Study of Ferumoxytol Enhanced MRI for Detecting Lymph Node Metastases in Prostate, Bladder, and Kidney Cancers

Background:

- Conventional imaging modalities (e.g. computed tomography [CT] and magnetic resonance
imaging [MRI]) are currently used for the detection of lymph node metastases in many
cancer types, including prostate, bladder and kidney cancers, however diagnosis is based
on node enlargement which is neither sensitive nor specific (i.e. small nodes harbor
metastases, large nodes can be hyperplastic).

- As a consequence, the standard of care is to remove numerous lymph nodes during surgery
or to biopsy enlarged nodes to ascertain lymph node status.

- In 2003 Dextran coated ultra small superparamagnetic iron oxide particles (USPIO), also
known as Ferumoxtran-10 (Combidex , AMAG Pharmaceuticals, Inc. Lexington, MA, US) was
shown to localize lymph node metastases with much greater accuracy than unenhanced MRI.
Although a large study in prostate cancer was successful, an FDA Advisory Panel did not
recommend approval and the company abandoned the agent.

- In 2009 Ferumoxytol (Feraheme AMAG Pharmaceuticals, Inc. Lexington, MA, US) a
semi-synthetic carbohydrate coated, magnetic iron oxide preparation similar to
ferumoxtran 10 was approved for iron replacement therapy. Like ferumoxtran 10, this
compound is taken up by normal lymph nodes and excluded from malignant nodal tissue.

- Results of a recent NCI trial (11-C-0098) in 15 patients revealed that using the dose of
7.5 mg/kg Fe is safe and yields homogenous and accurate signal changes in benign lymph
nodes in comparison with the 4 and 6 mg/kg Fe doses. This dose was further tested in 5
patients with known or suspected nodal involvement from prostate cancer and in four of
five patients positive lymph nodes had a lower signal drop than the benign nodes. The
one case in which there was uptake by positive nodes may have been on a vascular basis.
This pilot study stimulated interest in a larger study involving a variety of cancer
types.

Primary Objective:

-To compare the difference in signal between metastatic and normal nodes in prostate, kidney
and bladder cancer patients.

Eligibility

- Subject must be greater than or equal to 18 years old.

- Eastern Cooperative Oncology Group Performance score of 0 to 2.

- There are 3 parallel arms in this study. All patients must have evidence of lymph node
involvement (with a short axis diameter greater than or equal to 1.5 cm).

- In addition:

- Arm 1: Subject must have a documented diagnosis of prostate cancer.

- Arm 2: Subject must have a documented diagnosis of bladder cancer (transitional cell
carcinoma).

- Arm 3: Subject must have a documented diagnosis of kidney cancer (all renal cell cancer
types).

Design:

- This is a single site 3-arm (arm 1=prostate cancer, arm 2=bladder cancer, arm 3=kidney
cancer) study enrolling 50 evaluable patients (30 evaluable in each arm 1, 10 evaluable
in arms 2 and 3) with documented prostate, bladder or kidney cancer with evidence of
lymph node involvement [with a size of greater than or equal to 1.5 cm measured on
conventional imaging (e.g. CT, MRI)].

- All subjects will undergo pre-infusion, 24, 48 hours post-Ferumoxytol infusion (dose of
7.5mg/kg Fe) MRI consisting of T1 weighted (W), T2W and T2*W 3 Tesla MRI.

- Imaging will be correlated with histology of resected or biopsied lymph nodes when
available. Occasionally, patients may not undergo biopsy or surgical excision of their
lymph nodes. This may occur if their lymph nodes are overtly large and therefore highly
likely to represent lymph node involvement. In such cases, patients will be evaluated
with clinical follow up which typically occurs every three months in most NCI protocols.
If the lesion demonstrates growth or regression based on RECIST 1.1 criteria on these
follow up studies then the lesion will be considered positive for tumor. If it is stable
for at least one year then it will be considered non-malignant. The MR imaging analysis
will be intra-patient.

- Patients will also undergo ultrasound examination of imageable lymph nodes (e.g.
inguinal nodes) at pre-infusion and 24, 48 hours post-Ferumoxytol infusion time points.
The signal changes at post-infusion ultrasound will be visually evaluated to determine
if the uptake of ferumoxytol alters sonographic features.

- INCLUSION CRITERIA

2.1.1.1 Subject must be greater than or equal to 18 years old.

2.1.1.2 Diagnosis

- Arm 1: Subject must have a documented diagnosis of prostate cancer with evidence of
lymph node involvement (with a short axis diameter of greater than or equal to 1.5 cm
on a conventional CT or MRI obtained within 8 weeks of the Ferumoxytol imaging
procedure)

- Arm 2: Subject must have a documented diagnosis of bladder cancer (transitional cell
carcinoma) with evidence of lymph node involvement (with a short axis diameter of
greater than or equal to 1.5cm on a conventional CT or MRI obtained within 8 weeks of
the Ferumoxytol imaging procedure)

- Arm 3: Subject must have a documented diagnosis of kidney cancer (all renal cell
cancer types) with evidence of lymph node involvement (with a short axis diameter of
greater than or equal to 1.5 cm on a conventional CT or MRI obtained within 8 weeks of
the Ferumoxytol imaging procedure)

2.1.1.3 Subject must have Eastern Cooperative Oncology Group Performance score greater than
or equal to 2.

2.1.1.4 Ability to provide informed consent. All subjects must sign an informed consent
form indicating their understanding of the investigational nature and risks of the study
before any protocol-related studies are performed.

2.1.EXCLUSION CRITERIA

2.1.2.1 Subjects with known hypersensitivity and allergy to iron.

2.1.2.2 Subjects with evidence of iron overload with a pre-study ferritin level greater
than 370 ng/ml and percent saturation of transferrin level greater than 40%. Patients with
lab values above these limits may be included in the study if documented hematology
consultation rules out hemochromatosis, idiopathic or iatrogenic iron overload.

2.1.2.3 Subjects with any coexisting medical or psychiatric condition that is likely to
interfere with study procedures and/or results.

2.1.2.4 Subjects with severe claustrophobia unresponsive to oral anxiolytics.

2.1.2.5 Subjects with contraindications to MRI.

2.1.2.6 Subjects weighing >136 kg (weight limit for scanner table).

2.1.2.7 Subjects with any type of pacemaker, cerebral aneurysm clips, shrapnel injury, or
other implanted electronic devices or metal not compatible with MRI.

2.1.2.8 Subjects with abnormal liver function tests suggesting liver dysfunction (AST and
ALT greater than or equal to 3 x of the upper limits of normal; total bilirubin greater
than or equal to 2 x the upper limits of normal or >3.0 mg/dl in patients with Gilbert s
syndrome).

2.1.2.9 Subjects with other medical conditions deemed by the principal investigator (or
associates) to make the subject ineligible for protocol procedures.

2.1.2.10 Women who are pregnant or breast-feeding. The effects of ferumoxytol on the
developing human fetus are unknown. For this reason, 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 1 day after study related imaging is completed.
Should a woman become pregnant or suspect she is pregnant while she or her partner is
participating in this study, she should inform her treating physician immediately.

2.1.3 Inclusion of Women and Minorities.

Members of all races and ethnic groups are eligible for this trial. Women are excluded from
arm 1 of this trial as prostate cancer does not occur in females.