POETIC Plerixafor as a Chemosensitizing Agent for Relapsed Acute Leukemia and MDS in Pediatric Patients
Condition: Relapsed/Refractory AML; Relapsed/Refractory ALL; Secondary AML/MDS; Acute Leukemia of Ambiguous Lineage; AML; ALL
MeSH terms: Leukemia; Acute Disease
Study type: Interventional
Phase: Phase 1

Summary: 
      In this Phase I study, we will test the safety of the drug plerixafor (MOBOZIL) at different
      dose levels, used together with other anti-cancer drugs-cytarabine and etoposide. We want to
      find out what effects, good and /or bad, this combination of drugs has on leukemia.
      Plerixafor is a drug that blocks a receptor on the leukemia cell, which prevents it from
      staying in the bone marrow where it can be resistant to chemotherapy. Plerixafor is FDA
      approved for mobilizing stem cells from the bone marrow in preparation for an autologous stem
      cell transplant. Cytarabine and etoposide have been used as part of standard chemotherapy for
      ALL and AML. However, the use of plerixafor with cytarabine and etoposide in pediatric
      patients with relapsed or refractory ALL, AML and MDS is considered experimental.
    

Detailed description: 
      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.
    

Intervention name(s): Plerixafor Dose Escalation
Intervention type(s): Drug
Intervention description(s): Plerixafor dose escalation Dose Level -1 = 3 mg/m2/dose Dose Level 1 = 6 mg/m2/dose Dose Level 2 = 9 mg/m2/dose Dose Level 3 = 12 mg/m2/dose Dose Level 4 = 15 mg/m2/dose
Doses administered 4 hours prior to chemotherapy, then at the same approximate time of day on subsequent days, through the end of that cycle of chemotherapy.
Other intervention name(s): AMD3100; MOBOZIL
Intervention MeSH terms: Plerixafor
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: leukemia