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Phase I Pharmacodynamic Trial of Sequential Sunitinib With Bevacizumab in Patients With Renal Cell Carcinoma and Other Advanced Solid Malignancies

Phase 1
18 Years
Open (Enrolling)
Clear Cell Renal Cell Carcinoma, Recurrent Renal Cell Cancer, Stage I Renal Cell Cancer, Stage II Renal Cell Cancer, Stage III Renal Cell Cancer, Stage IV Renal Cell Cancer, Unspecified Adult Solid Tumor, Protocol Specific

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Trial Information

Phase I Pharmacodynamic Trial of Sequential Sunitinib With Bevacizumab in Patients With Renal Cell Carcinoma and Other Advanced Solid Malignancies


I. To evaluate the safety and tolerability of sequential sunitinib (sunitinib malate) with
bevacizumab in patients with clear cell kidney cancer.

II. To assess the objective response rate of sequential sunitinib with bevacizumab in
patients with clear cell kidney cancer.


I. To determine the pharmacodynamic change in standardized uptake values (SUV) peak and
tumor perfusion using fluorine F 18 fluorothymidine positron emission tomography
(FLT-PET)/computed tomography (CT) scans at baseline, during sunitinib exposure, and during
bevacizumab exposure (during sunitinib withdrawal period) in patients with renal cell and
other solid malignancies.

II. To characterize changes in the ratio of free: bound plasma vascular endothelial growth
factor (VEGF) in patients treated with sequential sunitinib with bevacizumab.

OUTLINE: This is a dose-escalation study of sunitinib malate.

Patients receive sunitinib malate orally (PO) on days 1-28 and bevacizumab intravenously
(IV) over 30-90 minutes on day 29. Courses repeat every 6 weeks in the absence of disease
progression or unacceptable toxicity.

Inclusion Criteria:

- Patients must have histologically or cytologically confirmed renal cell; or other
solid malignancy (excluding lymphoma) that is metastatic or unresectable and for
which no standard curative therapy exists; for the renal cell cancer subset, a
component of clear cell histology is required (a minimum of 6 subjects with clear
cell kidney cancer will be enrolled per treatment stratification; additional subjects
enrolled per imaging cohort will allow "other" solid tumors)

- Patients must have 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 >= 2 times the slice width with spiral CT
scan (i.e. 10 mm if the CT slice width is 5 mm, 14 mm if the CT slice width is 7 mm)

- Life expectancy of greater than 12 weeks

- Leukocytes >= 3,000/mcL

- Absolute neutrophil count >= 1,500/mcL

- Platelets >= 100,000/mcL

- Hemoglobin >= 9 g/dL

- Serum calcium =< 12.0 mg/dL

- Total serum bilirubin within normal institutional limits

- Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase
[SGOT]))/alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase [SGPT])
=< 2.5 x institutional upper limit of normal, unless subjects have liver metastases,
in which case both AST and ALT must be =< 5 × institutional upper limit of normal

- Creatinine =< 1.5 x normal institutional limits OR

- Creatinine clearance (measured) >= 50 mL/min/1.73m^2 for patients with creatinine
levels above 1.5 x normal institutional limits

- Urine protein should be screened by urine analysis for urine protein creatinine (UPC)
ratio; for a UPC ratio > 0.5, a 24-hour urine protein should be obtained and the
level should be < 1,000 mg for eligibility; Note: UPC ratio of spot urine is an
estimation of the 24 hour urine protein excretion; A UPC ratio of 1 is roughly
equivalent to a 24-hour urine protein of 1 gram; UPC ratio is calculated by the
following formula:

- [urine protein]/[urine creatinine] (if both urine protein and creatinine
reported as mg/dL)

- [(urine protein) x 0.088]/[urine creatinine] (if urine creatinine is reported in

- All patients being evaluated for the imaging cohort need to be willing to undergo
planned pharmacodynamic assessments, including serial PET imaging, plasma markers,
and pharmacokinetic sampling

- Women of childbearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry, for
the duration of study participation, and for at least 6 months after the completion
of bevacizumab therapy; all women of childbearing potential must have a negative
pregnancy test prior to receiving sunitinib; should a woman become pregnant or
suspect she is pregnant while participating in this study, she should inform her
treating physician immediately

- Breastfeeding is not allowed while on study and for the duration of study
participation; the duration of such precautions after discontinuation of bevacizumab
should take into consideration the half-life of bevacizumab (average 21 days, range
11—50 days)

- Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

- Patients who have had chemotherapy, radiotherapy, experimental therapy within 4 weeks
(6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who
have not recovered (to grade =< 1 or baseline) from clinically significant adverse
events due to agents administered more than 4 weeks earlier (alopecia excluded);
clinical significance to be determined by investigator

- Patients may not be receiving any other investigational agents

- Patients who have received prior treatment with any other VEGF signaling pathway
inhibitors (e.g., bevacizumab, sorafenib, pazopanib, AZD2171, PTK787, VEGF Trap,
etc.) are ineligible

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to sunitinib or bevacizumab

- Patients with QTc prolongation (defined as a QTc interval greater than or equal to
500 msec) or other significant electrocardiogram (ECG) abnormalities (per
investigator discretion) are excluded

- Patients who require use of therapeutic doses of Coumarin-derivative anticoagulants
such as warfarin are excluded, although doses of up to 2 mg daily are permitted for
prophylaxis of thrombosis; Note: full-dose low-molecular weight heparin (or other
blood thinners) will be excluded as well given potential for bleeding with this
regimen; prophylactic doses of low-molecular weight heparin (LMWH) will be allowed if
prothrombin time (PT)/international normalized ratio (INR) is =< 1.5

