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A Phase II Study of Bevacizumab and Lapatinib in Children With Recurrent or Refractory Ependymoma


Phase 2
N/A
21 Years
Open (Enrolling)
Both
Brain Cancer, Pediatric Cancers

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Trial Information

A Phase II Study of Bevacizumab and Lapatinib in Children With Recurrent or Refractory Ependymoma


The Study Drugs:

Bevacizumab is designed to block the growth of blood vessels that supply nutrients necessary
for tumor growth. This may prevent and/or slow down the growth of cancer cells.

Lapatinib is designed to prevent or slow down the growth of cancer cells by blocking
proteins inside the cancer cells.

Study Drug Administration:

If you are found to be eligible to take part in this study, you will receive bevacizumab
every 2 weeks while you are on study (2 times during each 4-week "study cycle"). The first
time you receive the drug, it will be given by vein over 90 minutes. If this dose is well
tolerated, you may receive future doses over 30 minutes.

You will take pills of lapatinib 2 times each day while you are on study. The pills should
be taken at about the same time each day. You should not eat or drink anything except water
for 1 hour before or 1 hour after you take the pills. If you miss a dose, do not take extra
pills the next day to try and make up for the missed dose. You should report any missed
pills or any trouble you may have with taking the pills to your study doctor.

You will be given a patient diary in which you must record what time you take lapatinib each
time.

Study Visits:

At all study visits, you will be asked about any other drugs that you may be taking and
about any side effects that you may be experiencing.

During Cycle 1 the following tests and procedures will be performed at least 1 time each
week:

- You will have a physical exam, including measurement of your vital signs.

- Your performance status will be recorded.

Two (2) times each week during Cycle 1, blood (about 2-3 teaspoons) will be drawn for
routine tests.

At the end of Cycle 1, urine will be collected for routine tests.

On Days 1 and 15 of Cycle 2, the following tests and procedures will be performed:

- You will have a physical exam, including measurement of your vital signs.

- Your performance status will be recorded.

- Blood (about 2-3 teaspoons) will be drawn for routine tests.

At the end of Cycle 2, you will have an MRI scan of your head to check the status of the
disease. If your doctor thinks it is needed, you will also have an MRI of your spine and a
spinal tap to check your CSF for presence of disease.

On Day 1 of Cycle 3 and beyond, the following tests and procedures will be performed:

- You will have a physical exam, including measurement of your vital signs.

- Your performance status will be recorded.

- Blood (about 2-3 teaspoons) and urine will be collected for routine tests.

Every 8 weeks, starting with the end of Cycle 4, while you are on study, the following tests
and procedures will be performed:

- You will have an MRI scan of the brain to check the status of the disease.

- If your doctor thinks it is needed, you will have an MRI scan of the spine to check the
status of the disease.

- If your doctor thinks it is needed, you will have a spinal tap to check your CSF for
the presence of disease.

Every 12 weeks while you are on study, the following tests and procedures will be performed
to check for possible side effects:

- You will have an echocardiogram or a MUGA scan (if the study doctor thinks it is
necessary) to test your heart function.

- You will have an x-ray of your right knee.

- If your doctor thinks it is needed, you will have an MRI scan of both knees.

Length of Study:

You will be on study for up to 2 years. You will be taken off study if the disease gets
worse, if you experience intolerable side effects, or if the doctor thinks it is in your
best interest.

End-of-Treatment Visit:

After you have finished receiving the study drugs, the following tests and procedures will
be performed:

- You will have a physical exam, including measurement of your vital signs.

- You will be asked about any other drugs that you may be taking and about any side
effects that you may be experiencing.

- Your performance status will be recorded.

- Blood (about 2-3 teaspoons) will be collected for routine tests.

- You will have an echocardiogram or a MUGA scan (if the study doctor thinks it is
necessary) to test your heart function.

- You will have an x-ray of your right knee.

- You will have MRI scans of the brain and spine to check the status of the disease.

- If your doctor thinks it is needed, you will have a spinal tap to check the status of
the disease.

Long-Term Follow-up:

You will have a follow-up visit 30 days after you have finished receiving the study drugs.
The following tests and procedures will be performed:

- You will have a physical exam, including measurement of your vital signs.

- You will be asked about any other drugs that you may be taking and about any side
effects that you may be experiencing.

- Your performance status will be recorded.

- Blood (about 2-3 teaspoons) will be collected for routine tests.

