NIH Clinical Research Studies

Protocol Number: 08-C-0179

Active Accrual, Protocols Recruiting New Patients

Title:
A Phase I Study of VEGF Trap (NSC #724770, IND #100137) in Children with Refractory Solid Tumors
Number:
08-C-0179
Summary:
Background:

One way tumors are able to grow is by forming new blood vessels that supply it with nutrients and oxygen. Blocking the growth of these vessels may slow tumor growth.

Cancers release proteins, including one called VEGF, that stimulate the formation of new blood vessels within the cancer.

VEGF Trap is a genetically engineered antibody that binds to the VEGF protein, blocking the formation of new blood vessels.

Objectives:

To find the highest safe dose of VEGF Trap that can be given without causing severe side effects.

To determine how VEGF Trap is handled by the body and how it affects body cells and proteins.

To examine the effect of VEGF Trap on tumor blood flow and determine if the drug is beneficial in treating cancer.

Eligibility:

Patients between 12 months and 21 years of age with solid tumor cancers that do not respond to standard treatments.

Design:

VEGF Trap is given as a 60-minute infusion into a vein once every 2 weeks for patients enrolled in Part A and once every 3 weeks for patients enrolled in part B of this dose escalation study.

The first group of three to six patients in study part A takes the smallest study dose of VEGF Trap. If they do not develop significant side effects, successive small groups of patients take the drug at increasingly higher doses until the highest safe dose is determined. Up to five different doses may be studied.

All patients in study part B receive the highest safe dose determined in part A.

Patients are evaluated periodically with physical examinations, blood and urine tests, and imaging tests (x-rays, CT and MRI scans) for safety studies and to evaluate the response to treatment.

Patients have additional blood tests for research.

Sponsoring Institute:
National Cancer Institute (NCI)
Recruitment Detail
Type: Participants currently recruited/enrolled
Gender: Male & Female
Referral Letter Required: No
Population Exclusion(s): None

Eligibility Criteria:
INCLUSION CRITERIA:

1) Age: Patients must be greater than 12 months and less than or equal to 21 years of age at the time of study enrollment.

2) Diagnosis: Patients must have had histologic verification of malignancy at original diagnosis or relapse. Patients with recurrent or refractory solid tumors are eligible, including primary CNS tumors or patients with known CNS metastases.

3) Disease Status: Patients must have either measurable or evaluable disease.

4) Therapeutic Options: Patient's current disease state must be one for which there is no known curative therapy or therapy proven to prolong survival with an acceptable quality of life.

5) Performance Level: Karnofsky greater than or equal to 50% for patients older than 16 years of age and Lansky greater than or equal to 50 for patients less than or equal to 16 years of age. Note: Neurologic deficits in patients with CNS tumors must have been relatively stable for a minimum of 1 week prior to study enrollment. Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.

6) Prior Therapy: Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study.

a) Myelosuppressive chemotherapy: Must not have received within 3 weeks of enrollment onto this study (6 weeks if prior nitrosourea).

b) Hematopoietic growth factors: At least 7 days since the completion of therapy with a growth factor.

c) Biologic (anti-neoplastic agent): At least 7 days since the completion of therapy with a biologic agent. At least 6 weeks must have elapsed since prior therapy that includes a monoclonal antibody. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur. The duration of this interval must be discussed with the study chair.

d) XRT: greater than or equal to 2 wks for local palliative XRT (small port); greater than equal to 3 months must have elapsed if prior TBI, craniospinal XRT or if greater than or equal to 50% radiation of pelvis; greater than or equal to 6 wks must have elapsed if other substantial BM radiation.

e) Stem Cell Transplant or Rescue: No evidence of active graft vs. host disease and greater than 2 months must have elapsed since transplant.

7) Organ Function Requirements:

Adequate Bone Marrow Function defined as:

a. For patients with solid tumors without bone marrow involvement:

1) Peripheral absolute neutrophil count (ANC) greater than or equal to 1000/microL

2) Platelet count greater than or equal to 100,000/microL (transfusion independent, defined as not receiving platelet transfusions within a 7 day period prior to enrollment)

3) Hemoglobin greater than or equal to 8.0 g/dL (may receive RBC transfusions)

b. Patients with known bone marrow metastatic disease will be eligible for study but not evaluated for hematologic toxicity. These patients must not be known to be refractory to red cell or platelet transfusion. At least 2 of every cohort of 3 patients must be evaluable for hematologic toxicity. If dose limiting hematologic toxicity is observed, all subsequent patients enrolled must be evaluable for hematologic toxicity.

Adequate Renal Function Defined as:

a) Negative protein dipstick or less than 500 mg protein/24 hour urine collection

b) Creatinine clearance or radioisotope GFR greater than or equal to 70mL/min/1.73 m(2) or serum creatinine based on age/gender as follows:

1 to less than 2 years of age, male: 0.6; female: 0.6 maximum serum creatinine (mg/dL)

2 to less than 6 years of age, male: 0.8, female: 0.8 maximum serum creatinine (mg/dL)

6 to less than 10 years or age, male: 1, female: 1 maximum serum creatinine (mg/dL)

10 to less than 13 years of age, male: 1.2, female: 1.2 maximum serum creatinine (mg/dL)

13 to less than 16 years of age, male: 1.5, female: 1.4 maximum serum creatinine (mg/dL)

Greater than or equal to 16 years of age, male: 1.7, female: 1.4 maximum serum creatinine (mg/dL)

Adequate Liver Function Defined As:

a) Bilirubin (sum of conjugated + unconjugated) less than or equal to 1.5 times the upper limit of normal (ULN) for age

b) SGPT (ALT) less than or equal to 110 U/L (approx. 2.5 times ULN). For the purpose of this study, the ULN for SGPT is 45 U/L

c) Serum albumin greater than or equal to 2 g/dL.

