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

Study Overview
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Brief Summary
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Background: At the present time, there are no drugs that have been proven to work in patients with papillary kidney cancer that has spread (metastasized) beyond the kidneys. Researchers are interested in determining whether the combination of the drugs bevacizumab and erlotinib can be used to treat metastatic papillary kidney cancer. Hereditary Leiomyomatosis and Renal Cell Carcinoma (HLRCC) is an inherited type of papillary kidney cancer (it runs in families). Papillary kidney cancer can also occur sporadically, or without a family connection. More research is needed to determine whether treatments for papillary kidney cancer, such as bevacizumab and erlotinib, work in inherited or sporadic types of kidney cancer, and if so, whether there are any differences. Objectives: -To determine the effectiveness of the combination of bevacizumab and erlotinib as a treatment for patients with (1) metastatic HLRCC kidney cancer and (2) metastatic kidney cancer not associated with HLRCC (or sporadic papillary RCC). Eligibility: Individuals 18 years of age or older who have been diagnosed with papillary kidney cancer that has spread beyond the kidneys. Participants may have either HLRCC or sporadic papillary kidney cancer. Design: Participants will be screened with a full medical history, physical examination, blood and urine tests, and computed tomography (CT) and other scans to evaluate tumor size and treatment options. Participants will receive 28-day treatment cycles of bevacizumab (given intravenously every 2 weeks) and erlotinib (a tablet taken by mouth daily). Every cycle, participants will return for regular blood and urine tests. Every other cycle, participants will have imaging scans to assess tumor size and response to treatment. Female participants who have uterine fibroid tumors related to their kidney cancer may have additional scans to assess tumor size and response to treatment. Participants will continue to receive treatment on the study until their tumors grow or spread to new areas (disease progression), intolerable side effects develop, a better treatment option becomes available, the study closes, it is unsafe to continue treatment, or the participant decides not to remain in the study.

Detailed Description
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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 Von Hippel-Lindau (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 vascular endothelial growth factor (VEGF) and transforming growth factor-alpha/epidermal growth factor receptor (EGFR), may be of benefit in this patient population. We propose to test the hypothesis that dual VEGF/EGFR blockade with bevacizumab/erlotinib is likely to be clinically active in patients with HLRCC associated RCC as well as those with sporadic papillary sporadic RCC. Objective Primary Objective -To determine the overall response rate (Response Evaluation Criteria in Solid Tumors (RECIST) in patients with 1) metastatic RCC associated with HLRCC and 2) metastatic sporadic/non-HLRCC papillary renal cancer treated with a combination of bevacizumab and erlotinib Eligibility Diagnosis of advanced RCC associated with HLRCC (cohorts 1 and 3) or sporadic/non-HLRCC papillary RCC (cohorts 2 and 4) Eastern Cooperative Oncology Group (ECOG) PS 0-2 Measurable disease, consistent with RECIST 1.1 No history of major bleeding, recent or active myocardial ischemia, gastrointestinal (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 Adequate liver function (total bilirubin <= 1.5 mg/dL or < 3 x upper limit of normal (ULN) in subjects with Gilbert's disease, and aspartate aminotransferase (AST) serum glutamic oxaloacetic transaminase (SGOT)/alanine aminotransferase (ALT) serum glutamic pyruvic transferase (SGPT) 2.5 x ULN Adequate renal function (creatinine <= 2.0 x ULN or creatinine clearance > 30 mL/min Neutrophils >1500/microL and platelets >100,000 No brain metastases No more than 2 prior regimens containing a VEGF-pathway inhibitor; no prior therapy with bevacizumab Ability to understand and sign informed consent Design Patients will receive a fixed starting dose of bevacizumab (10mg/kg intravenous (IV) every 2 weeks) and erlotinib (150mg/day by mouth (po). 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.