This is an investigational study. Bevacizumab is FDA approved and commercially available
for the treatment of colon, rectum, lung and certain types of breast cancer. Lapatinib is
FDA approved and commercially available for the treatment of certain types of breast cancer.
The use of this drug combination in ependymomas in pediatric patients is investigational.

Up to 40 patients will take part in this multicenter study. Up to 6 patients will be
enrolled at MD Anderson.


Inclusion Criteria:



1. Age: Patient must be < or = 21 years of age.

2. Tumor: Patients must have recurrent or refractory intracranial ependymoma (including
myxopapillary, clear cell, papillary, tanycytic, and anaplastic ependymoma) or
subependymoma. Patients with primary diagnosis of intracranial ependymoma with spinal
cord metastases or relapse are eligible. The diagnosis must be confirmed by the CERN
enrolling site's pathologist on tissue from either the initial presentation or time
of recurrence prior to registration. For central pathology review and trial
biological studies, submission of a paraffin block with tumor measuring at least 1 cm
x 1 cm in area is preferred, but 15 x 5micro m unstained sections on slides may be
provided by the referring laboratory instead. Tissue must be submitted within 60 days
after enrollment for central processing and analysis.

3. Patients must have measureable disease which is defined as at least one measurable
lesion that can be accurately measured in 2 planes. Diffuse leptomeningeal
involvement ("sugar coating") that does not allow measurement of at least one lesion
in 2 planes will not be considered measurable disease.

4. Patients may have had any number of prior treatment regimens (including biologic)
before or after radiotherapy. Patients may not have previously been treated with
Bevacizumab or Lapatinib. Gliadel wafers must be approved by CERN PI (Project Leader,
Co-Leader and Protocol PI).

5. Neurological Deficits: Patients with neurological deficits should have deficits that
are stable or improving for a minimum of 1 week prior to registration.

6. Performance Score: Karnofsky Performance Scale (KPS for > 16 years of age) or Lansky
Performance Score (LPS for < or = 16 years of age) > or = 50 assessed within 2 weeks
prior to registration.

7. Evidence of recovery from any prior chemotherapy. No myelosuppressive anticancer
chemotherapy or biological therapy within 3 weeks (6 weeks if a nitrosourea or
mitomycin C agent) prior to registration.

8. Prior/Concurrent Therapy: XRT: Patients must have had prior radiation therapy for
treatment of their ependymoma. XRT must be > or = 3 months prior to registration for
craniospinal irradiation (> or = 18 Gy); > or = 4 weeks for local radiation to
primary tumor; and > or = 2 weeks prior to registration for focal irradiation to
symptomatic metastatic sites.

9. Prior/Concurrent Therapy: Bone Marrow Transplant: > or = 3 months prior to
registration for autologous bone marrow/stem cell transplant.

10. Prior/Concurrent Therapy: Anti-convulsants: Patients with seizure disorder may be
enrolled if well controlled. Patients receiving enzyme-inducing anticonvulsants are
not eligible for this study. Patients must be off EIACD for at least 2 weeks prior to
registration.

11. Prior/Concurrent Therapy: Corticosteroids: Patients who are receiving corticosteroids
must be on a stable or decreasing dose for at least 1 week prior to registration.

12. Prior/Concurrent Therapy: Growth Factors: Off all colony forming growth factor(s) >
or = 2 weeks prior to registration (G-CSF, GM-CSF, Erythropoietin).

13. Patients must not have received: CYP3A4 inhibitors within seven (7) days prior to
registration on protocol and for the duration of the study. However, amiodarone,
another CYP3A4 inhibitor, should have been discontinued 6 months prior to
registration and for the duration of the study.

14. Patient must not have received: CYP3A4 inducers within fourteen (14) days prior to
registration and for the duration of the study.

15. Patient must not have received: Cimetidine within 48 hours prior and for the duration
of the study.

16. The following laboratory values must be assessed within 7 days prior to registration
and must be repeated if initial labs were done greater than (>seven) (7) calendar
days prior to the start of therapy. Organ Function: Must have adequate organ function
and marrow function as defined by the following parameters: Bone Marrow: Absolute
neutrophil count >or =1000microliter, Platelets > or = 100,000 microliter
(transfusion independent), Hemoglobin >or =8.0 g/dL. Renal: Serum creatinine 1.5 times upper limit of institutional for age or GFR>or = 70ml/min/1.73m2 Hepatic:
Total bilirubin < or = 1.5 times upper limit of normal for age: SGPT (ALT)<2.5x
institutional upper limit of normal for age and albumin > or = 2g/dL. No overt renal,
hepatic, cardiac or pulmonary disease.

