Sorafenib and Cyclophosphamide/Topotecan in Patients With Relapsed and Refractory Neuroblastoma

This study will combine three drugs: sorafenib, cyclophosphamide and topotecan.

This study involves the use of an experimental drug, called sorafenib. Sorafenib blocks the
function of a protein that is important in the growth of cancer cells. This drug has been
tested by itself (as a single-agent) in children with relapsed solid tumors, including
patients with neuroblastoma. In the laboratory, sorafenib appears to make neuroblastoma
tumors smaller, and in addition can help immune cells to be more active in attacking tumors
and blocks other harmful immune cells from promoting tumor growth and function. Sorafenib
also helps to block tumor cells from developing blood vessels used to "feed" to tumor.
Sorafenib is an FDA-approved drug currently widely used for adults with specific types of
liver and kidney cancer.

Cyclophosphamide and topotecan are both FDA-approved chemotherapy drugs. These drugs are
approved for the treatment of certain adult cancers, but have also been used to treat
children with cancer. These drugs have been used in combination in many people with
neuroblastoma. In some neuroblastoma patients, this combination has reduced the amount of
tumor burden.

Adding sorafenib to cyclophosphamide and topotecan may increase the effectiveness of this
combination. The investigators first need to find out the highest dose of sorafenib that can
be given safely together with cyclophosphamide and topotecan. This is the first study to test
giving these three drugs together and will help determine the highest dose of sorafenib that
can safely be given together with cyclophosphamide and topotecan to patients with
resistant/relapsed neuroblastoma.

Inclusion Criteria:

- Patients must be < 30 years of age when registered on study.

- Patients must have a diagnosis of neuroblastoma either by histologic verification of
neuroblastoma and/or demonstration of tumor cells in the bone marrow with increased
urinary catecholamines.

- Patients must have high-risk neuroblastoma according to COG risk classification at the
time of study enrollment. Patients who were initially considered low or intermediate
risk, but then reclassified as high risk are also eligible.

- Patients must have at least ONE of the following:

Recurrent/progressive disease at any time prior to study enrollment - regardless of
response to frontline therapy.

Refractory disease: persistent sites of disease after achieving a best overall response of
no response to front line therapy after a minimum of 4 cycles of induction therapy AND
patient has never had recurrent/progressive disease.

Persistent disease: persistent sites of disease after achieving a best overall response of
partial response to frontline therapy after a minimum of 4 cycles of induction therapy AND
patient has never had recurrent/progressive disease.

- Patients must have at least ONE of the following (lesions may have received prior
radiation therapy as long as they meet the other criteria listed below):

- At least one MIBG avid bone site or diffuse MIBG uptake.

- For recurrent/progressive or refractory disease, a biopsy is not required
regardless of number of MIBG avid lesions

- For persistent disease, if patient has only 1 or 2 MIBG avid lesions OR a Curie
core of 1 - 2, then biopsy confirmation of neuroblastoma and/or ganglioneuroma in
at least one site present at the time of enrollment (bone marrow, bone or soft
tissue) is required to be obtained at any time point prior to enrollment and two
weeks subsequent to most recent prior therapy. If a patient has 3 or more MIBG
avid lesions OR a Curie Score of ≥ 3 then no biopsy is required for eligibility.

- Any amount of neuroblastoma tumor cells in the bone marrow based on routine morphology
(with or without immunocytochemistry) in at least one sample from bilateral aspirates
and biopsies.

- At least one soft tissue site that meets criteria for a TARGET lesion defined by:

- Size: Lesion can be accurately measured in at least one dimension with a longest
diameter ≥ 10mm, or for lymph nodes ≥ 15mm short axis. Lesions meeting size
criteria will be considered measurable.

- In addition to size, a site needs to meet one of the following criteria:

MIBG avid. For patients with persistent disease only: If a patient has only 1 or 2 MIBG
avid lesions OR a Curie Score of 1 - 2, then biopsy confirmation of neuroblastoma and/or
ganglioneuroblastoma in at least one site present at time of enrollment (either bone
marrow, bone and/or soft tissue) is required to be obtained at any time point prior to
enrollment and at least two weeks subsequent to most recent prior therapy. If a patient has
3 or more MIBG avid lesions OR a Curie Score of ≥ 3 then no biopsy is required for
eligibility.

- FDG-PET avid (only if tumor known to be MIBG non-avid). These patients must have had a
biopsy confirming neuroblastoma and/or ganglioneuroblastoma in at least one FDG-PET
avid site present at the time of enrollment done prior to enrollment and at least two
weeks subsequent to the most recent prior therapy.

- Non-avid lesion (both MIBG and FDG-PET non-avid). These patients must have had a
biopsy confirming neuroblastoma and/or ganglioneuroblastoma in at least one non-avid
lesion present at the time of enrollment done prior to enrollment and at least two
weeks subsequent to the most recent prior therapy.

- Patients must have a life expectancy of at least 8 weeks and a Lansky (< 16 years age)
or Karnofsky (> 16 years age) score of at least 50

- Patients must have fully recovered from the acute toxic effects of all previous
chemotherapy, immunotherapy, or radiotherapy prior to study enrollment.

