Vandetanib to Treat Women With Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Terminated
• CT.gov ID: NCT00445549
• Collaborator: (none)
• Enrollment: 12
• Location: 1
• Arm: 1
• Duration (Months): 33
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

Background:

• Vandetanib is a drug that attacks a group of proteins on the surface of many cells, especially blood vessel cells and tumor cells.

• Tumors require the development of new blood vessels in order to grow and spread.

• In laboratory experiments, vandetanib slowed the growth of certain tumors and regulated their blood vessel growth.

• In early clinical trials, some patients' tumors did not grow for a period of time while they were receiving vandetanib.

Objectives:

• To determine whether vandetanib can cause tumors to shrink or stabilize in some patients with ovarian cancer, fallopian tube cancer or primary peritoneal cancer.

• To determine, by tumor biopsy, if features of the tumor change with vandetanib treatment may predict if the tumor will likely respond to vandetanib.

Eligibility:

• Women 18 years of age and older with ovarian, fallopian tube or primary peritoneal cancer that does not respond to standard treatment.

Design:

• Patients take vandetanib daily, by mouth in 28-day cycles until their disease worsens or they develop unacceptable side effects.

• Tumor biopsies (surgical removal of a sample of tumor tissue) are done before starting vandetanib treatment and after 6 weeks of treatment.

• Patients are followed in the clinic every 4 weeks during treatment for a physical examination, blood tests, and review of laboratory studies and side effects.

• Patients have a computed tomography (CT) scan every 8 weeks to monitor tumor growth and magnetic resonance imaging (MRI) before starting vandetanib treatment, on the third day after taking vandetanib and 6 weeks into treatment.

• Patients quality of life is assessed with regularly scheduled questionnaires.

Condition or Disease	Intervention/Treatment	Phase
Ovarian Neoplasms; Fallopian Tube Neoplasms; Peritoneal Neoplasms	Drug: Vandetanib	Phase 2

Detailed Description

Background:

• 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.

Objectives:

• 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).

Eligibility:

• 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 biopsy.

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

Design:

• 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 concentrations.

• Quality of life will be assessed during treatment.

Study Design

• Study Type: Interventional
• Actual Enrollment: 12 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: Jan 1, 2007
• Actual Primary Completion Date: Dec 1, 2008
• Actual Study Completion Date: Oct 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Vandetanib treatment 300 mg daily oral dose, 28 day cycle	Drug: Vandetanib; 300 mg daily dose, 28 day cycle; Other Names: Zactima ZD6474

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Clinical Efficacy [24 weeks]

   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.

Secondary Outcome Measures

1. The Number of Participants With Adverse Events [22 months]

   Here are the total # of participants with adverse events. For the detailed list of adverse events, see the adverse event module.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

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 better.

• 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 [phone] between the hours of 8:30am and 5:00 pm, Monday through Friday.

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 drug).

• 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	National Institutes of Health Clinical Center, 9000 Rockville Pike	Bethesda	Maryland	United States	20892

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Elise C Kohn, M.D., National Cancer Institute, National Institutes of Health

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• MedlinePlus
• Drug Information
• U.S. FDA Resources
• RECIST

Publications

• Hollingsworth HC, Kohn EC, Steinberg SM, Rothenberg ML, Merino MJ. Tumor angiogenesis in advanced stage ovarian carcinoma. Am J Pathol. 1995 Jul;147(1):33-41.
• Ryan AJ, Wedge SR. ZD6474--a novel inhibitor of VEGFR and EGFR tyrosine kinase activity. Br J Cancer. 2005 Jun;92 Suppl 1:S6-13. Review.
• Spentzos D, Levine DA, Ramoni MF, Joseph M, Gu X, Boyd J, Libermann TA, Cannistra SA. Gene expression signature with independent prognostic significance in epithelial ovarian cancer. J Clin Oncol. 2004 Dec 1;22(23):4700-10. Epub 2004 Oct 25. Erratum in: J Clin Oncol. 2005 Jan 1;23(1):248.

