Bevacizumab and Erlotinib Hydrochloride in Treating Patients with Hereditary Leiomyomatosis and Advanced Kidney Cancer

Status: Active


This phase II trial studies how well bevacizumab and erlotinib hydrochloride work in treating patients with hereditary leiomyomatosis and kidney cancer that has spread to other places in the body and usually cannot be cured or controlled with treatment. Bevacizumab binds to a protein called vascular endothelial growth factor (VEGF) and may prevent the growth of new blood vessels that tumors need to grow. Erlotinib hydrochloride may stop the growth of tumor cells by blocking a protein called epidermal growth factor receptor (EGFR) that is needed for cell growth. Giving bevacizumab and erlotinib hydrochloride may be an effective treatment for hereditary leiomyomatosis and kidney cancer.

Eligibility Criteria

Inclusion Criteria

  • Diagnosis of advanced RCC associated with HLRCC (cohort 1) or sporadic/non-HLRCC papillary RCC (cohort 2)
  • Measurable disease as outlined in RECIST 1.1
  • No more than two prior regimens targeting the VEGF pathway; no prior bevacizumab therapy
  • Performance status Eastern Cooperative Oncology Group (ECOG) 0-2
  • White blood cell (WBC) count >= 3,000/uL
  • Absolute neutrophil count >= 1,500/uL
  • Platelet count >= 100,000/uL
  • Serum creatinine =< 2 x upper limit of reference range or creatinine clearance >= 30 ml/min
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2.5 x upper limit of reference range
  • Total bilirubin < 1.5 x 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 principal investigator [PI])
  • Recovery from acute toxicity of prior treatment for RCC (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 enrollment) in women of childbearing potential
  • No myocardial infarction, gastrointestinal (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

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 > 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
  • 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; ticlopidine, cimetidine, amiodarone, etc.)
  • Pregnant women are excluded from this study; 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 > 1000 mg/day on 24 hour urine collection; only patients with 1+ or greater proteinuria on urinalysis (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

Locations & Contacts


National Cancer Institute Urologic Oncology Branch
Status: Active
Contact: Ramaprasad Srinivasan
Phone: 240-760-6251 Email:
National Institutes of Health Clinical Center
Status: Active
Contact: Ramaprasad Srinivasan
Phone: 240-760-6251 Email:

Trial Objectives and Outline


I. To determine the overall response rate (Response Evaluation Criteria in Solid Tumors [RECIST]) in patients with 1) metastatic renal cell cancer (RCC) associated with hereditary leiomyomatosis (HL) RCC and 2) metastatic sporadic/non-HLRCC papillary RCC, treated with a combination of bevacizumab and erlotinib (erlotinib hydrochloride).


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

II. 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.

III. To investigate the effect of bevacizumab/erlotinib on potential biomarkers of angiogenesis in plasma such as VEGF and soluble vascular endothelial growth factor receptor 2 (VEGFR2).

IV. To evaluate the prevalence of somatic fumarate hydratase (FH) mutations/inactivation in patients with sporadic papillary RCC.

V. To determine the extent of transforming growth factor (TGF)-alpha upregulation and/or EGFR expression/pathway activation in leiomyomas/RCC tumor tissue (when available).

VI. To evaluate modulation of hypoxia-inducible factor 1 (HIF), VEGF and EGFR pathways in cutaneous leiomyomas (in patients with HLRCC) and in renal tumors (when tumors are accessible for biopsy) following therapy.

VII. To assess the effect of therapy on HLRCC associated skin leiomyomas.


Patients receive bevacizumab intravenously (IV) over 30-90 minutes on days 1 and 15 and erlotinib hydrochloride orally (PO) once daily (QD) on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and every 3 months thereafter.

Trial Phase & Type

Trial Phase

Phase II

Trial Type


Lead Organization

Lead Organization
NCI - Center for Cancer Research

Principal Investigator
Ramaprasad Srinivasan

Trial IDs

Primary ID 10-C-0114
Secondary IDs NCI-2013-01459, 100114, P10628 ID NCT01130519