POETIC Plerixafor as a Chemosensitizing Agent for Relapsed Acute Leukemia and MDS in Pediatric Patients
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|ClinicalTrials.gov Identifier: NCT01319864|
Recruitment Status : Completed
First Posted : March 22, 2011
Last Update Posted : September 7, 2018
|Condition or disease||Intervention/treatment||Phase|
|Relapsed/Refractory AML Relapsed/Refractory ALL Secondary AML/MDS Acute Leukemia of Ambiguous Lineage AML ALL||Drug: Plerixafor Dose Escalation||Phase 1|
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.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||20 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Phase I Study Using Plerixafor as a Chemosensitizing Agent for Relapsed Acute Leukemia and MDS in Pediatric Patients|
|Study Start Date :||March 2011|
|Actual Primary Completion Date :||June 28, 2013|
|Actual Study Completion Date :||June 28, 2016|
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.
- Maximum Tolerated Dose (MTD) of Plerixafor given in combination with chemotherapy [ Time Frame: 6 months post final enrollment ]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)
- Response Rate [ Time Frame: 6 months post completion of treatment for final enrollment ]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.
- Measure Peak Plasma Concentration (Cmax) of Plerixafor using serial peripheral blood sampling [ Time Frame: 12 months following last sample collection ]Plasma pharmacokinetic parameters are estimated by noncompartmental analysis using PhoenixWinNonlin 7.0 (Certara) and are estimated from the observed concentration-time data.
- Leukemic blast mobilization [ Time Frame: 12 months after final sample collection ]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 ]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.
- Measure Area Under the Concentration-Time Curve (AUC) of Plerixafor using serial peripheral blood sampling [ Time Frame: 12 months following last sample collection ]Plasma pharmacokinetic parameters are estimated by noncompartmental analysis using PhoenixWinNonlin 7.0 (Certara) and are estimated from the observed concentration-time data.
- Measure terminal half life (t1/2) of Plerixafor using serial peripheral blood sampling [ Time Frame: 12 months following last sample collection ]Plasma pharmacokinetic parameters are estimated by noncompartmental analysis using PhoenixWinNonlin 7.0 (Certara) and are estimated from the observed concentration-time data.
- Measure systemic clearance of Plerixafor using serial peripheral blood sampling [ Time Frame: 12 months following last sample collection ]
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01319864
|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|
|Alberta Children's Hospital|
|Calgary, Alberta, Canada, T3B 6A8|
|Principal Investigator:||Todd Cooper, DO||Emory University/Children's Healthcare of Atlanta|