• ClinicalTrials.gov Identifier: NCT00445549
• Other Study ID Numbers: 070061; 07-C-0061; 070061
• First Posted: Mar 9, 2007
• Last Update Posted: Jun 26, 2012
• Last Verified: May 1, 2012

• Keywords provided by , ,: Ovarian; VEGFR2; EGFR; Angiogenesis; Tyrosine Kinase; Protein Phosphorylation; Vandetanib; Ovarian Cancer; Fallopian Tube Cancer; Peritoneal Cancer
• Additional relevant MeSH terms: Neoplasms; Ovarian Neoplasms; Peritoneal Neoplasms; Fallopian Tube Neoplasms

Study Results

Participant Flow

Recruitment Details	If 2-3 patients per month enroll onto this trial, it is expected that approximately one and a half years will be required to enroll the 35 evaluable patients required for evaluation in this study. To make an allowance for a small drop-out of patients from the study and still preserve the intended accrual goal, the total accrual will be38 patients.

Arm/Group Title	Vandetanib Treatment
Arm/Group Description	300 mg daily oral dose, 28 day cycle
Period Title: Overall Study
STARTED	12
COMPLETED	0
NOT COMPLETED	12

Baseline Characteristics

Arm/Group Title	Vandetanib Treatment
Arm/Group Description	300 mg daily oral dose, 28 day cycle
Overall Participants	12
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	8 66.7%
>=65 years	4 33.3%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	59.13 (9.88)
Sex: Female, Male (Count of Participants)
Female	12 100%
Male	0 0%
Region of Enrollment (participants) [Number]
United States	12 100%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Clinical Efficacy
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.
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Vandetanib Treatment
Arm/Group Description	300 mg daily oral dose, 28 day cycle
Measure Participants	12
Number [participants]	0 0%

2. Secondary Outcome

Title	The Number of Participants With Adverse Events
Description	Here are the total # of participants with adverse events. For the detailed list of adverse events, see the adverse event module.
Time Frame	22 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Vandetanib Treatment
Arm/Group Description	300 mg daily oral dose, 28 day cycle
Measure Participants	12
Number [Participants]	12 100%

