained at approximately 3-month 
intervals following discontinuation of treatment. Survival status may be obtained through 
publicly available data sources as well as other NIH protocols in which participants are co-

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enrolled.
3.10.3 Off Study Criteria 

Investigator discretion

Death

Participant requests to be removed from study

Patients will be taken off study at progression or if the patient is unable to comply 
with follow-up visits/evaluations. 
4
SUPPORTIVE CARE
Supportive care will be provided in accordance with good medical practice.
5
DATA COLLECTION AND EVALUATION
5.1
Data Collection
Data will be prospectively collected and entered in a designated database (C3D). All 
radiographic images will be stored in the Dept. of Radiology, Clinical Center, NIH and will 
be reviewed by NIH CC staff radiologists.
Patients treated both inside and outside of NIH will require source documentation regarding 
dosage and timing of drug administration.  For patients treated outside NIH, results of lab, 
radiology and pathology tests should be faxed to the PI.   Data from NIH will be located in 
the CRIS.  Data managers can enter the data from both sources electronically into the NCI 
C3D database.  
Note: No patients are treated outside of NIH starting with Amendment V.
The PI will be responsible for overseeing entry of data into an in-house password protected 
electronic system and ensuring data accuracy, consistency and timeliness. The principal 
investigator, associate investigators/research nurses and/or a contracted data manager will 
assist with the data management efforts. Primary and final analyzed data will have identifiers 
so that research data can be attributed to an individual human subject participant.
All adverse events, including clinically significant abnormal findings on laboratory 
evaluations, regardless of severity, will be followed until return to baseline or stabilization of 
event. Document AEs from the first study intervention, Study Day 1, through 30 days after 
the agent was last administered. 
End of study procedures: Data will be stored according to HHS, FDA regulations, and NIH 
Intramural Records Retention Schedule as applicable. 
Loss or destruction of data: Should we become aware that a major breach in our plan to 
protect subject confidentiality and trial data has occurred, this will be reported expeditiously 
per requirements in section 8.2.1. 
5.2
Response Evaluation
For the purposes of this study, patients should be re-evaluated for response every 8 weeks 
during the first 32 weeks and every 12 weeks thereafter.  In addition to a baseline scan, 

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confirmatory scans should also be obtained ≥4 weeks following initial documentation of 
objective response.
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1).(48)  Changes in the largest diameter (unidimensional measurement) of the 
tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the 
RECIST criteria.
In patients with HLRCC, renal tumors, uterine leiomyomas and skin leiomyomas will be 
assessed independently.  Renal tumors and uterine leiomyomas will be evaluated using 
RECIST criteria.  For skin leiomyomas up to three lesions will be measured in the longest 
dimension.  The following criteria will be used to determine response/progression.  

Partial response – decreased of 30% or more in sum of longest dimension 
compared to baseline.

Complete response – complete disappearance of all measured/target and non 
target lesions.

Progressive disease – increase of 20% or more in sum of longest dimension 
compared to smallest recorded sum of target lesions or appearance of one or more 
new lesions.

Stable disease – no change in lesions or change insufficient to meet criteria for 
response or progressive disease. 
5.2.1
Definitions
Evaluable for toxicity.  All patients will be evaluable for toxicity from the 
time of their first treatment with either bevacizumab or erlotinib.
Evaluable for objective response.  Only those patients who have measurable 
disease present at baseline, have received at least one cycle of therapy, and have had 
their disease re-evaluated will be considered evaluable for response.  These patients 
will have their response classified according to the definitions stated below.  (Note:  
Patients who exhibit objective disease progression prior to the end of cycle 1 will also 
be considered evaluable.)
Evaluable Non-Target Disease Response.  Patients who have lesions present 
at baseline that are evaluable but do not meet the definitions of measurable disease, 
have received at least one cycle of therapy, and have had their disease re-evaluated 
will be considered evaluable for non-target disease.  The response assessment is 
based on the presence, absence, or unequivocal progression of the lesions. 

