A Trial of Everolimus and Bevacizumab in Children With Recurrent Solid Tumors

This is a traditional phase I dose finding study to estimate the maximum tolerated dose
(MTD) and describe the dose limiting toxicities (DLT) of the combination of bevacizumab,
administered every 2 weeks IV and everolimus administered orally daily to children with
recurrent or refractory solid tumors including CNS malignancies. Patients will receive
bevacizumab every two weeks IV, and everolimus orally daily. Four consecutive weeks will
constitute one course and subsequent courses will immediately follow with no break in the
administration of either drug. In the absence of disease progression or unacceptable
toxicity, treatment can continue for 2 years. The bevacizumab dose will start at 10 mg/kg.
Everolimus will start at 4 mg/m2, 80% of the MTD established in our current phase I trial. A
traditional 3+3 dose escalation/de-escalation design will be used to determine the joint MTD
for these two agents. Doses to be studied are detailed in the table below. Consistent with
the traditional design, we will enroll cohorts of 3 patients at each dose level starting
with dose level 1 and will escalate to the next higher dose, if none of these 3 experiences
a DLT. If one of 3 patients experiences a DLT at a dose level then 3 more patients will be
studied at this level. If none of these 3 experiences a DLT then escalation to the next
level will occur. Otherwise the current dose will be considered too toxic and de-escalation
will occur. Under this setting, MTD will be the dose level at which 0/3 or 1/6 patient would
have experienced DLT and the next dose level is determined to be too toxic.

Exploratory objectives:

1. To preliminarily define the antitumor activity of the combination of everolimus and
bevacizumab within the confines of a phase I study

2. To assess the incidence of PTEN and PI3Kinase pathway activation in recurrent or
refractory solid tumors of childhood

3. To assess everolimus pharmacokinetics in children, including the effect of concomitant
drug therapy (e.g., dexamethasone).

4. To explore changes in correlative magnetic resonance imaging in children receiving
everolimus and bevacizumab

5. To identify additional genes both within and outside of the mTOR pathway that may act
as determinants of response to everolimus

6. To explore the pharmacogenetic polymorphisms responsible for everolimus disposition
(e.g., metabolism and elimination)

7. To test the ability of everolimus to inhibit mTOR pathway signaling in patients with
recurrent solid tumors including CNS malignancies in peripheral blood mononuclear cells

8. To estimate blood levels of VEGF, BFGF, TSP-1, I-CAM, v-CAM and circulating endothelial
cells prior to, during therapy and after therapy

Inclusion Criteria:

- Diagnosis: Solid tumor, including central nervous tumors, that is recurrent or
refractory to standard therapy or for which standard therapy is not available. All
research participants must have a pathologic diagnosis either from their initial
presentation, or at the time of recurrence or progression. The requirement for
histologic verification may be waived for patients with brainstem glioma and optic
pathway glioma.

- Performance Status: Karnofsky > 50% for > 10 years of age; Lansky > 50% for children
< 10 years of age. Patients who are unable to walk because of paralysis, but who are
up in a wheelchair, will be considered ambulatory for the purposes of assessing
performance score.

- Neurologic deficits. Patients with CNS tumors must have stable neurological deficits
for a minimum of 1 week prior to study entry.

- Life Expectancy: Must be greater than 8 weeks.

- Prior/Concurrent Therapy: Research participants must have recovered from the acute
effects of prior treatment and:

- Chemotherapy: Must not have received myelosuppressive chemotherapy within 3 weeks
prior to study entry (6 weeks if prior nitrosurea,).

- Stem Cell Transplant or Rescue: No evidence of active graft vs. host disease and
greater than or equal to 2 months must have elapsed.

- Steroids: Dose should be stable or decreasing for at least one week prior to starting
therapy. Corticosteroid therapy is permissible only for the treatment of increased
intracranial pressure in patients with malignancies in the CNS or for spinal cord
compression. Corticosteroid should be used at the lowest dose to control symptoms and
discontinued if possible.

