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Abbreviated Title: *Bev/Erlotinib in Papillary RCC* Version Date: *07/02/2021* 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 1
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precis 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.
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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
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eligibility

Diagnosis of advanced RCC associated with HLRCC (cohorts 1 and 3) or sporadic/nonHLRCC 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
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
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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                                                                                                                                    |                                                                                                                                            |
| TABLE OF CONTENTS ......................................................................................................................4 |                                                                                                                                            |
| STATEMENT OF COMPLIANCE                                                                                                                   |                                                                                                                                            |
| l                                                                                                                                         | INTRODUCTION .                                                                                                                             |
| 1.1                                                                                                                                       | Study Objectives                                                                                                                           |
| Background and Rationale.....................................................................................................8            |                                                                                                                                            |
| 1.2                                                                                                                                       |                                                                                                                                            |
| 2                                                                                                                                         | ELIGIBILITY ASSESSMENT AND ENROLLMENT ................................................30                                                   |
| 2.1                                                                                                                                       | Eligibility Criteria                                                                                                                       |
| 2.2                                                                                                                                       | Screening Evaluation ...............................................................................................................32     |
| 2.3                                                                                                                                       | Patient Registration and Status Update Procedures .........................................................32                              |
| 3                                                                                                                                         | STUDY IMPLEMENTATION .................................................................................................................33   |
| 3.1                                                                                                                                       | Study Design                                                                                                                               |
| 3.2                                                                                                                                       | Drug Administration                                                                                                                        |
| 3.3                                                                                                                                       | T Treatment Modifications ......................................................................................................34         |
| 3.4                                                                                                                                       | Correlative Studies for Research ....................................................................................42                    |
| Study Evaluation                                                                                                                          |                                                                                                                                            |
| 3.5                                                                                                                                       | Concurrent, Restricted and Excluded Therapies ..............................................................54                             |
| 3.6                                                                                                                                       |                                                                                                                                            |
| 3.7                                                                                                                                       | Surgical Guidelines                                                                                                                        |
| 3.8                                                                                                                                       | Radiation Therapy Guidelines ...........................................................................................................54 |
| Cost and Compensation                                                                                                                     |                                                                                                                                            |
| 3.9                                                                                                                                       |                                                                                                                                            |
| 3.10                                                                                                                                      | Criteria for Removal from Protocol Therapy and Off Study Criteria ......................55                                                 |
| 4                                                                                                                                         | SUPPORTIVE CARE                                                                                                                            |
| S                                                                                                                                         | DATA COLLECTION AND EVALUATION .........................................................................56                                 |
| 5.1                                                                                                                                       | DATA COLLECTION                                                                                                                            |
| 5.2                                                                                                                                       | Response Evaluation                                                                                                                        |
| 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                                                                                                                            |
| 7                                                                                                                                         | HUMAN SUBJECTS PROTECTION ......................................................................................67                         |
| 7.1                                                                                                                                       | Rationale for Subject Selection ............................................................................................67             |  
| 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 |                                                       |  
13 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 6
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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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1 introduction 1.1 study objectives

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
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1.2 background and rationale 1.2.1

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 HLRCCassociated 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 RCC variants for evidence of somatic inactivation of FH is ongoing.
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genetic and biochemical basis of

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 proangiogenic 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).  
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).
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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 firstline 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.
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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 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.
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1.2.2.3 bevacizumab phase i clinical

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 (5fluorouracil/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.
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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 halflife 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.
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1.2.2.5 bevacizumab phase ii/iii clinical

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 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)
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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 tumorassociated 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.
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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 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 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.
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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)
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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. 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)
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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.
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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.
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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 RPLS. MRI scans are key to diagnosis and typically demonstrate vasogenic edema (hyperintensity 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.
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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.
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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 C08 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.
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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.
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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 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
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epidermal growth factor receptor expression

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, placebocontrolled 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)
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1.2.3.2 erlotinib preclinical data -

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), 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.
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1.2.3.3 erlotinib phase i clinical

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 singleagent 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.
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1.2.3.4 erlotinib pharmacokinetic studies and

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 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 steadystate 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 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 coadministered 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.
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1.2.3.4.2 erlotinib use in hepatic

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 hepaticimpaired 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.
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1.2.3.5 erlotinib phase ii /

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 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 platinumcontaining 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)
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1.2.4.2 erlotinib and bevacizumab combination

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 doselimiting 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 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%).
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1.2.4.3 erlotinib and bevacizumab combination

