Satraplatin in Children and Young Adults With Refractory Solid Tumors Including Brain Tumors

BACKGROUND

The platinum compounds cisplatin and carboplatin are standard agents in the treatment of a
variety of childhood cancers. However, cumulative and long-term renal and ototoxicity are a
concern related to cisplatin administration, particularly in young children.

Several mechanisms of resistance to platinum compounds have been described including
decreased drug accumulation due to altered drug uptake or the presence of a membrane efflux
pump, increased intracellular levels of thiol-containing groups that detoxify and modulate
platinum, and removal of the platinum-DNA adducts by DNA repair pathways called nucleotide
excision repair (NER) and base excision repair (BER) pathways.

Polymorphisms in DNA repair genes have been shown in some cancers to predict better treatment
response to platinum treatment.

Satraplatin is an oral platinum analog with similar preclinical in vitro and in vivo activity
to that of cisplatin and carboplatin, and with activity in platinum resistant models.

Dose-limiting satraplatin toxicities in adults include nausea, vomiting, and
myelosuppression. Neither renal nor neurologic toxicities have been described.

Satraplatin has demonstrated clinical activity in adult refractory tumors at the recommended
phase II and III dose of 80 mg/m2/dose daily for 5 days every 28 or 35 days.

OBJECTIVES

To determine the maximum tolerated dose (MTD) of oral satraplatin administered on a once
daily for 5 days every 28 days schedule in pediatric patients with relapsed or refractory
solid tumors including brain tumors.

To define the toxicities of oral satraplatin and characterize the pharmacokinetics of oral
satraplatin in children with refractory cancer.

To determine the preliminary antitumor activity of satraplatin.

To evaluate the pharmacogenomic expression of DNA repair genes in peripheral blood
mononuclear blood cells.

ELIGIBILITY

Patients greater than or equal to 3 years and less than or equal to 25 years at enrollment
with relapsed or refractory solid tumors including brain tumors.

Adequate organ function

DESIGN

This is a phase I trial of satraplatin administered once daily orally for 5 days every 28
days. A cycle of therapy is considered to be 28 days. The starting dose level is 60
mg/m(2)/dose with escalations to 80, 110, 140 mg/m(2)/dose. The MTD will be defined based on
satraplatin tolerability during cycle one.

Disease status will be evaluated prior to every odd treatment cycle and therapy may continue
for up to 2 years in the absence of progressive disease or unacceptable toxicity.

Plasma pharmacokinetics and pharmacogenomics will be evaluated during the first treatment
cycle.

- INCLUSION CRITERIA:

1. Age: greater than or equal to 3 years and less than or equal to 25 years of age
at the time of study enrollment.

2. Diagnosis: Patients with refractory solid tumors including brain tumors
(including brain metastases). All patients must have had histological
verification of the solid tumor at initial diagnosis or relapse with the
exception of patients with diffuse intrinsic brainstem tumors, optic pathway
tumors, or CNS germ cell tumors with elevations of reliable serum or CSF tumor
markers (alpha-fetoprotein or beta-HCG).

3. Disease status: Patients must have measurable or evaluable disease.

4. Prior Therapy: Refractory to standard therapy and no other standard curative
treatment options are available. Patients must have fully recovered to less than
or equal to grade 1 from the acute toxic effects of all prior chemotherapy,
immunotherapy, or radiotherapy prior to entering this study.

i. Stem Cell Transplantation: Patients must be greater than or equal to 3 months
since autologous stem cell transplant and greater than or equal to 6 months since
allogeneic stem cell transplant prior to study entry.

ii. Radiation Therapy: Extensive radiation therapy (craniospinal, more than half
of the pelvis, TBI) must be completed at least 3 months prior to study entry. The
last dose of all other local palliative radiation must be at least 2 weeks prior
to study entry.

iii. Myelosuppressive chemotherapy: The last dose of myelosuppressive
chemotherapy must be at least 21 days prior to study entry. Therapy with
nitrosoureas must be at least 6 weeks prior to study entry; and therapy with
temozolomide must be 4 weeks prior to study entry.

iv. Investigational anti-cancer agents: The last dose of all investigational
agents must be at least 30 days prior to study entry.

v. Growth factors: The last dose of growth factors such as filgrastim and epoetin
must be at least one week prior to study entry. The last dose of long-acting
colony stimulating factors, such as pegfilgrastim, must be 2 weeks prior to study
entry.