- Must not be receiving tacrolimus or cyclosporine

- Biologic (anti-neoplastic) agent: At least 7 days since the completion of therapy
with a biologic agent.

- XRT: Must not have received XRT within 3 months prior to study entry for craniospinal
irradiation (>24 Gy) or total body irradiation or if greater than or equal to 50%
radiation of pelvis; > 8 weeks for local irradiation to primary tumor; > 2 weeks for
focal irradiation for symptomatic metastatic sites.

- Growth factors: Must be off growth factor(s) > 1 week prior to study entry (GCSF, GM
CSF, erythropoietin).

- Age: ≤ 21 years.

- Organ Function: Must have adequate organ function and marrow function as defined by
the following parameters:

- Bone marrow: peripheral ANC > 1,000/µl, hemoglobin > 8 g/dl (may be transfusion
dependent), platelets > 100,000/µ (transfusion independent). (Patients with bone
marrow involvement are eligible provided they meet these criteria).

- Hepatic: Bilirubin < 1.5 x institutional upper limit of normal (IULN), SGPT < 3 x
IULN.

- Renal: Normal creatinine for age or GFR > 70/ml/min/1.73m2.

- Cardiac: Must have normal EKG and Echocardiogram with shortening fraction > 27% or
ejection fraction > 50%.

- Pulmonary: No evidence of dyspnea at rest, no exercise intolerance, and a pulse
oximetry > 94% in room air, if there is clinical indication for determination

- Central Nervous System: Patients without seizure disorder OR patients with
well-controlled seizure disorder receiving anticonvulsants may be enrolled on this
protocol. Anticonvulsants must not be enzyme-inducing (i.e., no barbiturates,
phenytoin, carbamazepine, etc, please see Appendix II for a list of drugs that are
inducers and inhibitors of CYP3A)

- Informed consent explained to and signed by parent/legal guardian or patient if the
patient is ≥ 18 years.

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

- Patient must be able to swallow whole tablets

Exclusion Criteria:

- Concurrently receiving any other concomitant anticancer or experimental drug therapy.

- Have ≥ Grade 2 uncontrolled hypertension

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

- Evidence of a bleeding diathesis or PT INR>1.5

- Pre-existing Coagulopathy

- Major surgical procedure(s) within previous 4 weeks prior to study enrollment

- Minor surgical procedures within 7 days prior to study enrollment

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

- A serious, non-healing wound, ulcer, or bone fracture

- In patients with CNS tumors or known CNS metastases, evidence of intracranial or
intratumoral hemorrhage on baseline MRI obtained within 14 days prior to study
registration.

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

- Require treatment with any of the medications listed in Appendix II (Excluding
dexamethasone: Corticosteroid therapy is permissible only for the treatment of
increased intracranial pressure in patients with malignancies in the CNS or for
spinal cord compression. Corticosteroid should be used at the lowest dose to control
symptoms and discontinued if possible).

Use of H2 antagonists such as ranitidine, cimetidine and proton pump blockers such as
omeprazole are permissible only in conjunction with corticosteroids in the setting of
increased intracranial pressure or for spinal cord compression, as these drugs interfere
with CYP3A4. If patients are given such drugs, they must be taken at least 4 hours after
intake of everolimus.

- Have an uncontrolled infection.

- History of infection with the hepatitis B and/or C viruses or positive hepatitis B
virus surface antigen and hepatitis C virus antibody.

- Pregnant. Females of childbearing potential must have negative serum or urine
pregnancy test within 7 days prior to study entry. The effects of everolimus on the
developing human fetus are unknown. However, bevacizumab is known to be teratogenic
and detrimental to fetal development in animal models. In addition, bevacizumab may
alter corpus luteum development and endometrial proliferation, thereby having a
negative effect on fertility. For these reasons, 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.

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

- Inability or unwillingness of research participant or legal guardian/representative
to give written informed consent.