Phase I Study of Bevacizumab in Combination With Everolimus and Erlotinib in Advanced Cancer
18 Years
N/A
Both
Unspecified Adult Solid Tumor, Protocol Specific
Trial Information
Phase I Study of Bevacizumab in Combination With Everolimus and Erlotinib in Advanced Cancer
OBJECTIVES:
Primary
- Estimate the maximum tolerated dose (MTD)/recommended phase II regimen of everolimus
and erlotinib hydrochloride when given with bevacizumab in patients with advanced solid
tumors.
- Evaluate safety of bevacizumab, everolimus, and erlotinib hydrochloride in these
patients.
Secondary
- Describe the impact of this combination therapy on dermal wound angiogenesis and
inhibition of vascular endothelial growth factor receptor 1 (VEGFR1), mTOR/p70S6K, and
other related markers in granulation tissue.
- Evaluate clinical activity (partial response, complete response, or stable disease > 6
months) associated with this regimen.
OUTLINE: This is a dose-escalation study followed by a randomized study.
- Part 1: Patients receive bevacizumab IV on days 1 and 15 and oral everolimus and oral
erlotinib hydrochloride* once daily on days 1-28. Treatment repeats every 28 days in
the absence of disease progression or unacceptable toxicity.
Cohorts of patients receive escalating doses of everolimus or escalating doses of everolimus
and erlotinib hydrochloride* until the maximum tolerated dose (MTD) is determined. Patients
in part 2 of the study are treated at the MTD of everolimus and erlotinib hydrochloride.
NOTE: *The first cohort of patients receive bevacizumab and everolimus only until the MTD is
determined, the subsequent cohorts of patients receive bevacizumab, everolimus, and
erlotinib hydrochloride
- Part 2: Patients are randomized to 1 of 2 treatment arms.
- Arm I: Patients receive oral everolimus once daily beginning on day 1, oral
erlotinib hydrochloride once daily beginning on day 15, and bevacizumab IV once
every 2 weeks beginning on day 15. Treatment continues in the absence of disease
progression or unacceptable toxicity.
- Arm II: Patients receive oral erlotinib hydrochloride once daily beginning on day
1, oral everolimus once daily beginning on day 15, and bevacizumab IV once every 2
weeks beginning on day 15. Treatment continues in the absence of disease
progression or unacceptable toxicity.
After completion of study treatment, patients are followed periodically.
PROJECTED ACCRUAL: A total of 40 patients will be accrued for this study.
Inclusion Criteria
DISEASE CHARACTERISTICS:
- Histologically confirmed malignancy
- Metastatic or unresectable disease
- Standard curative or palliative measures do not exist OR are no longer effective
- No CNS metastases
- No centrally-located non-small cell lung cancer
PATIENT CHARACTERISTICS:
- ECOG performance status 0-2
- Leukocytes ≥ 3,000/mm³
- Absolute neutrophil count ≥ 1,500/mm³
- Platelet count ≥ 100,000/mm³
- Bilirubin ≤ 1.5 times upper limit of normal (ULN)
- AST/ALT ≤ 2.5 times ULN (5 times ULN if known hepatic metastases)
- Urine protein to creatinine ratio ≤ 1.0 OR urine protein < 1 g by 24 hour urine
collection
- Creatinine clearance ≥ 50 mL/min OR creatinine normal
- Not pregnant or nursing
- Negative pregnancy test
- Fertile patients must use effective contraception during study and for up to 4 months
after study treatment has stopped
- No uncontrolled hypertriglyceridemia (i.e., fasting serum triglyceride > 350 mg/dL)
- No uncontrolled hypercholesterolemia (i.e., fasting serum cholesterol > 300 mg/dL)
- No poorly controlled hypertension (i.e., blood pressure > 160/100 mm Hg)
- No poorly controlled or clinically significant atherosclerotic vascular disease
- No thrombosis within 6 months
- No venous thromboembolic event within 6 months
- No arterial thromboembolic events within 12 months
- No cerebrovascular accident or transient ischemic attack in past 12 months
- No myocardial infarction or unstable angina in past 12 months
- No clinically significant peripheral vascular disease in past 12 months
- No New York Heart Association class II-IV congestive heart failure
- Atrial or supraventricular tachycardias well controlled with beta blocker or
calcium channel blocker allowed
- Chronic pacemaker use allowed
- No serious cardiac arrhythmia requiring medication
- No other clinically significant cardiovascular disease
- No hemoptysis > 1 tablespoon within 6 months
- No presence of bleeding diathesis
- No coagulopathy
- No presence of significant gastrointestinal (GI) disorders that would affect drug
absorption
- No hemodynamically significant GI bleeding
- No history of intolerance to bevacizumab, everolimus, or erlotinib
- No other major bleeding event
- No ongoing or active infection
- No psychiatric illness or social situations that would limit safety or compliance
with study requirements
- No other uncontrolled intercurrent illness
PRIOR CONCURRENT THERAPY:
- No angioplasty or cardiac or vascular stenting within the past 12 months
- No major surgery within past 28 days
- No other investigational agents within past 28 days
- No chemotherapy for cancer within past 21 days
- No biologic therapy for cancer within past 21 days
- No radiation therapy for cancer within past 21 days
- No hormonal therapy for cancer within past 21 days
- No minor surgical procedures within past 14 days
- No concurrent antiplatelet agents other than aspirin < 325 mg/day
- No use of statin drugs other than pravastatin or atorvostatin
- Initiation of blood pressure (BP) medication is permitted prior to study entry
provided that BP < 150/90 mm Hg on 3 measurements over one week (study day -7 to 1)
before starting treatment
- No concurrent grapefruit juice
- No concurrent therapeutic anticoagulation
- Prophylactic low-dose anticoagulation for indwelling catheters is permitted
- No concurrent administration of any of the following drugs:
- Nicardipine
- Verapamil
- Clotrimazole
- Fluconazole
- Itraconazole
- Ketoconazole
- Clarithromycin
- Erythromycin
- Troleandomycin
- Cisapride
- Metoclopramide
- Bromocriptine
- Cimetidine
- Danazol
- HIV-protease inhibitors (e.g., ritonavir, indinavir)
- Hypericum perforatum (St. John's wort)
- Carbamazepine
- Phenobarbital
- Phenytoin
- Diltiazem
- Rifabutin
- Rifapentine
- Rifampin
Type of Study:
Interventional
Study Design:
Allocation: Non-Randomized, Intervention Model: Single Group Assignment, Primary Purpose: Treatment
Outcome Measure:
Maximum Tolerated Dose
Outcome Description:
Its primary objective is to estimate the MTD/recommended phase II dose combination or regimen
Outcome Time Frame:
Until study completion
Safety Issue:
Yes
Principal Investigator
Herbert I. Hurwitz, MD
Investigator Role:
Principal Investigator
Investigator Affiliation:
Duke Cancer Institute
Authority:
United States: Food and Drug Administration
Study ID:
Pro00008048
NCT ID:
NCT00276575
Start Date:
March 2005
Completion Date:
Related Keywords:
- Unspecified Adult Solid Tumor, Protocol Specific
- unspecified adult solid tumor, protocol specific
- Neoplasms
Name | Location |
|---|---|
| Duke Comprehensive Cancer Center | Durham, North Carolina 27710 |