vi. Biologic anti-cancer agents: The last dose of nonmyelosuppressive biologic
agents for the treatment of the patient s cancer must be at least 7 days prior to
study entry.

vii. Immunotherapy: At least 6 weeks since the completion of any type of
immunotherapy, e.g. tumor vaccines.

viii. Monoclonal antibody: At least 3 half-lives of the antibody after the last
dose of a monoclonal antibody. (See table on Children s Oncology Group Phase I
Consortium DVL homepage
https://members.childrensoncologygroup.org/Disc/devtherapeu tics/default.asp for
listing of monoclonal antibody half-lives.)

ix. Corticosteroids: Patients with brain tumors must be on a stable or tapering
dose of corticosteroids for 7 days prior to the date of the baseline scan
performed for the purpose of assessing response to therapy on this study.

5. Performance status: Patients greater than 10 years of age must have a Karnofsky
performance level of greater than or equal to 50%, and children less than or
equal to 10 years old must have a Lansky performance of greater than or equal to
50% (Appendix I). Patients who are wheelchair bound because of paralysis should
be considered ambulatory when they are up in their wheel chair.

6. Hematologic Function: Patients must have an absolute neutrophil count greater
than or equal to 1000/microL, hemoglobin greater than or equal to 9g/dl
(transfusion permitted), and platelet greater than or equal to 75,000/?l
(transfusion independent).

7. Hepatic Function: Patients must have bilirubin less than or equal to 1.5 times
the upper limit of normal (ULN) for age, with the exception of Gilbert syndrome,
and ALT within less than or equal to 3.0 times the ULN.

8. Renal Function: Patients must have a creatinine clearance or radioisotope GFR
greater than or equal to 60ml/min/1.73 m(2) or a normal serum creatinine based on
age described below.

- Less than or equal to 5 years of age: a maximum serum creatinine of 0.8 mg/dL

- Older than 5 years of age but less than or equal to the age of 10: a maximum serum
creatinine of 1.0 mg/dL

- Older than 10 years of age and less than or equal to the age of 15: a maximum serum
creatinine of 1.2 mg/dL

- Older than 15 years of age: a maximum serum creatinine of 1.5 mg/dL

9. Informed Consent: Diagnostic or laboratory studies performed exclusively to
determine eligibility for this trial must only be done after obtaining written
informed consent from all patients or their legal guardians (if the patient is <18
years old). When appropriate, pediatric patients will be included in all discussions.
This can be accomplished through one of the following mechanisms:

1. the NCI, POB screening protocol,

2. an IRB-approved institutional screening protocol or

3. the study-specific protocol.

Documentation of the informed consent for screening will be maintained in the
patient s research chart. Studies or procedures that were performed for clinical
indications (not exclusively to determine eligibility) may be used for baseline
values even if the studies were done before informed consent was obtained.

10. Durable Power of Attorney (DPA): All patients >18 years of age will be
offered the opportunity to assign DPA so that another person can make decisions
about their medical care if they become incapacitated or cognitively impaired.

EXCLUSION CRITERIA:

1. Pregnant or breast-feeding females are excluded due to potential risks of
fetal and teratogenic adverse events of an investigational agent. Pregnancy
tests (urine BhCG) must be obtained prior to enrollment on this study in
girls, age 9 years or older. Males or females of reproductive potential may
not participate unless they have agreed to use an effective contraceptive
method. Abstinence is an acceptable method of birth control.

2. Last dose of any investigational agent given within the past 30 days. 3.
Ongoing radiation therapy, chemotherapy, hormonal therapy directed at the
tumor, immunotherapy, or biologic therapy.

4. Active graft versus host disease.

5. Graft vs Host Disease (GVHD) therapy or agents to prevent organ rejection
post-transplant: Patients who are receiving cyclosporine, tacrolimus or other
agents to prevent either GVHD post bone marrow transplant or organ rejection post
transplant are not eligible for this trial.

6. Clinically significant uncontrolled unrelated systemic illness such as serious
infections or significant cardiac, pulmonary, hepatic or other organ dysfunction.

7. Patients who in the opinion of the investigator may not be able to comply with
the safety monitoring requirements of the study.

8. Inability to swallow capsules as capsules cannot be crushed or broken

9. Prior treatment with satraplatin.