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Bevacizumab, Everolimus, and Erlotinib in Treating Patients With Advanced Solid Tumors

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ClinicalTrials.gov Identifier: NCT00276575
Recruitment Status : Completed
First Posted : January 13, 2006
Last Update Posted : November 19, 2014
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Herbert Hurwitz, MD, Duke University

Brief Summary:

RATIONALE: Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Erlotinib and everolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Bevacizumab and everolimus may also block blood flow to the tumor. Giving everolimus and erlotinib together with bevacizumab may kill more tumor cells.

PURPOSE: This randomized phase I trial is studying the side effects and best dose of erlotinib and everolimus when given together with bevacizumab in treating patients with advanced solid tumors.


Condition or disease Intervention/treatment Phase
Unspecified Adult Solid Tumor, Protocol Specific Biological: bevacizumab Drug: erlotinib hydrochloride Drug: everolimus Phase 1

Detailed Description:

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.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 65 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I Study of Bevacizumab in Combination With Everolimus and Erlotinib in Advanced Cancer
Study Start Date : March 2005
Actual Primary Completion Date : October 2012
Actual Study Completion Date : September 2014

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Bevacizumab, Everolimus, and Erlotinib

Dose Level Dose Bevacizumab (mg/kg q2wks) Everolimus (mg daily) Erlotinib (mg daily) -1 5 5 ---

  1. 10 5 ---
  2. 10 10 ---
  3. 10* 10* 75
  4. 10* 10* 150
Biological: bevacizumab
Drug: erlotinib hydrochloride
Drug: everolimus



Primary Outcome Measures :
  1. Maximum Tolerated Dose [ Time Frame: Until study completion ]
    Its primary objective is to estimate the MTD/recommended phase II dose combination or regimen


Secondary Outcome Measures :
  1. Safety [ Time Frame: Until study completion ]
    endpoints will be evaluated in an exploratory fashion



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 atorvastatin
  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00276575


Locations
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United States, North Carolina
Duke Comprehensive Cancer Center
Durham, North Carolina, United States, 27710
Sponsors and Collaborators
Herbert Hurwitz, MD
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Herbert I. Hurwitz, MD Duke Cancer Institute

Publications of Results:
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Responsible Party: Herbert Hurwitz, MD, Associate Professor, Duke University
ClinicalTrials.gov Identifier: NCT00276575     History of Changes
Other Study ID Numbers: Pro00008048
DUMC-6026-05-6R1
GENENTECH-DUMC-6026-05-6R1
NOVARTIS-DUMC-6026-05-6R1
CDR0000449970 ( Other Identifier: NCI )
First Posted: January 13, 2006    Key Record Dates
Last Update Posted: November 19, 2014
Last Verified: November 2014

Keywords provided by Herbert Hurwitz, MD, Duke University:
unspecified adult solid tumor, protocol specific

Additional relevant MeSH terms:
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Bevacizumab
Everolimus
Sirolimus
Erlotinib Hydrochloride
Antineoplastic Agents, Immunological
Antineoplastic Agents
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors
Immunosuppressive Agents
Immunologic Factors
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action