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
HLRCC - Metastatic Papillary RCC
Conditions: official terms
Carcinoma, Renal Cell - Leiomyomatosis - Skin Neoplasms - Uterine Neoplasms
Conditions: Keywords
Advanced HLRCC, Sporadic Papillary Renal Cell Cancer, Papillary Kidney Cancer, Bevacizumab, Erlotinib, Kidney Cancer, Renal Cell Cancer, Hereditary Leiomyomatosis and Renal Cell Cancer, HLRCC
Study Type
Study Phase
Phase 2
Study Design
Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Name: Bevacizumab Type: Drug
Name: Erlotinib Type: Drug
Overall Status

- 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.


-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).


- 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.


- Participants will be screened with a full medical history, physical examination, blood and urine tests, and 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

- Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) is a familial cancer syndrome characterized by a propensity for developing renal cancer, uterine and cutaneous leiomyomas.The kidney cancer associated with HLRCC is associated with HLRCC is clinically aggressive and is characterized by unique histopathologic features that are sometimes described as type2 papillary RCC.

- Germline mutations in fumarate hydratase (FH) 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-alpha/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.


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

Secondary Objectives

- To assess progression-free survival, duration of response, and overall survival

- 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-alpha upregulation and/or EGFR expression or pathway activation in leiomyomas/ RCC tumor tissue (when available)

- To evaluate modulation of HIF, VEGF and EGFR pathways in leiomyomas (in patients with HLRCC) and in renal tumors (when tumors are accesible for biopsy) following therapy

- To assess the effect of therapy on HLRCC-associated leiomyomas


- Diagnosis of advanced RCC associated with HLRCC (cohort1) or sporadic/non-HLRCC papillary RCC (cohort2)

- ECOG PS 0-2

- Measurable disease

- 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:

- Adequate liver function (total bilirubin less than or equal to 1.5 mg/dL or < 3 times the upper limit of normal (ULN) in subjects with Gilbert s disease, and AST/ ALT less than or equal to 2.5 times the ULN)

- Adequate renal function (creatinine less than or equal to 2.0 times the 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 bevacizumab

- Ability to understand and sign informed consent


- Patients will receive a fixed dose of bevacizumab (10mg/kg IV every 2 weeks) and erlotinib (150mg/day 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 stratified into 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.
Criteria for eligibility
Healthy Volunteers: No
Maximum Age: N/A
Minimum Age: 18 Years
Gender: Both

Patients must meet all the following criteria to be eligible for study enrolment:

- Diagnosis of advanced RCC associated with HLRCC (cohort 1) or sporadic/non-HLRCC papillary RCC (cohort 2)

- Measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as greater than or equal to 20 mm with conventional techniques or as greater than or equal to 10 mm with spiral CT scan.

- No more than two prior regimens targeting the VEGF pathway; no prior bevacizumab therapy

- Age greater than or equal to 18 years.

- Performance status ECOG 0-2

- Patients must have normal organ and marrow function as defined below: 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, AST and 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 than or equal to 5 times the 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 less than or equal 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


- 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 has not required treatment for three 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 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) 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 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.
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States
Status: Recruiting
Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office - (888) NCI-1937
Start Date
May 2010
Completion Date
May 2016
National Cancer Institute (NCI)
National Institutes of Health Clinical Center (CC)
Record processing date
ClinicalTrials.gov processed this data on July 28, 2015
ClinicalTrials.gov page