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Phase II Study of Clinical Activity and Proteomic Pathway Profiling of the Vascular Endothelial Growth Factor 2 (VEGFR2) Inhibitor, ZD6474 (Vandetanib) in Women With Relapsed or Refractory Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

Phase 2
18 Years
Not Enrolling
Ovarian Neoplasms, Fallopian Tube Neoplasms, Peritoneal Neoplasms

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Trial Information

Phase II Study of Clinical Activity and Proteomic Pathway Profiling of the Vascular Endothelial Growth Factor 2 (VEGFR2) Inhibitor, ZD6474 (Vandetanib) in Women With Relapsed or Refractory Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer


- Epithelial ovarian cancer requires neovascularization for growth and metastasis.
Anti-angiogenesis agents have been shown to have promise in the treatment of recurrent
disease. Expression of vascular endothelial growth factor 2 (VEGFR2) and epidermal
growth factor receptor (EGFR) has been demonstrated in ovarian cancer specimens in
stroma and tumor. Blocking autocrine and paracrine loops acting through these receptors
may inhibit downstream phosphorylation targets in the mitogen activated protein kinase
(MAPK) and AKT pathways, thereby influencing disease progression and patient outcome.

- The multi-kinase inhibitor ZD6474 (vandetanib, AstraZeneca, Zactima) blocks
angiogenesis by targeting VEGFR2, and shows in vitro activity against a number of other
receptor tyrosine kinases including resonance energy transfer (RET), vascular
endothelial growth factor 3 (VEGFR3) and EGFR.

- Clinical efficacy of ZD6474 (vandetanib) in women with refractory or relapsed
epithelial ovarian cancer is unknown, but preclinical data suggests potential value.

- The maximum tolerated dose of ZD6474 (vandetanib) has been determined at 300mg/day,
limited by the dose-responsive adverse effect of prolonged (Q wave, T wave)QT interval.


- To assess the clinical activity (CR - complete response, PR - partial response, or
disease stabilization) of the VEGFR2 inhibitor ZD6474 (vandetanib), 300mg/d, in women
with ovarian, fallopian tube or primary peritoneal cancer.

- To study target signal events: quantity and activation of VEGFR2, EGFR, AKT and
extracellular signal-regulated kinases (ERK).


- Women with biopsy-proven epithelial ovarian, fallopian tube or primary peritoneal
cancer that is relapsed and/or refractory to prior therapy.

- Women must have measurable disease by NCI Response Evaluation Criteria in Solid Tumors
(RECIST) criteria and a sentinel lesion adequate for core biopsy through percutaneous

- Women must have had no more than four prior treatment regimens.


- Women will receive 300mg of ZD6474 (vandetanib) daily, orally in 28-day cycles until
disease progression, excessive toxicity, or withdrawal from study.

- Biopsy of tumor will be performed prior to starting ZD6474 (vandetanib) and after six
weeks of treatment. The quantity of phosphorylated VEGFR2, EGFR, ERK and AKT in the
biopsy tissue will be analyzed.

- Clinical outcome and toxicity will be measured and correlated with target inhibition.

- Women will also undergo serial imaging with dynamic contrast-enhanced MRI to estimate
tumor blood flow.

- Research blood samples will be taken to assess changes in circulating cytokine

- Quality of life will be assessed during treatment.

Inclusion Criteria:

- All patients 18 years and older with biopsy-proven epithelial ovarian, fallopian tube
or primary peritoneal cancer that is relapsed or refractory to prior standard
platinum-and taxane based therapy will be eligible.

- Histopathologic diagnosis must be confirmed in the Laboratory of Pathology (LP), NCI.
A block of the primary or later access to recut slides is required. If this is
unavailable, a recent resection of a metastatic site is required for entry.

- All patients must have measurable disease by NCI RECIST criteria and a sentinel
lesion adequate for core biopsy through percutaneous biopsy.

- Patients must have a performance status of Eastern Cooperative Oncology Group (ECOG)
= 0, 1, or 2.

- Patients must have good end organ function:

- white blood cells (WBC) greater than 3000/mm(3)

- absolute neutrophil count (ANC) greater than 1000/mm(3)

- platelets greater than 150,000/mm(3)

- serum creatinine less than 1.5 mg/dl

- liver function tests (AST and ALT) within 2.5 times the upper limit of normal (ULN)

- bilirubin less than 1.5 mg/dl

- potassium between 4.0 and ULN (supplementation allowed)

- magnesium (Mg) and calcium (Ca) within normal limits (supplementation allowed)

- Systolic blood pressure less than 160 mm Hg and diastolic blood pressure less than
100 mm Hg (therapy permitted)

- Patients must be at least 4 weeks from previous therapy (chemotherapy, hormonal
therapy, and radiation therapy, alternative therapy or investigational agents).
Carboplatin, must not have been received for at least 6 weeks prior to enrollment.

- Patients must have received no more than 4 prior regimens for the treatment of
ovarian cancer.

