Trial Information

A Phase I Study Using Plerixafor as a Chemosensitizing Agent for Relapsed Acute Leukemia and MDS in Pediatric Patients

Approximately 500 children are diagnosed with AML every year, of whom around 60% are cured
with current regimens based on anthracyclines and high dose cytarabine with or without stem
cell transplant (SCT). Among the remaining 40% who are refractory or who relapse, outcome is
dismal. Additionally, 20-30% of patients with childhood ALL relapse or become refractory to
frontline therapies. The prognosis is poor in this patient population, particularly in
patients with second or subsequent relapse and those who relapse following SCT. These
patients present myriad challenges, as they usually have received a high cumulative
anthracycline dose, and in the case of SCT, may have had significant organ toxicities and/or
total body irradiation (TBI). Therefore, new therapeutic strategies need to be identified to
enhance possible improved outcomes.

Recently, scientists have described a resistant, quiescent population of leukemia cells that
have limitless self-renewal potential. The identification of these "leukemia stem cells"
(LSCs) provides an additional strategy in treating and preventing relapsed/refractory acute
leukemia. One mechanism for resistance to treatment is the protection afforded LSCs via the
interaction between stem cell derived growth factor (CXCL-12/SDF-1α) and its receptor,
CXCR4. These interactions are implicated in chemotaxis, homing, and survival/apoptosis of
hematopoietic stem cells and progenitor cells. All AML and ALL cells express CXCR4 and
SDF-1α. AMD3100 (plerixafor, MOBOZIL®) is a bicyclam that blocks CXCL-12 binding to and
signaling through CXCR4, thus disrupting tumor-stroma interactions and mobilizing leukemia
cells from their protective stromal environment. Plerixafor is currently FDA approved for
use in stem cell mobilization for autologous transplantation in hematologic malignancies.
Clinical trials in adult patients with relapsed AML have demonstrated promising results when
combining plerixafor with cytotoxic chemotherapy.

This Phase I clinical trial will be the first to test the concept of a "chemosensitization"
approach in children using Plerixafor. Patients aged 3 to 30 with relapsed/refractory AML,
ALL or MDS will receive Plerixafor followed 4 hours later with combination chemotherapy
consisting of etoposide and cytarabine daily for five days. We will determine the safety and
tolerability of Plerixafor in combination with cytarabine and etoposide in pediatric and
young adults with relapsed/refractory acute leukemias. The secondary objectives of this
study will quantify the peripheral blood mobilization of blasts in response to Plerixafor
using flow cytometry, measure initial CXCR4 expression on leukemic blasts and correlate with
response, and determine the change in CXCR4 expression after protocol therapy. Finally, we
will determine the pharmacokinetics of Plerixafor when administered with cytotoxic
chemotherapy in this patient population.