Bevacizumab and Erlotinib Hydrochloride in Treating Patients with Hereditary Leiomyomatosis and Advanced Kidney Cancer
Basic Trial Information
|Phase II||Biomarker/Laboratory analysis, Treatment||18 and over||10-C-0114|
NCI-2013-01459, 100114, P10628, NCT01130519
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.
Further Study Information
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 vascular 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 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 uterine and 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 every 3 months.
Ability to understand and the willingness to sign a written informed consent document
No coagulopathy or bleeding diathesis
No myocardial infarction, gastrointestinal (GI) perforation/fistula, intraabdominal abscess, cerebrovascular accidents within six months prior to study entry
Negative pregnancy test (within 7 days of enrollment) in women of childbearing potential
At least 4 weeks from completion of major surgery and a healed surgical incision
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)
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 primary investigator [PI])
Total bilirubin < 1.5 x upper limit of reference range (< 3 x upper limit of reference range in patients with Gilbert's disease)
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2.5 x upper limit of reference range
Serum creatinine =< 2 x upper limit of reference range or creatinine clearance >= 30 ml/min
Platelet count >= 100,000/uL
Absolute neutrophil count >= 1,500/uL
White blood cell (WBC) count >= 3,000/uL
No more than two prior regimens targeting the VEGF pathway; no prior bevacizumab therapy
Measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as > 20 mm with conventional techniques or as >10 mm with spiral computed tomography (CT) scan
Diagnosis of advanced RCC associated with HLRCC (cohort 1) or sporadic/non-HLRCC papillary RCC (cohort 2)
Performance status Eastern Cooperative Oncology Group (ECOG) 0-2
Archival tissue block or unstained tumor tissue available for correlative studies
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
Concomitant therapy with potent inhibitors of cytochrome P450 family 3, subfamily A, polypeptide 4 (CYP450 3A4) (e.g. ketoconazole, verapamil etc) or with potent cytochrome P450 family 1, subfamily A, polypeptide 2 (CYP450 1A2) inhibitors (fluoroquinolone antibiotics including ciprofloxacin, levofloxacin, and norfloxacin; ticlopidine, cimetidine, amiodarone, etc.)
Any known hypersensitivity to bevacizumab, erlotinib or other excipients of these drugs
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
Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated on this study
Serious, non-healing wound or ulcer; bone fracture within 3 months prior to study entry
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
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)
Patients with known brain metastases unless treated with an appropriate modality with no evidence of progression/recurrence for > 3 months
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
Patient known to be human immunodeficiency virus (HIV)-positive and requiring antiretroviral therapy (due to the risk of potential drug interactions)
Left ventricular ejection fraction < 40% as measured on transthoracic echocardiogram
Trial Contact Information
Trial Lead Organizations / Sponsors / Collaborators
NCI - Center for Cancer Research
- National Cancer Institute
Mark O Hatfield-Warren Grant Magnuson Clinical Center
Link to the current ClinicalTrials.gov record.
NLM Identifer NCT01130519
Note: Information about participating sites on pharmaceutical industry trials may be incomplete. Please visit the ClinicalTrials.gov record via the link above for more information about participating sites.