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 threearm 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)
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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   | Cohort 2 [NonHLRCC] (%)         | Total (%)   |
|----------------------------------------------|------------|---------|-------------|
| [HLRCC] (%)                                  |            |         |             |
| Complete response (CR)                       | 0          | 0       | 0           |
| Confirmed Partial response                   | 13 (65%)   | 6 (29%) | 18 (44%)    |
| (PR)                                         |            |         |             |  
| 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                       | 100%                 | 86%                   | 93%      |
| (SD+PR) Median Progression Free            | 24.2                 |                       |          |
| Survival –Months [95%CI]                   | 7.4                  | 12.8                  |          |
| [95% CI 12.8 -  ]                          | [95% CI 3.73 - 10.2] | [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.
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1.2.4.4 erlotinib and bevacizumab combination

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 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

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 coenzyme 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 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.
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2 eligibility assessment and enrollment

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/nonHLRCC 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 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
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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
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.
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2.2 screening evaluation

Screening evaluation testing/procedures are conducted under the separate screening protocol, 01C0129. Subjects will be screened per **Study Calendar**.
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2.3 patient registration and status

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  
| Number   | Name     | Description         |
|----------|----------|---------------------|
| 1        | Cohort 1 | Patients with HLRCC |  
| 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.
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3 study implementation 3.1 study

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.
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3.2 drug administration 3.2.1 bevacizumab

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 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.
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3.3 treatment modifications 3.3.1 general

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
at least 6 months after bevacizumab therapy. Women who become pregnant while on bevacizumab will discontinue the drug.
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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.
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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 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.
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3.3.3 dose modifications for toxicities

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.  
Hypertension will be managed in accordance with the guidelines outlined in the table  
below:  
| 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 |    |                                                                                                |  
| Grade 1/2 nonpulmonary 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                                                                                                                                                                                                                                                                                                                                                                                                                                   |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        |
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2. hemorrhage/bleeding the following scheme

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
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.
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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  No intervention/dose modification Grade 3  Hold bevacizumab treatment. If the planned duration of full-dose  anticoagulation is < 2 weeks, bevacizumab should be held until the fulldose anticoagulation period is over. OR Asymptomatic  Grade 4  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  Discontinue bevacizumab Grade 4   |
|---|
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6. allergic reactions and cytokine

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.  
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.
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3.3.4 dose modifications for toxicities

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.
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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.  
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
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2. management of gastrointestinal (gi)

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.
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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 diarrheafree 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.
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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. 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.
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3.3.5 management of female study

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.
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3.4 correlative studies for research

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.
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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: 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.
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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.
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2. circulating endothelial cells (cep

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 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 therapyrelated 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.
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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. PD1, 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 Trepeltrepel@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 240-7606330. 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.
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3.4.2 collection storage use and

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.
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3.4.2.2 storage and research use

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.
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3.5 study evaluation 3.5.1 baseline