- Patients with any condition (e.g., gastrointestinal tract disease resulting in an
inability to take oral medication or a requirement for IV alimentation, prior
surgical procedures affecting absorption, or active peptic ulcer disease) that
impairs their ability to swallow and retain sunitinib tablets are excluded

- Patients must have blood pressure (BP) no greater than 140 mmHg (systolic) and 90
mmHg (diastolic) for eligibility; initiation or adjustment of BP medication is
permitted prior to study entry provided that the average of three BP readings at a
visit prior to enrollment is less than 140/90 mmHg

- Patients with clinically significant cardiovascular disease are excluded

- Any history of cerebrovascular accident (CVA) or transient ischemic attack
within 12 months prior to study entry

- History of myocardial infarction, cardiac arrhythmia, stable/unstable angina,
symptomatic congestive heart failure, or coronary/peripheral artery bypass graft
or stenting within 12 months prior to study entry

- Serious and inadequately controlled cardiac arrhythmia

- Significant vascular disease (e.g. aortic aneurysm, history of aortic

- Clinically significant peripheral vascular disease

- History of pulmonary embolism within the past 12 months

- Class III or IV heart failure as defined by the New York Heart Association
(NYHA) functional classification system

- Patients with any of the following conditions are excluded:

- Serious or non-healing wound, ulcer, or bone fracture

- History of abdominal fistula, gastrointestinal perforation, or intra-abdominal
abscess within 6 months prior to day 1

- Because sunitinib is metabolized primarily by the cytochrome P450 3A4 (CYP3A4) liver
enzyme, the eligibility of patients taking medications that are potent inducers or
inhibitors of that enzyme will be determined following a review of their case by the
principal investigator; every effort should be made to change medication regimens to
include only those that do not affect CYP3A4, particularly patients who are taking
enzyme-inducing anticonvulsant agents; any identified agent must be stopped at least
2 weeks prior to study registration

- Use of agents with proarrhythmic potential (including but not limited to:
terfenadine, quinidine, procainamide, disopyramide, sotalol, probucol, bepridil,
haloperidol, risperidone, indapamide, and flecainide) are not permitted during the
study; a comprehensive list of agents with proarrhythmic potential can be found at

- Steroid use is not recommended during sunitinib treatment unless absolutely necessary
(e.g., for treatment of adverse events or protocol-required premedication) because
many steroids (e.g., prednisone, prednisolone, dexamethasone, etc.) effectively lower
sunitinib exposure through CYP3A4 interactions; patients currently using steroids
must be discussed with investigator prior to enrollment

- Patients with a pre-existing thyroid abnormality who are unable to maintain thyroid
function in the normal range with medication are ineligible; patients with a history
of hypothyroidism are eligible provided they are currently euthyroid

- Patients with known brain metastases should be excluded because of their poor
prognosis and because they often develop progressive neurologic dysfunction that
would confound the evaluation of neurologic and other adverse events

- Patients with uncontrolled intercurrent illness including, but not limited to,
ongoing or active infections or psychiatric illness/social situations that would
limit compliance with study requirements are ineligible

- Pregnant (positive pregnancy test) women are excluded from this study; breastfeeding
should be discontinued if the mother is treated with sunitinib malate

- Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
therapy are ineligible; appropriate studies will be undertaken in patients receiving
combination antiretroviral therapy when indicated

- Evidence of a bleeding diathesis or coagulopathy

- Invasive procedures defined as follows:

- Major surgical procedure, open biopsy or significant traumatic injury within 28
days prior to day 1 therapy

- Core biopsy within 7 days prior to day 1 therapy

- It is also appropriate to exclude subjects for whom there is the reasonable
possibility that they will require major surgical procedures during the trial

- Patients with known hypersensitivity of Chinese hamster ovary cell products or other
recombinant human antibodies

- For subjects with lung cancer, the following exclusions apply:

- Lung carcinoma of squamous cell histology (mixed tumors will be categorized by
the predominant cell type unless small cell elements are present, in which case
the patient is ineligible; sputum cytology alone is not acceptable)

- History of hemoptysis (bright red blood of 1/2 teaspoon or more per episode)
within 3 months prior to study enrollment

- Current, ongoing treatment with full-dose warfarin or its equivalent (i.e.,
unfractionated and/or low molecular weight heparin)

- Current or recent (within 10 days of enrollment) use of aspirin (>325 mg/day) or
chronic use of other nonsteroidal anti-inflammatory drugs (NSAIDs)

- Subjects with a history of thrombotic microangiopathy are excluded

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Proportion of patients with grade 3 or higher toxicities and recommended phase II dose of sunitinib in the presence of bevacizumab or sunitinib alone graded by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0

Outcome Time Frame:

6 weeks

Safety Issue:


Principal Investigator

Glenn Liu

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of Wisconsin Hospital and Clinics


United States: Food and Drug Administration

Study ID:




Start Date:

October 2010

Completion Date:

Related Keywords:

  • Clear Cell Renal Cell Carcinoma
  • Recurrent Renal Cell Cancer
  • Stage I Renal Cell Cancer
  • Stage II Renal Cell Cancer
  • Stage III Renal Cell Cancer
  • Stage IV Renal Cell Cancer
  • Unspecified Adult Solid Tumor, Protocol Specific
  • Carcinoma
  • Carcinoma, Renal Cell



University of Wisconsin Hospital and Clinics Madison, Wisconsin  53792-0001