17. No overt renal, hepatic, cardiac or pulmonary disease.

18. Adequate cardiac function, assessed within 2 weeks prior to registration, defined as:
shortening fraction of > or = 27% by echocardiogram, or ejection fracture (LVEF) > or
= 50% by gated radionucleotide study.

19. Adequate pulmonary function, assessed within 2 weeks prior to registration, defined
as: no evidence of dyspnea at rest, no exercise intolerance, and a pulse oximetry >
94% if there is clinical indication for determination.

20. Signed informed consent according to institutional guidelines must be obtained.

21. Women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry and
for the duration of study participation. Should a woman become pregnant or suspect
she is pregnant while participating in this study, she should inform her treating
physician immediately and will be removed from the study.

22. Patient must begin therapy within 7 calendar days of registration.

Exclusion Criteria:

1. Patients may not have previously been treated with Bevacizumab or Lapatinib.

2. Patients with any significant medical illnesses that, in the investigator's opinion,
cannot be adequately controlled with appropriate therapy or would compromise the
patient's ability to tolerate this therapy.

3. Patients with any disease that would obscure toxicity or dangerously alter drug
metabolism.

4. Patients receiving any other anticancer or experimental drug therapy.

5. Patients with uncontrolled infection.

6. Patients on enzyme inducing anticonvulsants.

7. Patients with > / = Grade 2 uncontrolled hypertension.

8. History of a stroke, myocardial infarction, or unstable angina in the previous 6
months.

9. Evidence of a bleeding diathesis, coagulopathy or PT INR>1.5.

10. Patients who require the use of therapeutic anti-coagulation: except as required to
maintain patency of preexisting permanent vascular catheter.

11. Pre-existing coagulopathy or thrombosis: Patients must not have been previously
diagnosed with a deep venous or arterial thrombosis (including pulmonary embolism),
and must not have a known thrombophilic condition.

12. Patients must have recovered from any surgical procedure before enrolling on this
study.

13. History of an abdominal fistula, GI perforation, or intra-abdominal abscess within
previous 6 months.

14. A serious, non healing wound, ulcer, or bone fracture.

15. Evidence of a new intracranial or intratumoral hemorrhage that is larger than a
punctuate size on baseline MRI obtained within 14 days prior to study registration.

16. If there is proteinuria present on dipstick, patients must have a 24 hour urine
collection. Patients are excluded if they have >500 mg protein on 24 hour urine
collection.

17. Pregnancy: Females of childbearing potential must have negative serum or urine
pregnancy test within 7 days prior to study entry. The effects of lapatinib on the
developing human fetus are unknown. However, bevacizumab is known to be teratogenic
and detrimental to fetal development and endometrial proliferation, thereby having a
negative effect on fertility.

18. Breastfeeding: Because there is an unknown but potential risk for adverse events in
nursing infants secondary to treatment of the mother with lapatinib of bevacizumab,
breastfeeding should be discontinued if the mother is treated on this study.

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

Response Rates

Outcome Time Frame:

4 Years

Safety Issue:

No

Principal Investigator

Michael E. Rytting, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

M.D. Anderson Cancer Center

Authority:

United States: Institutional Review Board

Study ID:

CERN08-01

NCT ID:

NCT00883688

Start Date:

July 2009

Completion Date:

Related Keywords:

  • Brain Cancer
  • Pediatric Cancers
  • Brain Tumor
  • Recurrent Ependymoma
  • Refractory Ependymoma
  • Intracranial ependymoma
  • Ependymoblastoma
  • Subependymoma
  • Myxopapillary
  • Clear cell
  • Anaplastic
  • Bevacizumab
  • Avastin
  • Anti-VEGF Monoclonal Antibody
  • rhuMAb-VEGF
  • Lapatinib
  • Tykerb
  • GW572016
  • Brain Neoplasms
  • Ependymoma

Name

Location

Stanford University Medical CenterStanford, California  94305-5408
Children's Hospital of PittsburghPittsburgh, Pennsylvania  15213
St. Jude Children's Research HospitalMemphis, Tennessee  38105-2794
Cincinnati Children's Hospital Medical CenterCincinnati, Ohio  45229-3039
UT MD Anderson Cancer CenterHouston, Texas  77030
Children's Memorial HospitalChicago, Illinois  60614