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
Bone Scan 12 lead ECG
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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.
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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.  
| 3.5.6                                                                    | Study Calendar   |                                          |    |    |    |         |       |           |    |
|--------------------------------------------------------------------------|------------------|------------------------------------------|----|----|----|---------|-------|-----------|----|
| Cycle                                                                    | Screening        | Baseline                                 | 1  | 2  | 3  | Every 2 | Every | Restaging |    |
| weeks                                                                    | Cycle            | Disease  Progression / End of  Therapy m |    |    |    |         |       |           |    |
| cyclesl  (End of  Cycle 2 onward)                                        |                  |                                          |    |    |    |         |       |           |    |
| Day (D) of Cycle                                                         | 1                | 15                                       | 1  | 15 | 1  | 1       |       |           |    |
| (+/- 5 days) Informed consent                                            | X                |                                          |    |    |    |         |       |           |    |
| Complete Medical  history and  physical exam                             | Xa               | Xb                                       |    |    |    |         |       |           |    |
| Study Eligibility  incl availability of  tissue and  confirmation of  dx | X                |                                          |    |    |    |         |       |           |    |
| Targeted History &                                                       | Xd               | X                                        | X  | X  | X  |         |       |           |    |
| Focused Physical o Vital signs/weight o                                  | Xa, j            | X                                        | X  | X  | X  | X       | X     | X         | X  |
| ECHO                                                                     | Xa               | Xb                                       |    |    |    |         |       |           |    |
| 12-lead ECG                                                              | Xa               | Xb                                       |    |    |    |         |       |           |    |  
| Cycle                                                                                                                       | Screening   | Baseline                                 | 1   | 2   | 3   | Every 2   | Every   | Restaging   |
|-----------------------------------------------------------------------------------------------------------------------------|-------------|------------------------------------------|-----|-----|-----|-----------|---------|-------------|
| weeks                                                                                                                       | Cycle       | Disease  Progression / End of  Therapy m |     |     |     |           |         |             |
| cyclesl  (End of  Cycle 2 onward)                                                                                           |             |                                          |     |     |     |           |         |             |
| Day (D) of Cycle                                                                                                            | 1           | 15                                       | 1   | 15  | 1   | 1         |         |             |
| (+/- 5 days) 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                                                                                                         | Xd          | Xd                                       | X   | X   | X   | X         | X       | X           |
| protein/creatp 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                                       |     |     |     |           |         |             |  
| Cycle                                                             | Screening   | Baseline                                 | 1   | 2   | 3   | Every 2   | Every   | Restaging   |
|-------------------------------------------------------------------|-------------|------------------------------------------|-----|-----|-----|-----------|---------|-------------|
| weeks                                                             | Cycle       | Disease  Progression / End of  Therapy m |     |     |     |           |         |             |
| cyclesl  (End of  Cycle 2 onward)                                 |             |                                          |     |     |     |           |         |             |
| Day (D) of Cycle                                                  | 1           | 15                                       | 1   | 15  | 1   | 1         |         |             |
| (+/- 5 days) PET Scanq                                            | Xa          | Xb                                       | Xf  |     |     |           |         |             |
| Bone Scanq                                                        | Xa          | Xb                                       | Xe  |     |     |           |         |             |
| Sample for                                                        | X           | X                                        | X   | Xg  | X   |           |         |             |
| Biomarkers Tumor biopsy                                           | X           | X                                        |     |     |     |           |         |             |
| (optional) Review of Patient  Side Effect  Diary/Pill Count  Form | X           | X                                        | X   | X   |     |           |         |             |
| Tolerability/                                                     | X           | X                                        | X   | X   |     |           |         |             |
| AE reportingn Concurrent                                          | Xa          | X                                        | X   | X   | X   | X         |         |             |
| treatment Dermatology                                             | Xh          |                                          |     |     |     |           |         |             |
| Consult                                                           |             |                                          |     |     |     |           |         |             |  
| Cycle                                                                                                           | Screening   | Baseline                                 | 1   | 2   | 3   | Every 2   | Every   | Restaging   |
|-----------------------------------------------------------------------------------------------------------------|-------------|------------------------------------------|-----|-----|-----|-----------|---------|-------------|
| weeks                                                                                                           | Cycle       | Disease  Progression / End of  Therapy m |     |     |     |           |         |             |
| cyclesl  (End of  Cycle 2 onward)                                                                               |             |                                          |     |     |     |           |         |             |
| Day (D) of Cycle                                                                                                | 1           | 15                                       | 1   | 15  | 1   | 1         |         |             |
| (+/- 5 days) Photography of skin                                                                                | Xa, h       | Xb, h                                    | Xh  |     |     |           |         |             |
| lesions TSH                                                                                                     | Xa,i        | Xb, i                                    | X   | X   | X   |           |         |             |
| Anti-Mullerian  Hormone, FSH,  LH, estradiol,  progesteronek                                                    | Xa          | Xb                                       | X   |     |     |           |         |             |
| Serum Lactic Acid                                                                                               | Xa          | Xb                                       | X   |     |     |           |         |             |
| Xa                                                                                                              | Xb          |                                          |     |     |     |           |         |             |
| Free T4; anti-TPO  and TSI; and lipid  panel 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 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

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**).
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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).
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3.9 cost and compensation 3.9.1

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.
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3.10 criteria for removal from

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
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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 coenrolled. 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.
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4 supportive care

Supportive care will be provided in accordance with good medical practice.
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5 data collection and evaluation

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**.
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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, 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.
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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.
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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 nonmeasurable) 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.
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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 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 **nontarget 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 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 PETCT 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:
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.
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5.2.2.1 response criteria 5.2.2.2 evaluation

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
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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)
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.  
| Target   | Non-Target            | New     | Overall   | Best Overall Response when                        |
|----------|-----------------------|---------|-----------|---------------------------------------------------|
| Lesions  | Lesions               | Lesions | Response  | Confirmation is Required*                         |
| CR       | CR                    | No      | CR        | >4 wks. Confirmation**                            |
| CR       | Non-CR/NonPD                       | No      | PR        | >4 wks. Confirmation**                            |
| CR       | Not evaluated         | No      | PR        |                                                   |
| PR       | Non-CR/NonPD/not  evaluated                       | No      | PR        |                                                   |
| SD       | Non-CR/NonPD/not  evaluated                       | No      | SD        | documented at least once >4 wks.  from baseline** |
| PD       | Any                   | Yes or  | PD        |                                                   |
| No       | no prior SD, PR or CR |         |           |                                                   |
| Any      | PD***                 | Yes or  | PD        |                                                   |
| No       |                       |         |           |                                                   |  
| 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.  
| 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                 |
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for patients with non-measurable disease

* '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
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5.2.3 confirmatory measurement/duration of response

To be assigned a status of PR or CR, changes in tumor measurements must be confirmed by repeat assessments that should be performed ≥4 weeks after the criteria for response are first met. In the case of SD, follow-up measurements must have met the SD criteria at least once after study entry at a minimum interval of 8 weeks
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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).
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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 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.