Now Available for Public Comment: Notice of Proposed Rulemaking (NPRM) for FDAAA 801 and NIH Draft Reporting Policy for NIH-Funded Trials

POETIC Plerixafor as a Chemosensitizing Agent for Relapsed Acute Leukemia and MDS in Pediatric Patients

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborators:
Children's Healthcare of Atlanta
Pediatric Oncology Experimental Therapeutics Investigation Consortium
Information provided by (Responsible Party):
Todd M. Cooper, Emory University
ClinicalTrials.gov Identifier:
NCT01319864
First received: March 11, 2011
Last updated: July 28, 2014
Last verified: July 2014
  Purpose

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.


Condition Intervention Phase
Relapsed/Refractory AML
Relapsed/Refractory ALL
Secondary AML/MDS
Acute Leukemia of Ambiguous Lineage
AML
ALL
Drug: Plerixafor Dose Escalation
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I Study Using Plerixafor as a Chemosensitizing Agent for Relapsed Acute Leukemia and MDS in Pediatric Patients

Resource links provided by NLM:


Further study details as provided by Emory University:

Primary Outcome Measures:
  • Maximum Tolerated Dose (MTD) of Plerixafor given in combination with chemotherapy [ Time Frame: 6 months post final enrollment ] [ Designated as safety issue: Yes ]
    To determine the safety and tolerability of plerixafor in combination with reinduction chemotherapy in pediatric and young adult patients with relapsed/refractory acute leukemia (AML/MDS and ALL)


Secondary Outcome Measures:
  • Response Rate [ Time Frame: 6 months post completion of treatment for final enrollment ] [ Designated as safety issue: No ]
    To estimate the response rate, within the context of a Phase I study, of Plerixafor given in sequential combination with cytarabine/etoposide (AE) in patients with relapsed or refractory ALL and AML/MDS.

  • Pharmacokinetics [ Time Frame: 12 months following last sample collection ] [ Designated as safety issue: No ]
    To determine the pharmacokinetics of Plerixafor when administered to pediatric and young adult patients with relapsed acute leukemias.

  • Leukemic blast mobilization [ Time Frame: 12 months after final sample collection ] [ Designated as safety issue: No ]
    To measure peripheral blood mobilization of leukemic blasts by flow cytometry by comparing blood samples obtained before and after dose 1 of plerixafor, and to correlate degree of mobilization (expressed as % increase in circulating blasts) with response.

  • CXCR4 expression on leukemic blasts [ Time Frame: 12 months after last patient completes therapy ] [ Designated as safety issue: No ]
    To measure the quantitative expression of CXCR4 on leukemic blasts at baseline and end of first course of treatment using flow cytometry and qRT-PCR, and correlate expression level with response.


Estimated Enrollment: 21
Study Start Date: March 2011
Estimated Study Completion Date: July 2014
Estimated Primary Completion Date: July 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Plerixafor, Dose Escalation
Dose escalation of plerixafor administered intravenously in combination with IV cytarabine and IV etoposide in pediatric patients wtih relapsed/refractory AML/ALL.
Drug: Plerixafor Dose Escalation

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 Names:
  • AMD3100
  • MOBOZIL

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.

  Eligibility

Ages Eligible for Study:   3 Years to 29 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • >= 3 years of age and <30 years old at study entry
  • diagnosis of relapsed/refractory AML, ALL, secondary AML/MDS, or acute leukemia of ambiguous lineage and meet the following criteria:
  • AML/MDS or leukemia with ambiguous lineage must have >5% blast in bone marrow
  • ALL must have an M3 marrow
  • ALL and AML must not have CNS disease
  • patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy or radiotherapy prior to entering study
  • Karnofsky score >50% for patients >16 years of age and Lansky >50% for patients <= 16 years of age
  • adequate renal and hepatic function as defined in protocol
  • adequate cardiac function as defined in protocol

Exclusion Criteria:

  • ALL and AML patients with CNS disease
  • Absolute blast count greater than 50,000/mcl
  • Systemic fungal, bacterial, viral or other infection without improvement despite appropriate antibiotics or other treatment
  • Significant concurrent disease, illness, psychiatric disorder or social issue that would compromise patient safety or compliance
  • Patients who have second cancer, not including secondary AML
  • Patients who are pregnant
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01319864

Locations
United States, Arizona
Phoenix Children's Hospital
Phoenix, Arizona, United States, 85016
United States, Colorado
The Children's Hospital of Denver
Denver, Colorado, United States, 80045
United States, Georgia
Children's Healthcare of Atlanta/Emory University
Atlanta, Georgia, United States, 30322
United States, Maryland
Johns Hopkins Medical Center
Baltimore, Maryland, United States, 21231
United States, Missouri
The Children's Mercy Hospital and Clinics
Kansas City, Missouri, United States, 64108
United States, New York
Memorial Sloan-Kettering Cancer Center
New York, New York, United States, 10021
United States, Ohio
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, United States, 45229
United States, Pennsylvania
Penn State Hershey Children's Hospital
Hershey, Pennsylvania, United States, 17033
Canada, Alberta
Alberta Children's Hospital
Calgary, Alberta, Canada, T3B 6A8
Sponsors and Collaborators
Emory University
Children's Healthcare of Atlanta
Pediatric Oncology Experimental Therapeutics Investigation Consortium
Investigators
Principal Investigator: Todd Cooper, DO Emory University/Children's Healthcare of Atlanta
  More Information

Additional Information:
No publications provided

Responsible Party: Todd M. Cooper, Assistant Professor, Emory University
ClinicalTrials.gov Identifier: NCT01319864     History of Changes
Other Study ID Numbers: IRB00047475, POETIC Plerixafor
Study First Received: March 11, 2011
Last Updated: July 28, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Emory University:
leukemia

Additional relevant MeSH terms:
Acute Disease
Leukemia
Disease Attributes
Neoplasms
Neoplasms by Histologic Type
Pathologic Processes
JM 3100
Anti-HIV Agents
Anti-Infective Agents
Anti-Retroviral Agents
Antiviral Agents
Pharmacologic Actions
Therapeutic Uses

ClinicalTrials.gov processed this record on November 24, 2014