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Phase I Study of Bevacizumab in Combination With Everolimus and Erlotinib in Advanced Cancer


Phase 1
18 Years
N/A
Open (Enrolling)
Both
Unspecified Adult Solid Tumor, Protocol Specific

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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 CenterDurham, North Carolina  27710