To Evaluate the Safety, Activity and Pharmacokinetics of Marqibo in Children and Adolescents With Refractory Cancer

BACKGROUND

- Vincristine sulfate is a widely used antineoplastic agent of the alkaloid class of drugs
derived from the periwinkle plant (Vinca rosea Linn.). It has activity against a wide
number of malignancies. It is a cell-cycle-specific agent that arrests cell growth in
the M-phase (metaphase) by binding specifically with tubulin and disrupting cell
division. Its dose limiting toxicity (DLT) is virtually always neurological.

- Investigations over the past two decades have demonstrated that liposomal drug carriers
are capable of increasing the therapeutic index of anticancer drugs by altering the drug
s pharmacological behavior.

- Marqibo(Registered Trademark) is vincristine encapsulated in sphingomyelin/cholesterol
(SM/CHOL) liposomes, developed to increase the activity of vincristine. It has been
shown to have activity in Phase 2 studies in adults. Previous investigation of
Marqibo(Registered Trademark) in children is limited. A small phase 2 study was
conducted with dosing of 2.0mg/m2 every 14 days. The agent appeared to be well tolerated
and some activity was seen, although data were quite limited.

OBJECTIVES

- To define the maximum tolerated dose (MTD), toxicity profile, dose-limiting toxicities,
and pharmacokinetics in children and adolescents with solid tumors or hematologic
malignancies receiving weekly intravenous doses of Marqibo(Registered Trademark).

- To define the tolerability and potential activity of Marqibo(Registered Trademark) in
children and adolescents with relapsed or refractory acute lymphoblastic leukemia (ALL)
at the pediatric MTD.

ELIGIBILITY

- Children and adolescents (greater than or equal to 2 years and < 21 years of age) with
histologically confirmed relapsed or refractory malignant disease that is measurable or
evaluable.

DESIGN

- Marqibo(Registered Trademark) will be administered intravenously over 60 minutes (+ or
-10 minutes) every 7 days (+ or - 3 days) (Days 1, 8, 15, 22) for four doses (1 cycle).
Cycles may be repeated every 28 days for a maximum of 6 cycles; additional cycles may be
offered with evidence of acceptable toxicity and clinical benefit.

- The trial follows a standard phase I design with 3 to 6 subjects per dose level and
standard definitions of MTD and DLT. At the MTD, a total of 6 additional subjects with
relapsed or refractory ALL will be evaluated.

- Detailed pharmacokinetic studies will be performed during the first treatment cycle.

- INCLUSION CRITERIA

AGE: Subjects must be greater than or equal to 2 years and < 21 years of age.

DIAGNOSIS: Histologically confirmed solid tumors, which may include but are not limited to
rhabdomyosarcoma and other soft tissue sarcomas, Ewing sarcoma family of tumors,
osteosarcoma, neuroblastoma, Wilms tumor, hepatic tumors, germ cell tumors, and primary
brain tumors. In subjects with brain stem or optic gliomas the requirement for histological
confirmation may be waived.

-Histologically confirmed diagnosis of hematologic malignancy, including but not limited to
acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), Hodgkin's lymphoma,
and non-Hodgkin's lymphoma (NHL). Isolated CNS or testicular disease is NOT allowed.

MEASURABLE/EVALUABLE DISEASE: Subjects must have measurable or evaluable malignant disease.

PRIOR THERAPY:

- The subject s cancer must have relapsed after or failed to respond to frontline
curative therapy and there must not be other potentially curative treatment options
available to that subject at the time of study entry.

- Subjects must have had their last doses of therapy prior to receiving the first dose
of the investigational agent as follows (provided there is complete recovery from any
acute toxic effects of such):

1. Chemotherapy at least 14 days (6 weeks for nitrosoureas);

2. Radiation at least 21 days;

3. Any investigational cancer therapy or monoclonal antibody therapy (e.g.,
rituximab) at least 30 days.

Exceptions to these requirements:

- Intrathecal chemotherapy: There is no time restriction in regard to prior intrathecal
chemotherapy provided there is complete recovery from any acute toxic effects of such.

- Radiation therapy: There is no time restriction in regard to prior radiation provided
the volume of bone marrow treated is less than 10% and that there is measurable
disease outside the radiation port.

- Patients receiving corticosteroids or hydroxyurea are eligible provided all of the
following conditions are met.

- Patients with CNS tumors who are managed with steroids are eligible if they are on a
stable or decreasing dose of steroids and have no worsening neurologic deficits for
greater than or equal to 7 days prior to registration.

- The subject is not on both corticosteroids and hydroxyurea

- Corticosteroids are not being used to manage GVHD.

- There has been no increase in the hydroxyurea dose for 2 weeks prior to starting
Marqibo.