Official Title
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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

Conditions
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HLRCC, Sporadic Papillary Renal Cell Cancer

Intervention / Treatment
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* Drug: Bevacizumab
* Drug: Erlotinib


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Patients must meet all the following criteria to be eligible for study enrolment: Diagnosis of advanced renal cell cancer (RCC) associated with hereditary leiomyomatosis and renal cell cancer (HLRCC) (cohorts 1 & 3) or sporadic/non-HLRCC papillary RCC (cohort 2 & 4) Measurable disease outlined in Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 No more than two prior regimens targeting the vascular endothelial growth factor (VEGF) pathway; no prior bevacizumab therapy Age greater than or equal to 18 years. Performance status Eastern Cooperative Oncology Group (ECOG) 0-2 Patients must have normal organ and marrow function as defined below: white blood cell (WBC) count greater than or equal to 3,000/microL, absolute neutrophil count greater than or equal to 1,500/microL, platelet count greater than or equal to 100,000/microL, serum creatinine greater than or equal to 2 times the upper limit of reference range or creatinine clearance greater than or equal to 30 ml/min, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than 2.5 times the upper limit of reference range, total bilirubin less than 1.5 times the upper limit of reference range ( less than 3 x upper limit of reference range in patients with Gilbert's disease), alkaline phosphatase less than or equal to 2.5 times the upper limit of reference range (or less than or equal to 5 times the upper limit of reference range if considered to be related to liver or bone metastases by the principal investigator (PI) Recovery from acute toxicity of prior treatment for RCC (to less than or equal to grade 1 the active version of Common Terminology Criteria for Adverse Events (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, gastrointestinal (GI) perforation/fistula, intra-abdominal 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 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 greater than or equal to 2 years. Patients with known brain metastases unless treated with an appropriate modality with no evidence of progression/recurrence for greater than 3 months 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), 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 human immunodeficiency virus (HIV)-positive and requiring antiretroviral therapy (due to the risk of potential drug interactions) Concomitant therapy with potent inhibitors of Cytochrome P450 3A4 (CYP450 3A4) (e.g., ketoconazole, verapamil etc.) 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 enrolment 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 greater than 1000mg/day on 24-hour urine collection. Only patients with 1+ or greater proteinuria on urinalysis (UA) and a spot urine protein: creatinine ratio of greater than 0.5 will undergo a 24-hour urine collection for quantitation of proteinuria. Left ventricular ejection fraction less than 40% as measured on transthoracic echocardiogram. INCLUSION OF WOMEN AND MINORITIES: Both men and women and members of all races and ethnic groups are eligible for this trial.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1 - Bevacizumab and Erlotinib<br>All patients will be receiving fixed starting dose of bevacizumab (10 mg/kg intravenous (IV) every 2 weeks) and erlotinib (150 mg/day by mouth (PO) | Drug: Bevacizumab<br>* Commercially available. Administered by intravenous infusion.<br>* Other names: Avastin;Drug: Erlotinib<br>* Commercially available. Administered orally.<br>* Other names: Tarceva;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate | Participants whose tumors regressed (Complete Response (CR) plus Partial Response (PR)) after therapy as measured by the Response Evaluation Criteria in Solid Tumors (RECIST). CR is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR is at least a 30% decrease in the sum of the longest diameters of target lesions. Progressive Disease (PD) is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. The appearance of one or more new lesions is also considered progressions. Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Data shown with 95% confidence intervals. | Every 8 weeks during the first 32 weeks and every 12 weeks thereafter, a median of 64.3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival | Median amount of time subject survives without disease progression after treatment. Progression was measured by the Response Evaluation Criteria in Solid Tumors (RECIST) and is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. The appearance of one or more new lesions is also considered progressions. | Amount of time subject survives without disease progression after treatment; a median of 15 months. | 
| Duration of Response | Duration of overall response is measured from the time measurement criteria are met for Complete Response (CR) or Partial Response (PR) (whichever is first recorded) until the first date that recurrent or progressive disease (PD) is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started), measured by the Response Evaluation Criteria in Solid Tumors (RECIST). CR is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR is at least a 30% decrease in the sum of the diameters of target lesions. PD is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. The appearance of one or more new lesions is also considered progressions. | 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; a median of 19 months. | 
| Overall Survival (OS) | Overall survival is defined as the duration of time from the date of study enrolment until time of death estimated using a Kaplan Meier analysis. Participants without a death event will be censored at the date survival assessment was last evaluated (e.g., clinic visit, phone call). | Time from the date of study enrolment until time of death; a median of 29.3 months. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Immunotherapy, Biomarker, Kidney Cancer, Renal Cell Cancer, Hereditary Leiomyomatosis and Renal Cell Cancer, HLRCC