Carboplatin and Bevacizumab for Recurrent Ependymoma

Background:

Ependymomas are glial based tumors arising from the ependymal lining of the ventricular
system and central canal of the spinal cord These tumors affect both adults and children and
represent approximately 1.2%-7.8% of all intracranial cancers. Currently, the standard
therapy for newly diagnosed low-grade ependymoma includes total surgical excision, when
possible, followed by radiation therapy. Complete surgical resection is often not possible
because of the location of the tumor and the concern for damage to surrounding eloquent brain
during surgery. The situation is even more critical for patients with anaplastic ependymomas
because of the higher proliferative rate and greater propensity for tumor infiltration into
surrounding normal brain, preventing any possibility of complete tumor removal by surgery.

For patients with the more aggressive anaplastic ependymoma, chemotherapy is often
administered either before or after the radiation in the hope that infiltrating tumor cells
will be eliminated. Extensive experience has been gathered with the use of bevacizumab in
other neuroepithelial tumors such as malignant gliomas. Based on the interesting results
observed in the reported small series of patients with recurrent ependymomas treated with
bevacizumab, as well as on the evidence of VEGF-promoted angiogenesis in these tumors, we
designed a phase II study to test the efficacy of bevacizumab in patients with recurrent
ependymoma. As results in most types of tumors have indicated that anti-angiogenesis
therapies are more effective when given in combination with cytotoxic chemotherapy, in this
study bevacizumab will be combined with carboplatin. The choice of carboplatin is justified
by the fact that, as detailed above, this remains the most effective agent in this disease,
and extensive toxicity data is available for the combination of bevacizumab and carboplatin
in a variety of tumor types, including GBMs.

Objective:

To evaluate the efficacy of carboplatin and bevacizumab for the treatment of recurrent low
grade or anaplastic ependymoma. The primary endpoint will be progression-free survival (PFS)
at one year.

Eligibility:

- Histologically proven intra-cranial or spinal ependymoma or anaplastic ependymoma. There
must be pathologic or imaging confirmation of tumor progression or regrowth.

- Patients must be greater than or equal to18 years old.

- Patients must have a Karnofsky performance status of greater than or equal to 60.

- Patients must have adequate bone marrow function, adequate liver function and adequate
renal function before starting therapy.

- Patients must have recovered from the toxic effects of prior therapy.

- Patients having undergone recent resection of recurrent or progressive tumor will be
eligible.

- Patients must have failed prior radiation therapy and must have an interval of greater
than or equal to 42 days from the completion of radiation therapy to study entry.

- Women of childbearing potential must have a negative B-HCG pregnancy test documented
within 14 days prior to registration.

- Women of childbearing potential and male participants agree to practice adequate
contraception.

- Patients must not have any significant medical illnesses or active infection.

- Patients must not have history of any other cancer.

- Patients must not be pregnant/breast feeding.

- Patients must not have received prior therapy with bevacizumab, or related drugs.

- No active bleeding or pathological condition that carries a high risk of bleeding.

- No major surgical procedure, open biopsy, or significant traumatic injury within 28
days.

Design:

- This is a phase II study to evaluate the efficacy of carboplatin and bevacizumab for the
treatment of recurrent low grade or anaplastic ependymoma. This trial is designed
utilizing a Simon optimal two-stage design.

- Carboplatin will be given on day 1 of each cycle. Bevacizumab will be administered on
days 1 and 15 of each cycle. The total duration of treatment will be 6 cycles. After
cycle 6, carboplatin should be discontinued, but bevacizumab may be continued at the
discretion of the treating physician.

- Patients will be monitored for hematologic or serologic evidence of myelosuppression,
hepatic injury, renal injury, and electrolyte disturbances and for clinical evidence of
other toxicity.

- INCLUSION CRITERIA:

Histologically proven intra-cranial or spinal ependymoma or anaplastic ependymoma. There
must be pathologic or imaging confirmation of tumor progression or regrowth.

The patient must have at least 1 block of tissue or 15 unstained slides at a minimum
available for central pathology review and molecular profiling of the tissue sample.

All patients must sign an informed consent indicating that they are aware of the
investigational nature of this study. Patients must have signed an authorization for the
release of their protected health information.

Patients must be > 18 years old.

Patients must have a Karnofsky performance status of > 60.

Patients must have adequate bone marrow function (WBC > 3,000/microliter, ANC > 1,500/mm^3,
platelet count of > 100,000/mm^3, and hemoglobin > 10 gm/dl), adequate liver function (SGOT
[AST <92.5 Units/L] and bilirubin < 1.5 mg/dL), and adequate renal function (creatinine <
1.5 mg/dL and calculated creatinine clearance > 60 cc/min) before starting therapy.
Eligibility level for hemoglobin may be reached by transfusion.