Adequate Blood Clotting Defines As:

a) PT/aPTT less than1.2 times the upper limit of normal

Blood Pressure

a) Patients must have a blood pressure (BP) less than or equal to the 95th percentile for age, height, and gender, and not be receiving medication for treatment of hypertension.

8) Informed Consent: All patients and/or their parents or legal guardians must sign a written informed consent. Assent, when appropriate, will be obtained according to institutional guidelines.

EXCLUSION CRITERIA:

1) Pregnancy or Breast-Feeding: Pregnant or breast-feeding women will not be entered on this study due to risks of fetal and teratogenic adverse events as seen in animal/human studies. Pregnancy tests must be obtained in girls who are post-menarchal. Males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method.

2) Concomitant Medications:

a) Growth factor(s): Growth factors that support platelet or white cell number or function must not have been administered within the 7 days prior to enrollment.

b) Corticosteroids: Patients receiving corticosteroids who have not been on a stable or decreasing dose of corticosteroid for the prior 7 days.

c) Investigational Drugs: Patients who are currently receiving another investigational drug.

d) Anti-cancer Agents: Patients who are currently receiving other anticancer agents.

e) Antihypertensives: Patients who are currently receiving medication(s) for blood pressure control.

f) Anti-thrombotic and anti-platelet agents: warfarin (coumadin ® (Registered Trademark)), heparin, low molecular weight heparin, aspirin, and/or ibuprofen, or other NSAIDs.

3) Infection: Patients who have an uncontrolled infection.

4) CNS disease: Evidence of CNS hemorrhage based upon baseline MRI obtained within 14 days prior to study enrollment.

5) Surgery: Patients who have had or are planning to have the following invasive procedures:

a) Major surgical procedure, laparoscopic procedure, open biopsy or significant traumatic injury within 28 days prior to Day 1 therapy. Subcutaneous port placement or central line placement is not considered major surgery but must be placed greater than 48 hours from planned Day 1 of therapy.

b) Core biopsy within 7 days prior to Day 1 therapy.

c) Fine needle aspirate or central line placement within 48 hours prior to Day 1 therapy.

6) Patients with serious or non-healing wound, ulcer, or bone fracture.

7) History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 28 days of treatment.

8) Patients with clinically significant cardiovascular disease (any of the following):

a) History of CVA within past 6 months, or

b) New York Heart Association grade III or greater congestive heart failure, serious cardiac arrhythmia requiring medication, unstable angina pectoris within past 6 months, or

c) Pulmonary embolism, DVT, or other thromboembolic event within past 6 months.

9) Patients with evidence of a current bleeding diathesis or coagulopathy.

10) Patients with known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies, and patients with a history of allergic reactions attributed to compounds of similar chemical or biologic composition to VEGF Trap.

11) Patients who have previously received study drug.

12) Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study.

Special Instructions:
Currently Not Provided
Keywords:
Angiogenesis
Vascular Endothelial Growth Factor Receptor
Childhood Cancer
Pharmacokinetics
Recruitment Keyword(s):
Cancer
Solid Tumor
Osteosarcoma
Ewing Sarcoma
Neuroblastoma
Rhabdomyosarcoma
Childhood Brain Tumor
Condition(s):
Osteosarcoma
Ewing's Sarcoma
Neuroblastoma
Rhabdomyosarcoma
Childhood Brain Tumor
Investigational Drug(s):
Aflibercept (VEGF Trap)
Investigational Device(s):
None
Intervention(s):
Drug: Aflibercept (VEGF Trap)
Supporting Site:
National Cancer Institute

Contact(s):
NCI Referral Office
National Institute of Health Clinical Center (CC), 9000 Rockville Pike, Bethesda, Maryland 20892, United States: NCI Clinical Trials Referral Office
Phone: 1-888-NCI-1937
Fax: Not Listed
Electronic Address: ncicssc@mail.nih.gov

Citation(s):
Dvorak HF, Dvorak AM, Manseau EJ, Wiberg L, Churchill WH. Fibrin gel investment associated with line 1 and line 10 solid tumor growth,angiogenesis, and fibroplasia in guinea pigs. Role of cellular immunity, myofibroblasts, microvascular damage, and infarction in line 1 tumor regression. J Natl Cancer Inst. 1979 Jun;62(6):1459-72.

Dvorak HF, Orenstein NS, Carvalho AC, Churchill WH, Dvorak AM, Galli SJ, Feder J, Bitzer AM, Rypysc J, Giovinco P.Induction of a fibrin-gel investment: an early event in line 10 hepatocarcinoma growth mediated by tumor-secreted products. J Immunol. 1979 Jan;122(1):166-74.

Bigler SA, Deering RE, Brawer MK. Comparison of microscopic vascularity in benign and malignant prostate tissue. Hum Pathol. 1993 Feb;24(2):220-6.

Active Accrual, Protocols Recruiting New Patients

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