Adverse Events

Time Frame	22 months
Arm/Group Title	Vandetanib Treatment
Arm/Group Description	300 mg daily oral dose, 28 day cycle
All Cause Mortality
	Vandetanib Treatment
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Vandetanib Treatment
	Affected / at Risk (%)	# Events
Total	0/12 (0%)
Other (Not Including Serious) Adverse Events
	Vandetanib Treatment
	Affected / at Risk (%)	# Events
Total	12/12 (100%)
Blood and lymphatic system disorders
Leukocytes (total WBC)	2/12 (16.7%)	2
Lymphopenia	2/12 (16.7%)	3
Platelets	2/12 (16.7%)	4
Eye disorders
Photosensitivity	1/12 (8.3%)	1
Vision-flashing lights/floaters	1/12 (8.3%)	1
Gastrointestinal disorders
Constipation	1/12 (8.3%)	1
Diarrhea	10/12 (83.3%)	21
Distension/bloating, abdominal	2/12 (16.7%)	2
Dry mouth/salivary gland (xerostomia)	1/12 (8.3%)	1
Heartburn/dyspepsia	1/12 (8.3%)	1
Hemorrhage, GI::Rectum	1/12 (8.3%)	1
Mucositis/stomatitis (functional/symptomatic)::Oral cavity	1/12 (8.3%)	1
Nausea	4/12 (33.3%)	4
Obstruction, GI::Small bowel NOS	1/12 (8.3%)	1
General disorders
Edema: limb	1/12 (8.3%)	1
Fatigue (asthenia, lethargy, malaise)	6/12 (50%)	6
Fever (in the absence of neutropenia, where neutropenia is defined as ANC <1.0 x 10e9/L)	3/12 (25%)	3
Pain::Abdomen NOS	5/12 (41.7%)	6
Pain::Chest/thorax NOS	1/12 (8.3%)	1
Hepatobiliary disorders
Bilirubin (hyperbilirubinemia)	3/12 (25%)	8
Infections and infestations
Infection with normal ANC or Grade 1 or 2 neutrophils::Upper airway NOS	1/12 (8.3%)	1
Infection with normal ANC or Grade 1 or 2 neutrophils::Vulva	1/12 (8.3%)	1
Infection with normal ANC or Grade 1 or 2 neutrophils::Vagina	1/12 (8.3%)	1
Infection with unknown ANC::Urinary tract NOS	1/12 (8.3%)	1
Injury, poisoning and procedural complications
Burn	1/12 (8.3%)	1
Investigations
ALT, SGPT (serum glutamic pyruvic transaminase)	8/12 (66.7%)	15
AST, SGOT(serum glutamic oxaloacetic transaminase)	11/12 (91.7%)	16
Alkaline phosphatase	4/12 (33.3%)	6
Creatinine	2/12 (16.7%)	3
Hemoglobin	2/12 (16.7%)	2
Hemoglobinuria	3/12 (25%)	3
Neutrophils/granulocytes (ANC/AGC)	2/12 (16.7%)	2
PTT (Partial Thromboplastin Time)	2/12 (16.7%)	2
Prolonged QTc interval	8/12 (66.7%)	13
Weight loss	2/12 (16.7%)	3
Metabolism and nutrition disorders
Albumin, serum-low (hypoalbuminemia)	9/12 (75%)	14
Anorexia	5/12 (41.7%)	5
Calcium, serum-low (hypocalcemia)	1/12 (8.3%)	1
Dehydration	1/12 (8.3%)	1
Glucose, serum-high (hyperglycemia)	4/12 (33.3%)	6
Glucose, serum-low (hypoglycemia)	1/12 (8.3%)	1
Magnesium, serum-high (hypermagnesemia)	2/12 (16.7%)	2
Magnesium, serum-low (hypomagnesemia)	6/12 (50%)	12
Potassium, serum-high (hyperkalemia)	4/12 (33.3%)	5
Sodium, serum-low (hyponatremia)	4/12 (33.3%)	5
Uric acid, serum-high (hyperuricemia)	5/12 (41.7%)	6
Musculoskeletal and connective tissue disorders
Pain::Extremity-limb	1/12 (8.3%)	1
Pain::Joint	1/12 (8.3%)	2
Pain::Muscle	2/12 (16.7%)	2
Nervous system disorders
Neuropathy: sensory	1/12 (8.3%)	1
Pain::Head/headache	1/12 (8.3%)	1
Taste alteration (dysgeusia)	1/12 (8.3%)	1
Psychiatric disorders
Insomnia	2/12 (16.7%)	2
Renal and urinary disorders
Hemorrhage, GU::Ureter	1/12 (8.3%)	1
Incontinence, urinary	1/12 (8.3%)	1
Obstruction, GU::Ureter	1/12 (8.3%)	1
Proteinuria	2/12 (16.7%)	2
Urinary frequency/urgency	1/12 (8.3%)	1
Reproductive system and breast disorders
Hemorrhage, GU::Vagina	1/12 (8.3%)	1
Pain::Pelvis	1/12 (8.3%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnea (shortness of breath)	2/12 (16.7%)	4
Hemorrhage, pulmonary/upper respiratory::Nose	1/12 (8.3%)	1
Nasal cavity/paranasal sinus reactions	2/12 (16.7%)	2
Voice changes/dysarthria (e.g., hoarseness, loss or alteration in voice, laryngitis)	2/12 (16.7%)	2
Cough	3/12 (25%)	3
Skin and subcutaneous tissue disorders
Dermatology/Skin - Other (Specify, __)	3/12 (25%)	3
Dry skin	2/12 (16.7%)	2
Hair loss/alopecia (scalp or body)	1/12 (8.3%)	1
Nail changes	1/12 (8.3%)	1
Pruritus/itching	1/12 (8.3%)	1
Rash/desquamation	6/12 (50%)	8
Rash: acne/acneiform	6/12 (50%)	7
Rash: hand-foot skin reaction	2/12 (16.7%)	2
Vascular disorders
Hot flashes/flushes	1/12 (8.3%)	1

Limitations/Caveats

The study closed after the first stage of accrual because of inadequate early activity with 32 cycles of administered treatment.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.