Patients must have shown unequivocal radiographic evidence for tumor progression by MRI or
CT scan.

At the time of registration: Patients must have recovered from the toxic effects of prior
therapy: > 28 days from any investigational agent, >28 days from prior cytotoxic therapy,
>14 days from vincristine, >42 days from nitrosoureas, >21 days from procarbazine
administration, and >7 days for non-cytotoxic agents, e.g., interferon, tamoxifen,
thalidomide, cis-retinoic acid, etc. (radiosensitizer does not count). Any questions
related to the definition of non-cytotoxic agents should be directed to the Principal
Investigator.

Patients having undergone recent resection of recurrent or progressive tumor will be
eligible as long as all of the following conditions apply:

They have recovered from the effects of surgery.

A minimum of 28 days have elapsed from the day of surgery to the day of registration Step
2.

For core or needle biopsy, a minimum of 7 days must have elapsed prior to registration Step
2.

Residual disease following resection of recurrent ependymoma is not mandated for
eligibility into the study. To best assess the extent of residual disease post-operatively,
a CT/ MRI should be done no later than 96 hours in the immediate post-operative period or
at least 4 weeks post-operatively, within 14 days prior to consent. If the within 96-hour
after surgery scan is more than 14 days before consent the scan needs to be repeated. If
the steroid dose is increased between the date of imaging and consent, a new baseline
MRI/CT is required on a stable steroid dosage for at least 5 days.

Patients must have failed prior radiation therapy* and must have an interval of greater
than or equal to 42 days from the completion of radiation therapy to study entry. Note:
Patients with an indication for craniospinal radiotherapy (i.e., extensive leptomeningeal
disease) but have refused palliative craniospinal radiotherapy are eligible.

Patients with prior therapy that included interstitial brachytherapy or stereotactic
radiosurgery must have confirmation of true progressive disease rather than radiation
necrosis based upon either PET or Thallium scanning, MR spectroscopy, or
surgical/pathological documentation of disease.

Women of childbearing potential must have a negative B-HCG pregnancy test documented within
14 days prior to registration.

Women of childbearing potential and male participants agree to practice adequate

contraception.

EXCLUSION CRITERIA:

Patients withany 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.

Patients with a history of any other cancer (except non-melanoma skin cancer or carcinoma
insitu of the cervix), unless in complete remission and off of all therapy for that disease
for a minimum of 3 years are ineligible.

Patients with an active infection or serious intercurrent medical illness.

Patients found to be pregnant/breast feeding. Patients must not be pregnant because animal
studies show that carboplatin and bevacizumab are teratogenic

Patients with any disease that will obscure toxicity or dangerously alter drug

metabolism.

Patients who have received prior therapy with bevacizumab, or related drugs (previous
therapy with carboplatin is allowed).

Inadequately controlled hypertension (defined as systolic blood pressure >150 mmHg and/or
diastolic blood pressure > 100 mmHg) despite antihypertensive medication.

New York Heart Association (NYHA) Grade II or greater congestive heart failure.

9 History of myocardial infarction or unstable angina within 12 months prior to Day 1.

History of stroke or transient ischemic attack.

Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent
peripheral arterial thrombosis) within 6 months prior to Day 1.

History of hemoptysis (greater than or equal to 1/2 teaspoon of bright red blood per
episode) within 1 month prior to Day 1.

Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic
anticoagulation). (To be eligible, Prothrombin time/international normalized ratio (PT INR)
should be < 1.4 for patients not on warfarin.)

Patients receiving full-dose anticoagulants therapy (e.g., warfarin or LMW heparin) and
does not meet both of the following criteria:

No active bleeding or pathological condition that carries a high risk of bleeding (e.g.,
tumor involving major vessels or known varices).

In-range INR (usually between 2 and 3) on a stable dose of oral anticoagulant or on a
stable dose of low molecular weight heparin.

Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior
to Day 1 of treatment or anticipation of need for major surgical procedure during the
course of the study.

Core biopsy or other minor surgical procedure, excluding placement of a vascular access
device, within 7 days prior to Day 1.

History of abdominal fistula or gastrointestinal perforation within 6 months prior to Day
1.

Serious, non-healing wound, active ulcer, or untreated bone fracture.

Proteinuria as demonstrated by a UPC ratio greater than or equal to 1.0 at screening, or
Urine dipstick for proteinuria greater than or equal to 2+ (patients discovered to have
greater than or equal to 2+ proteinuria on dipstick urinalysis at baseline should undergo a
24 hour urine collection and must demonstrate less than or equal to 1g of protein in 24
hours to be eligible).

Known hypersensitivity to any component of bevacizumab.

Patients has current active hepatic or biliary disease (with exception of patients with
Gilbert s syndrome, asymptomatic gallstones, or stable chronic liver disease per
investigator assessment).