- Subjects must have recovered from the toxic effects (Grade 1 or baseline) of all prior
therapy before entry onto this trial.

- Subjects should be off hematopoietic colony stimulating factors for at least 72 hours
prior to study entry.

- Subjects with prior history of stem cell transplantation must be off immunosuppressive
therapy for at least 4 weeks and have no active graft-versus-host disease (GVHD) with
the exception of Grade 1 acute at the time of entry onto this trial.

PERFORMANCE STATUS: Subjects have a performance level greater than or equal to 50.

HEPATIC FUNCTION: Subjects must have adequate liver function, defined as bilirubin < 2.0
times the upper limit of normal, SGPT (ALT) and SGOT (AST) < 2.5 times the upper limit of
normal.

RENAL FUNCTION: Subjects must have an age-adjusted normal serum creatinine OR a creatinine
clearance greater than or equal to 60 mL/min/1.73 m(2):

- For age less than or equal to 5 - Maximum Serum Creatinine: 0.8

- For age less than 5 or less than or equal to 10 - Maximum Serum Creatinine: 1.0

- For age less than 10 or less than or equal to 15 - Maximum Serum Creatinine: 1.2

- For age greater than 15 - Maximum Serum Creatinine: 1.5

INFORMED CONSENT/ASSENT: All subjects or their legal guardians (for subjects < 18 years of
age) must sign a document of informed consent (POB eligibility screening protocol) prior to
performing studies to determine subject eligibility. After confirmation of subject
eligibility all subjects or their legal guardians must sign the protocol-specific informed
consent to document their understanding of the investigational nature and the risks of this
study before any protocol related studies are performed (other than the studies that were
performed to determine subject eligibility). Where deemed appropriate by the clinician and
the child s parents or guardian, the child will also be included in all discussions about
the trial and verbal assent will be obtained. The parent or guardian will sign the
designated line on the informed consent attesting to the fact that the child has given
assent.

DURABLE POWER OF ATTORNEY (DPA): Subjects who have brain tumors and who are 18 years of age
will be offered the opportunity to assign a DPA so that another person can make decisions
about their medical care if they become incapacitated or cognitively impaired.

BIRTH CONTROL: Subjects of childbearing or child-fathering potential must be willing to use
a medically acceptable form of birth control, which includes abstinence, while they are
being treated on this study. Females of childbearing potential must have a negative
pregnancy test within 7 days prior to starting study drug.

ADDITIONAL INCLUSION CRITERIA FOR EXPANDED COHORT OF ACUTE LYMPHOBLASTIC LEUKEMIA (ALL)
SUBJECTS

DIAGNOSIS: Subjects must have a diagnosis of relapsed or refractory ALL or lymphoblastic
lymphoma with > 5% marrow blasts (M2 or M3). Isolated CNS or testicular disease is not
allowed. If < 5% marrow blasts must have histologically confirmed leukemia in
extramedullary organ(s).

EXCLUSION CRITERIA

Clinically significant unrelated systemic illness, such as uncontrolled serious infection
or organ dysfunction, which in the judgment of protocol investigators would compromise the
subject s ability to tolerate the investigational agent or interfere with the study
procedures or results. This includes any condition or circumstance that in the opinion of
the investigator would significantly interfere with the subject s protocol compliance and
put the subject at increased risk.

CNS leukemia or lymphoma as manifested by any of the following:

- CSF WBC > 5/microL and confirmation of CSF blasts.

- Cranial neuropathies deemed secondary to underlying malignancy

- CT or MRI scan evidence.

* Note: History of CNS involvement is not an exclusion criterion.

- Neutrophil count < 1,000/microL or platelet count of < 50,000/microL (except for the
expanded ALL cohort, where there is no blood count requirement).

- Pregnant or breast-feeding females are excluded because Marqibo(Registered Trademark)
may be harmful to the developing fetus or nursing child.

- Currently receiving other investigational agents.

- History of previously receiving Marqibo(Registered Trademark).

- History of allergic reactions or serious adverse events attributed to compounds of
similar chemical or biologic composition to vincristine or components of
Marqibo(Registered Trademark) (vincristine sulfate injection,
sphingomyelin/cholesterol liposomes, sodium phosphate injection).

- Are eligible for stem cell transplantation. This implies that a suitable donor is
readily available, that the primary oncology team and Principal Investigator recommend
this as a preferred treatment option at the time of protocol evaluation, and that the
subject is willing to undergo stem cell transplantation.

- Presence of preexisting Grade 2 or greater sensory or motor neuropathy.

- History of persistent greater than or equal to Grade 2 active neurologic disorders
unrelated to chemotherapy.

- Positive for human immunodeficiency virus (HIV) due to the increased risk of
complications.