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

Sponsor

Seattle Children's Hospital (Other)

Overall Status

Completed

CT.gov ID

NCT01319864

Collaborator

Children's Healthcare of Atlanta (Other), Pediatric Oncology Experimental Therapeutics Investigation Consortium (Other)

Enrollment

Locations

Arm

63.9

Duration (Months)

2.2

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief 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.

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

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

20 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (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

Study Start Date :

Mar 1, 2011

Actual Primary Completion Date :

Jun 28, 2013

Actual Study Completion Date :

Jun 28, 2016

Arms and Interventions

Arm	Intervention/Treatment
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

Arm

Intervention/Treatment

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

Outcome Measures

Primary Outcome Measures

Maximum Tolerated Dose (MTD) of Plerixafor given in combination with chemotherapy [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)

Secondary Outcome Measures

Response Rate [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 [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 [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 [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 [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 [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 [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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

3 Years to 29 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Locations

	Site	City	State	Country	Postal Code
1	Phoenix Children's Hospital	Phoenix	Arizona	United States	85016
2	The Children's Hospital of Denver	Denver	Colorado	United States	80045
3	Children's Healthcare of Atlanta/Emory University	Atlanta	Georgia	United States	30322
4	Johns Hopkins Medical Center	Baltimore	Maryland	United States	21231
5	The Children's Mercy Hospital and Clinics	Kansas City	Missouri	United States	64108
6	Memorial Sloan-Kettering Cancer Center	New York	New York	United States	10021
7	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229
8	Penn State Hershey Children's Hospital	Hershey	Pennsylvania	United States	17033
9	Alberta Children's Hospital	Calgary	Alberta	Canada	T3B 6A8