Imaging CXCR4 Expression in Subjects With Cancer Using 64 Cu-Plerixafor

In mouse models and in patients, expression of the chemokine receptor CXCR4 on various
cancers has been correlated with aggressive biological behavior, including increased rates
and certain sites of metastasis, and decreased survival. Plerixafor (Mozobil ; Genzyme;
Cambridge, MA) has been identified as a specific inhibitor of CXCR4, and it is currently
approved by the Food and Drug Administration as a stem-cell mobilizing agent in combination
with granulocyte colony-stimulating factor in the treatment of non-Hodgkin's lymphoma and
multiple myeloma. Our group has recently shown that plerixafor can be labeled with the
positron-emitting radionuclide copper-64(64Cu) to form 64Cu-plerixafor, which can be used to
visualize CXCR4-positive tumor xenografts in mice using small-animal positron emission
tomography (PET). Determining CXCR4 expression in tumors using 64Cu-plerixafor and
PET/computerized tomography (CT) scanning could be useful in predicting tumor behavior and
responses to current and experimental therapies, including therapies targeting CXCR4, which
could lead to more effective personalized cancer treatments.

This study s primary objective is to evaluate 64Cu-plerixafor as an imaging agent for
quantifying CXCR4 expression in subjects (greater than or equal to 18 years of age) with
cancer; at least 1 detectable solid tumor of greater than or equal to 1.5 cm in diameter
found outside of the vertebral bodies, liver, gallbladder, kidney, and bladder; and tissue
sample(s) of the tumors obtained since the first detection of the current
occurrence/recurrence of disease. The secondary objectives are to correlate 64Cu-plerixafor
standardized uptake value in the target lesion with the level of CXCR4 expression detected
via immunohistochemistry and to calculate human dosimetry for 64Cu-plerixafor.

Tumor samples from less than or equal to75 subjects recruited from the National Cancer
Institute and the Georgetown University Hospital will be evaluated for CXCR4 expression via
immunohistochemistry. With the exception of subjects with adrenocortical carcinoma,
evaluation of tissue for expression of CXCR4 will be required before PET scanning. Subjects
who meet the eligibility criteria will continue onto the study. Five subjects with
adrenocortical carcinoma and/or CXCR4-positive tumor samples will be administered an initial
intravenous infusion of 64Cu-plerixafor (up to 8+0.8 mCi; 0.48+0.048 rem; not to exceed 5 g
64Cu-plerixafor) at Day 0. They will then undergo an initial low-dose transmission CT scan
followed by 3 consecutive torso PET scans as soon as practical after the infusion, and 2
additional PET/CT scans at 4 hours +/- 1 hour and 24 hours +/- 3 hours post-infusion. Human
dosimetry will be calculated based on these results, and the dose may be adjusted, not to
exceed the calculated limit of a total effective dose of 5 rem, or the radiation exposure
limit for each organ. The remaining subjects will be administered 64Cu-plerixafor at the
same, or a newly calculated dose, and will undergo 1 PET/CT scan between 1 and 4 hours
post-infusion, depending on the dosimetry results. All subjects will undergo an assessment at
the NIH or by phone on study Day 14 3. Additionally, blood will be collected 3 more times at
Day 7 2, Day 14 3 and Day 21 3 to measure blood cell counts, and urine collected once more at
Day 7 2.

- INCLUSION CRITERIA:

Screening Phase

Subjects (greater than or equal to18 years of age) with cancer; at least 1 detectable solid
tumor of greater than or equal to 1.5 cm in diameter found outside of the vertebral bodies,
liver, gallbladder, kidney, and bladder; and, with the exception of adrenocortical
carcinoma, preexisting tumor sample(s) of the cancer obtained since the first detection of
the current occurrence/recurrence of disease are eligible to participate in the screening
portion of the study.

Study Phase

Subjects of reproductive potential are eligible to enter the study if they agree to use 2
forms of contraception 3 weeks prior to the study start and 1 month after the
administration of 64Cu-plerixafor, such as:

- Hormonal contraception.

- Male or female condoms with or without a spermicide.

- Diaphragm or cervical cap with a spermicide.

- Intrauterine device.

Male subjects may commence contraception beginning at the time of infusion of
64Cuplerixafor.

EXCLUSION CRITERIA:

Screening Phase

Subjects who are known to meet Study Phase exclusion criteria during the screening period
may be excluded from entering the Study Phase.

Study Phase

Individuals who meet any of the following criteria are not eligible to participate in the
study:

1. Karnofsky Performance Scale Index (KPSI) <70.

2. Women who are pregnant or lactating.

3. History of life-threatening cardiac arrhythmia.

4. Absolute neutrophil count <1000/microliters.

5. Platelet count <100,000/microliters.

6. Alanine transaminase, aspartate aminotransferase, alkaline phosphatase, or bilirubin
levels greater than or equal to 4 times the upper limits of normal, or a calculated
creatinine clearance rate of less than or equal to 50 mL/min.

7. Treatment with plerixafor or any imaging agent with a radioisotope or labeled molecule
administered <10 half-lives prior to administration of 64Cu-plerixafor.

8. Research radiation exposure over the past 12 months, which if added to the radiation
exposure in this study, exceeds 5 rem.

9. Allergy to plerixafor.

10. Severe claustrophobia unresponsive to anxiolytics.

11. Weight over 325 pounds.

12. History of any other illness or condition which, in the investigator s opinion, may
substantially increase the risk associated with the subject s participation in the
study, or may compromise the scientific objectives.

Co-Enrollment Guidelines

Co-enrollment in other trials that involve the infusion of radioactive isotopes/molecules
for research purposes or plerixafor is prohibited.