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5.2.1.1
Measurable disease
Measurable disease:  Measurable lesions are defined as those that can be accurately measured 
in at least one dimension (longest diameter to be recorded) as: 

By chest x-ray: >20 mm; 

By CT scan: 
o
Scan slice thickness 5 mm or under: as >10 mm
o
Scan slice thickness >5 mm: double the slice thickness 

With calipers on clinical exam: >10 mm.  
All tumor measurements must be recorded in millimeters (or decimal fractions of 
centimeters).
Note:  Tumor lesions that are situated in a previously irradiated area might or might 
not be considered measurable.  If the investigator thinks it appropriate to include 
them, the conditions under which such lesions should be considered must be defined 
in the protocol.
Malignant lymph nodes.  To be considered pathologically enlarged and 
measurable, a lymph node must be >15 mm in short axis when assessed by CT scan 
(CT scan slice thickness recommended to be no greater than 5 mm).  At baseline and 
in follow-up, only the short axis will be measured and followed.
5.2.1.2
Non-measurable disease
Non-measurable disease.  All other lesions (or sites of disease), including 
small lesions (longest diameter <10 mm or pathological lymph nodes with ≥ 10 to 
<15 mm short axis), are considered non-measurable disease.  Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed 
by CT or MRI), are considered as non-measurable.
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non-
measurable) since they are, by definition, simple cysts.
‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if non-cystic lesions are present in the same patient, these are preferred for 
selection as target lesions.
5.2.1.3
Target lesions
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ 
and 5 lesions in total, representative of all involved organs, should be identified as 
target lesions and recorded and measured at baseline.  Target lesions should be 
selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend 
themselves to reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in which 

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circumstance the next largest lesion which can be measured reproducibly should be 
selected.  A sum of the diameters (longest for non-nodal lesions, short axis for nodal 
lesions) for all target lesions will be calculated and reported as the baseline sum 
diameters.  If lymph nodes are to be included in the sum, then only the short axis is 
added into the sum.  The baseline sum diameters will be used as reference to further 
characterize any objective tumor regression in the measurable dimension of the 
disease.
5.2.1.4
Non-target lesions
Non-target lesions.  All other lesions (or sites of disease) including any 
measurable lesions over and above the 5 target lesions should be identified as non-
target lesions and should also be recorded at baseline.  Measurements of these 
lesions are not required, but the presence, absence, or in rare cases unequivocal 
progression of each should be noted throughout follow-up. 
5.2.2
Guidelines for Evaluation of Measurable Disease
All measurements should be taken and recorded in metric notation using a ruler or calipers.  
All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 4 weeks before the beginning of the treatment.
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam.
Clinical lesions:  Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and 10 mm diameter as assessed 
using calipers (e.g., skin nodules).  In the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the lesion, is recommended. 
Chest x-ray:  Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung.  However, CT is preferable. 
Conventional CT and MRI:  This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm or less.  If CT scans have slice 
thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the 
slice thickness.  MRI is also acceptable in certain situations (e.g. for body scans).  
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the technical 
specifications of the scanning sequences used should be optimized for the evaluation of the 
type and site of disease.  Furthermore, as with CT, the modality used at follow-up should be 
the same as was used at baseline and the lesions should be measured/assessed on the same 
pulse sequence.  It is beyond the scope of the RECIST guidelines to prescribe specific MRI 
pulse sequence parameters for all scanners, body parts, and diseases.  Ideally, the same type 
of scanner should be used and the image acquisition protocol should be followed as closely 

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as possible to prior scans.  Body scans should be performed with breath-hold scanning 
techniques, if possible.
PET-CT:  At present, the low dose or attenuation correction CT portion of a combined PET-
CT is not always of optimal diagnostic CT quality for use with RECIST measurements.  
However, if the site can document that the CT performed as part of a PET-CT is of identical 
diagnostic quality to a diagnostic CT (with IV and oral contrast), then the CT portion of the 
PET-CT can be used for RECIST measurements and can be used interchangeably with 
conventional CT in accurately measuring cancer lesions over time.  Note, however, that the 
PET portion of the CT introduces additional data which may bias an investigator if it is not 
routinely or serially performed.  
Ultrasound:  Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement.  Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to 
the next.  If new lesions are identified by ultrasound in the course of the study, confirmation 
by CT or MRI is advised.  If there is concern about radiation exposure at CT, MRI may be 
used instead of CT in selected instances.
Endoscopy, Laparoscopy:  The utilization of these techniques for objective tumor evaluation 
is not advised.  However, such techniques may be useful to confirm complete pathological 
response when biopsies are obtained or to determine relapse in trials where recurrence 
following complete response (CR) or surgical resection is an endpoint.
Tumor markers: Tumor markers alone cannot be used to assess response. If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered in 
complete clinical response. Specific guidelines for both CA-125 response (in recurrent 
ovarian cancer) and PSA response (in recurrent prostate cancer) have been published. (49-51)   
I In addition, the Gynecologic Cancer Intergroup has developed CA-125 progression criteria 
which are to be integrated with objective tumor assessment for use in first-line trials in 
ovarian cancer.(52) 
Cytology, Histology:  These techniques can be used to differentiate between partial responses 
(PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as 
germ cell tumors, where known residual benign tumors can remain).
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side 
effect of the treatment) and progressive disease.
FDG-PET:  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis of 
FDG-PET imaging can be identified according to the following algorithm: 