- Patients must have recovered from any toxicity related to prior cancer therapy to NCI
grade 1, except for peripheral neuropathy, which must have recovered to grade 2 or

- Women of childbearing age and potential must agree to use adequate barrier
contraception (interaction with oral contraceptives is unknown) prior to study entry,
during therapy and for 3 months after completion of therapy.

- Patients must be able to give written informed consent.

- All eligible patients must be registered by contacting Central Registration personnel
by fax at (301) 480-0757 between the hours of 8:30am and 5:00 pm, Monday through

Exclusion Criteria:

- Evidence of severe or uncontrolled systemic disease or any concurrent condition which
in the investigators opinion makes it undesirable for the patient to participate in
the trial or which would jeopardize compliance with the protocol.

- Evidence of central nervous system (CNS) involvement (patients with abnormal clinical
exam or history will require a head CT or MRI.

- History of cardiac disorders including:

- Clinically significant cardiac event such as myocardial infarction, New York Heart
Association (NYHA) classification of heart disease greater than or equal to 2 within
3 months of entry, or presence of cardiac disease that, in the opinion of the
investigator,increases the risk of ventricular arrhythmia.

- Uncontrolled arrhythmia (multifocal premature ventricular contractions (PVCs),
bigeminy, trigeminy, ventricular tachycardia, or uncontrolled atrial fibrillation)
which is symptomatic.

- Previous history of medication-induced corrected QT interval (QTc) prolongation
requiring discontinuation of that medication.

- Congenital long (Q wave, T wave) QT syndrome, or 1st degree relative with unexplained
early sudden cardiac death(less than 40 years of age).

- Presence of left bundle branch block (LBBB).

- QTc, corrected per automated electrocardiogram (ECG) standards, that is unmeasurable,
or greater than or equal to 480 msec on screening ECG. If a patient has QTc greater
than or equal to 480 msec on screening ECG, the screen ECG may be repeated twice (at
least 24 hours apart). The average QTc from the three screening ECGs must be less
than 480 msec in order for the patient to be eligible for the study.

- Patients requiring any concomitant treatment with medication that may cause QTc
prolongation or induce Torsades de Pointes will not be permitted to enter this study
unless the agent can safely be changed to one not affecting QTc.

- Patients requiring any concomitant treatment with medication that may inhibit
(cytochrome p450 3A4) CYP3A4 will not be permitted to begin this study. If it is
considered medically safe to discontinue such medication, the patient may become
eligible once a sufficient amount of time after the last dose of such medications has
elapsed to consider the drug adequately eliminated (at least 5 half lives of the

- Patients with active infection will not be eligible, but may become eligible once
infection has resolved and they are at least 7 days from completion of antibiotics.

- Patients with incomplete wound healing from previous surgery or injury will be
ineligible. Patients must be at least 4 weeks from a major surgical procedure.

- Women who are actively breast-feeding will be excluded.

- Currently active diarrhea that is uncontrolled with medication (e.g. bulk agents or
loperamide) that may affect the ability of the patient to absorb the ZD6474.

- Previous or current malignancies within the last 5 years, with the exception of
cervical carcinoma in situ curatively treated, ductal or lobular carcinoma in situ
curatively treated and without ongoing therapeutic intervention.

- No concomitant use of complementary or alternative medication or other agents
(investigational or anti-cancer agents) will be allowed without approval of a
principal investigator (PI) or associate investigator (AI). Every effort will be made
to maximize patient safety and minimize changes in chronic medications.

- Patients with a history of deep venous thrombosis or pulmonary embolism within the
past 3 months or those patients requiring ongoing anticoagulation will be ineligible.

- Patients with a history of gastrointestinal (GI) bleed or gross hematuria within the
past 30 days will be ineligible.

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Number of Participants With Clinical Efficacy

Outcome Description:

Defined as complete response (CR), partial response (PR), or disease stabilization lasting 6 months or longer per RECIST criteria. CR-total disappearance of all evaluable disease. PR->30% reduction in the sum of the longest diameters (LD) of target lesions. Stable disease (SD) is <30% decrease and <20% increase in the sum of the LD of all target lesions. See the protocol Link module for full RECIST criteria.

Outcome Time Frame:

24 weeks

Safety Issue:


Principal Investigator

Elise C Kohn, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute, National Institutes of Health


United States: Federal Government

Study ID:




Start Date:

January 2007

Completion Date:

October 2009

Related Keywords:

  • Ovarian Neoplasms
  • Fallopian Tube Neoplasms
  • Peritoneal Neoplasms
  • Ovarian
  • VEGFR2
  • EGFR
  • Angiogenesis
  • Tyrosine Kinase
  • Protein Phosphorylation
  • Vandetanib
  • Ovarian Cancer
  • Fallopian Tube Cancer
  • Peritoneal Cancer
  • Neoplasms
  • Fallopian Tube Neoplasms
  • Ovarian Neoplasms
  • Peritoneal Neoplasms



National Institutes of Health Clinical Center, 9000 Rockville PikeBethesda, Maryland  20892