- Patients must not have received the therapies indicated below for the specified time
period prior to the first day of administration of protocol therapy on this study:

- Myelosuppressive chemotherapy: Last dose was given at least 14 days before the start
date for protocol therapy.

- Biologic (anti-neoplastic agent including retinoids): Last dose given at least 7 days
prior to the start date for protocol therapy.

- Monoclonal antibodies: Last dose of any monoclonal antibodies must have received at
least 7 days or 3 half-lives, whichever is longer, prior to the start date for
protocol therapy. Please refer to table posted at www.nant.org for definition of
half-lives for specific monoclonal antibodies.

- Patients must not have received radiation for a minimum of two weeks prior to study
enrollment.

- Patients are eligible 12 weeks after date of autologous hematopoietic stem cell
infusion following myeloablative therapy (timed from first day of this protocol
therapy).

- Patients are not eligible post allogeneic stem cell transplant.

- Patients who have received an autologous hematopoietic stem cell infusion to support
non-myeloablative therapy (such as 131I-MIBG) are eligible at any time as long as they
meet the other criteria for eligibility.

- A minimum of 6 weeks must have elapsed after 131I-MIBG therapy prior to start of
protocol therapy.

- Patients who have received prior treatment with cyclophosphamide and topotecan are
eligible if they did not have tumor relapse/progression while receiving this
combination.

- Patients who have received prior treatment with sorafenib are eligible, as long as the
sorafenib was not given in combination with cyclosphosphamide and/or topotecan.
Patients with tumor relapse/progression while on sorafinib or having dose
modifications or experiencing toxicity that required sorafenib to be discontinued are
also ineligible to participate in this study.

- Growth factors that support platelet or white cell number or function must not have
been administered within 7 days of blood draw documenting hematopoietic function (ANC,
Platelets) eligibility. .

- Patients must not be receiving any other anti-cancer agents or radiotherapy at the
time of study entry or while on study.

- Patients must not be receiving other investigational medications (covered under
another IND) while on study.

- Treatment with clinically significant enzyme inducers, such as the enzyme-inducing
antiepileptic drugs phenytoin, carbamazepine or phenobarbital, or rifampin, rifabutin,
rifapentine or St. John's wort within 14 days prior to the first dose of sorafenib and
during protocol therapy must not be used as these may interfere with sorafenib
metabolism. Non-enzyme inducing anticonvulsants (Keppra, etc.) can be used after
discussion with study chair.

- Patients must not be receiving active anti-coagulation therapy at the time of study
entry (or while on study).

- Patients with cardiac arrhythmias must not be receiving anti-arrhythmic medication at
time of study entry (or while on study).

- Patients must not be receiving anti-hypertensive medications at time of study entry.

- ANC: 1000/ul (no short acting hematopoietic growth factors within 7 7 days of blood
draw documenting eligibility and no long-acting hematopoietic growth factors within 14
days of blood draw documenting eligibility)

- Platelet count: 100,000/ul and transfusion independent (no platelet transfusions
within 7 days of blood draw documenting eligibility)

- Patients with known bone marrow metastatic disease will be eligible for study as long
as they meet hematologic function criteria above.

- Hematuria ≤ 1+ on urinalysis

- Age-adjusted serum creatinine 1.5 x normal for age/gender

- Total bilirubin 1.5 x normal for age, AND

- SGPT (ALT) ≤ 135 U/L and SGOT (AST) ≤ 3X ULN. (for the purpose of this study, the
upper limit of normal [ULN] for SGPT [ALT] is 45 U/L).

- Serum albumin > 2.5 g/dl

- Patient must have blood pressure ≤ 95th percentile for age, height, and gender

- Patients may not be on medical therapy for hypertension at time of enrollment.

- Patient must have a QT/QTc interval ≤ 450 msec.

- INR and aPTT < 1.2 times upper limit of normal for age.

- No history of bleeding diathesis.

- Amylase and Lipase < 1.5 x normal for age.

- Patients with other ongoing serious medical issues must be approved by the study chair
prior to registration.

Exclusion Criteria:

- Subjects with calculated BSA < 0.40 m2 are not eligible for study participation as
Sorafenib dosing for this study cannot accommodate subjects of this size utilizing
commercially available drug formulation.

- Pregnancy: Serum B-HCG must be negative 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.

- Pregnant or breast-feeding women will not be entered on this study due to risks of
fetal and teratogenic adverse events.

- Patients who have an active or uncontrolled infection are excluded. Patients on
prolonged antifungal therapy are still eligible if they are culture and biopsy
negative in suspected radiographic lesions and meet other organ function criteria.

- Patients with prior allogeneic transplant are not eligible.Patients with a documented
history of cerebrovascular accidents and/or TIA within the past 6 months are not
eligible.

- Patients with a history of intracranial hemorrhage are not eligible.

- Patients with a history of venous or arterial thrombosis personally or in a first
degree relative before the age of 40 years are not eligible unless the thrombotic
event was associated with a central line.

- Patient with prolonged QT/QTc (defined as QTc interval > 450 msec) are not eligible.

- Patient declines participation in NANT 04-05. (Neuroblastoma Biology Study)