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a.
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a 
sign of PD based on a new lesion.
b.
No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the 
positive FDG-PET at follow-up corresponds to a new site of disease confirmed by 
CT, this is PD.  If the positive FDG-PET at follow-up is not confirmed as a new site 
of disease on CT, additional follow-up CT scans are needed to determine if there is 
truly progression occurring at that site (if so, the date of PD will be the date of the 
initial abnormal FDG-PET scan).  If the positive FDG-PET at follow-up corresponds 
to a pre-existing site of disease on CT that is not progressing on the basis of the 
anatomic images, this is not PD.
c.
FDG-PET may be used to upgrade a response to a CR in a manner similar to a 
biopsy in cases where a residual radiographic abnormality is thought to represent 
fibrosis or scarring.  The use of FDG-PET in this circumstance should be 
prospectively described in the protocol and supported by disease-specific medical 
literature for the indication.  However, it must be acknowledged that both approaches 
may lead to false positive CR due to limitations of FDG-PET and biopsy 
resolution/sensitivity.
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an 
uptake greater than twice that of the surrounding tissue on the attenuation corrected 
image.
5.2.2.1
Response Criteria
5.2.2.2
Evaluation of Target Lesions
Complete Response (CR):
Disappearance of all target lesions.  Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to <10 mm.
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum diameters
Progressive Disease (PD):
At least a 20% increase in the sum of the diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum 
if that is the smallest on study).  In addition to the relative increase of 20%, the sum 
must also demonstrate an absolute increase of at least 5 mm.  (Note:  the appearance 
of one or more new lesions is also considered progressions).
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study
5.2.2.3
Evaluation of Non-Target Lesions
Complete Response (CR):
Disappearance of all non-target lesions and normalization of 
tumor marker level.  All lymph nodes must be non-pathological in size (<10 mm 
short axis)

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Note:  If tumor markers are initially above the upper normal limit, they must normalize for a 
patient to be considered in complete clinical response.
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or maintenance of 
tumor marker level above the normal limits
Progressive Disease (PD):  Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  Unequivocal progression should not 
normally trump target lesion status.  It must be representative of overall disease status 
change, not a single lesion increase.    
Although a clear progression of “non-target” lesions only is exceptional, the 
opinion of the treating physician should prevail in such circumstances, and the 
progression status should be confirmed at a later time by the review panel (or 
Principal Investigator).
5.2.2.4
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).  The patient's best response assignment 
will depend on the achievement of both measurement and confirmation criteria.
 For Patients with Measurable Disease (i.e., Target Disease)
Target 
Lesions
Non-Target 
Lesions
New 
Lesions
Overall 
Response
Best Overall Response when 
Confirmation is Required*
CR
CR
No
CR
>4 wks. Confirmation**
CR
Non-CR/Non-
PD
No
PR
CR
Not evaluated
No
PR
PR
Non-CR/Non-
PD/not 
evaluated
No
PR
>4 wks. Confirmation**
SD
Non-CR/Non-
PD/not 
evaluated
No
SD
documented at least once >4 wks. 
from baseline**
PD
Any
Yes or 
No
PD
Any
PD***
Yes or 
No
PD
no prior SD, PR or CR

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Any
Any
Yes
PD
*      See RECIST 1.1 manuscript for further details on what is evidence of a new lesion.
**    Only for non-randomized trials with response as primary endpoint.
***  In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression.
Note: Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document the 
objective progression even after discontinuation of treatment.
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease)
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PD*
Not all evaluated
No
not evaluated
Unequivocal PD
Yes or No
PD
Any
Yes
PD
* ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease 
since SD is increasingly used as an endpoint for assessment of efficacy in 
some trials so to assign this category when no lesions can be measured is not 
advised
5.2.3
Confirmatory Measurement/Duration of Response
5.2.3.1
Confirmation
To be assigned a status of PR or CR, changes in tumor measurements must be 
confirmed by repeat assessments that should be performed ≥4 weeks after the criteria for 
response are first met.  In the case of SD, follow-up measurements must have met the SD 
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5.2.3.2
Duration of Overall Response
Duration of overall response:  The duration of overall response is measured from 
the time measurement criteria are met for CR or PR (whichever is first recorded) until the 
first date that recurrent or progressive disease is objectively documented (taking as reference 
for progressive disease the smallest measurements recorded since the treatment started).
The duration of overall CR is measured from the time measurement criteria are first 
met for CR until the first date that progressive disease is objectively documented.
Duration of stable disease:  Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started, including the baseline measurements. 
5.2.3.3
Progression Free Survival
PFS is defined as the duration of time from start of treatment to time of progression or 
death, whichever occurs first.
5.2.3.4
Overall Survival 
5.3
Overall survival (OS) is defined as the duration of time from the date of study 
enrolment until time of death. Patients without a death event will be censored at 
the date survival assessment was last evaluated (e.g., clinic visit, phone 
call).Toxicity Criteria
CTCAE term (AE description) and grade:  The descriptions and grading scales found in 
the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 
will be utilized for AE reporting.  All appropriate treatment areas should have access to a 
copy of the CTCAE version 4.0.  A copy of the CTCAE version 4.0 can be downloaded from 
the CTEP web site (http://ctep.cancer.gov).
6
STATISTICAL CONSIDERATIONS
This is a phase II study to establish whether treatment with bevacizumab and erlotinib in 
patients with metastatic HLRCC and papillary type 2 renal cancer results in an adequate 
overall response rate to warrant further development.
Patients will be enrolled in four cohorts:
Cohorts 1 and 3: Patients with metastatic HLRCC renal cancer, diagnosed by either germline 
mutation of the FH gene, or based upon evidence of the clinical syndrome of HLRCC 
(characteristic renal cancer histology, cutaneous leiomyomas, uterine fibroids, and a family 
history)
Cohorts 2 and 4: Patients with sporadic papillary renal cancer.
6.1.1
For Cohorts 1 and 2 (see section 6.2 for cohorts 3 and 4)
The study will be designed with a Simon two-stage minmax design in two cohorts (i.e., 
separate design for each cohort).  In each cohort, 13 patients will be accrued in the first stage. 
If there are no responses (either CR or PR) in 13 patients, accrual to the cohort will be 
terminated, and the treatment will be considered ineffective for the cohort. If at least one 

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patient responds among the 13 patients, then 7 additional patients will be accrued to the 
cohort. If 3 or more patients of 20 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 minmax design is based on assuming an ineffective response 
rate of 5% and a targeted effective response rate of 25%. 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 51% 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 3.4. Analyses will focus on comparing changes in these 
biomarkers on treatment from the pre-study measurement.  Longitudinal changes in 
continuous biomarkers (e.g.  plasma VEGF) 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 incorporates 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. Overall survival will be 
determined using the Kaplan-Meier method and include any-cause death.
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 two-
stage 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 

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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 

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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 Newton-
Raphson 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.
7
HUMAN SUBJECTS PROTECTION
7.1
Rationale for Subject Selection
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.
7.2
Participation of Subjects Unable to Give Consent
Adults unable to give consent are excluded from enrolling in the protocol.  However, re-
consent may be necessary and there is a possibility, though unlikely, that subjects could 
become decisionally impaired. For this reason and because there is a prospect of direct 
benefit from research participation (section 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.
7.3
Evaluation of Benefits and Risks/Discomforts
7.3.1
Potential benefits
The potential benefit to a patient who enters study is a reduction in the bulk of his/her tumor, 
which may or may not have a favorable impact on symptoms and/or outcome.
7.3.2
Potential risks
7.3.2.1
Study Drugs
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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.
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.
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.
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.
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 Assurance
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.
8
NIH REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING 
PLAN
8.1
Definitions
Please refer to definitions provided in Policy 801: Reporting Research Events found here.
8.2
OHSRP Office and of Compliance and Training/IRB Reporting
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.
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.
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.
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 

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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.
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:
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., pre-
existing 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).
9.4
Procedures for Eliciting, Recording, and Reporting Adverse Events
9.4.1
Eliciting Adverse Events
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 Adverse Events
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.
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”.
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”).
d. Hospitalizations for Medical or Surgical Procedures
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.
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 

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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.
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 case-
by-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.
9.5
Adverse Event Reporting to Genentech 
9.5.1
Non-serious Adverse Events

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 
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
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:
Fax: 650-238-6067
Email: usds_aereporting-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:
SADRs
Serious AE reports that are related to the Product shall be transmitted to Genentech 
within fifteen (15) calendar days of the awareness date.
Other SAEs
Serious AE reports that are unrelated to the Product shall be transmitted to Genentech 

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within thirty (30) calendar days of the awareness date.
AESIs
AESIs shall be forwarded to Genentech within fifteen (15) calendar days of the 
awareness date.
9.6
Additional Reporting Requirements to Genentech
9.6.1.1
Special Situation Reports
Pregnancy reports
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.
Pregnancies in Female Partners of Male Patients 
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.
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.
MedWatch 3500A Reporting Guidelines

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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
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
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.
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.
9.11 Reporting to Regulatory Authorities and Investigators
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.
For questions related to safety reporting, please contact Genentech Drug Safety:
Tel: (888) 835-2555
Fax: (650) 225-4682 or (650) 225-4630
9.10 Other Reports
The investigator will forward a copy of the Final Study Report to Genentech upon 
completion of the Study. 
10 COLLABORATIVE AGREEMENTS
10.1 Cooperative Research and Development Agreement (CRADA)
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 

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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.
11 REGULATORY AND OPERATIONAL CONSIDERATIONS 
11.1 STUDY DISCONTINUATION AND CLOSURE
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause.  Written notification, documenting the reason for study suspension or 

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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).
11.2 Quality Assurance and Quality Control
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.
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 

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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.
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.
12 PHARMACEUTICAL INFORMATION
12.1 Bevacizumab
12.1.1 Source
Source: Bevacizumab is commercially available.  Bevacizumab will be supplied by 
Genentech. 

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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 complementarity-
determining 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 complementarity-
determining 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.
12.1.6 Stability and Storage
Upon receipt of the study drug, vials are to be refrigerated at 2C–8C (36F–46F) and 
should remain refrigerated until just prior to use.  DO NOT FREEZE.  DO NOT SHAKE. 
Vials should be protected from light.

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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
Route of Administration: Intravenous
12.1.8 Incompatibilities
Please refer to package insert for further information.
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, 

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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.
12.2.7 Administration Procedures
Route of Administration: Oral
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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JR. Novel mutations in FH and expansion of the spectrum of phenotypes expressed in 
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13 APPENDIX A: ECOG PERFORMANCE STATUS 
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 HEART ASSOCIATION (NYHA) CARDIAC 
CLASSIFICATION
The NYHA classification system relates symptoms to everyday activities and the patient’s 
quality of life.
Class
Symptoms
Class I (Mild)
No limitation of physical activity.  Ordinary physical activity does not 
cause undue fatigue, palpitation, or dyspnea (shortness of breath).
Class II (Mild)
Slight limitation of physical activity.  Comfortable at rest, but 
ordinary physical activity results in fatigue, palpitation, or dyspnea.
Class III (Moderate)
Marked limitation of physical activity.  Comfortable at rest, but less 
than ordinary activity causes fatigue, palpitation, or dyspnea.
Class IV (Severe)
Unable to carry out any physical activity without discomfort.  
Symptoms of cardiac insufficiency at rest.  If any physical activity is 
undertaken, discomfort is increased.

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15 APPENDIX C: LIST OF INTERACTING DRUGS
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

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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

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16 APPENDIX D: CASE TRANSMISSION VERIFICATION FORM
See below. 

Supported Study Case Transmission Verification Form
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 
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:
Case 
Number 
(Company 
Use Only)
Date of 
Awareness 
of AE 
(Day-Mon-Year)  
Date AE sent 
to 
US Drug 
Safety
Patient’s 
Study ID
Patient’s 
Initials
Suspect 
Drug(s)
Event Term 
Serious or 
Non Serious
Outcome
Causality
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.

Supported Study Case Transmission Verification Form
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: