AMD3100 (Plerixafor) With G-CSF in Poor Mobilizing Adult Patients Who Previously Failed Hematopoietic Stem Cell (HSC) Collection/Attempts

Phase 2

Completed

Conditions: Autologous Stem Cell Transplantation

Interventions: Drug: G-CSF plus plerixafor

Registration Number: NCT00396331

Lead Sponsor: Genzyme, a Sanofi Company

Brief Summary: This study evaluates the safety, efficacy, and pharmacokinetics (PK) of plerixafor given in addition to granulocyte-colony stimulating factor (G-CSF) for collection of peripheral blood stem cells (PBSCs) for autologous transplantation in patients who would benefit from an autologous stem cell transplant but have failed previous collections or collection attempts with a mobilization regimen of G-CSF alone, chemotherapy and G-CSF, or any other conventional therapy including cytokines, chemotherapy and cytokines and bone marrow harvests.

The only change to standard of care of a mobilization regimen that includes G-CSF is the addition of a dose of AMD3100 (plerixafor) on the evening prior to each day of apheresis.

Efficacy outcomes include quantification of CD34+ cells in the apheresis product and assessment of successful polymorphonuclear leukocyte (PMN) and platelet (PLT) engraftment after transplantation. PK outcomes include analysis of repeated doses of plerixafor.

Detailed Description: This is a Phase 2, multicenter, prospective, open-label study. Once 70 patients have enrolled, subsequent patients enrolled should have a diagnosis of lymphoma. Patients who would benefit from an autologous stem cell transplant, who have failed previous collections or collection attempts with a mobilization regimen of granulocyte colony-stimulating factor (G-CSF) alone, chemotherapy and G-CSF, or any other conventional therapy including cytokines, chemotherapy and cytokines and bone marrow harvests, and who meet the inclusion/exclusion criteria are eligible to receive plerixafor as outlined in this protocol. The only change to standard of care of a mobilization regimen that includes G-CSF is the addition of a dose of plerixafor on the evening prior to each day of apheresis.

Patients will undergo mobilization with G-CSF (10 µg/kg) for 4 days. On Day 4, plerixafor (240 µg/kg) will be administered in the evening prior to the first apheresis and each subsequent evening prior to apheresis thereafter, such that there is a 10 to 11 hour interval between dosing and the initiation of apheresis. Patients will continue to receive G-CSF on each day of apheresis. Patients will undergo a minimum of 2 and a maximum of 7 aphereses or until ≥2\*10\^6 CD34+ cells/kg are collected, whichever occurs first. In addition, the mobilization of NHL tumor cells and the pharmacokinetics of repeat doses of plerixafor will be examined.

After the last apheresis has been completed, or after the patient has collected ≥2\*10\^6 CD34+ cells/kg, he/she will be treated with high-dose chemotherapy in preparation for transplantation. Patients will be transplanted with cells obtained from the G-CSF with plerixafor mobilization regimen. In the event that the minimum number of ≥2\*10\^6 cells for transplantation are not obtained from the first mobilization with plerixafor, cells may be retained and pooled for transplantation with those from a second mobilization with plerixafor (or from prior mobilization with other agents), at the investigator's discretion. If a second mobilization with plerixafor is attempted, a minimum rest interval of one week should be allowed between the last apheresis of the first regimen and the first dose of G-CSF of the second. The number of CD34+ cells mobilized in the peripheral blood (PB), collected in the apheresis product, and the number of apheresis sessions performed will be measured. Success of the transplantation will be evaluated by the time to engraftment of polymorphonuclear leukocytes (PMN) and platelets (PLT). Participants will be assessed for durability of their transplant for 12 months after transplantation.

This study was previously posted by AnorMED, Inc. In November 2006, AnorMED, Inc. was acquired by Genzyme Corporation. Genzyme Corporation is the sponsor of the trial.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 100

Inclusion Criteria

Eligible to undergo autologous transplantation
Has failed previous collections or collection attempts with a mobilization regimen of granulocyte colony-stimulating factor (G-CSF), chemotherapy and G-CSF or any other conventional therapy including cytokines, chemotherapy and cytokines or bone marrow harvest.
Eastern Co-operative Oncology Group (ECOG) performance status of 0 or 1
≥3 weeks since last cycle of chemotherapy (thalidomide, dexamethasone, and Velcade™ are not considered prior chemotherapy for the purpose of this study) NOTE: Although thalidomide, dexamethasone, and Velcade™ are not considered prior chemotherapy for the purpose of this study, none are to be administered within 7 days prior to the first dose of G-CSF (see Exclusion Criteria).
The patient has recovered from all acute toxic effects of prior chemotherapy
White blood cell count (WBC) >2.5*10^9/L
Absolute neutrophil count >1.5*10^9/L
Platelet count >85*10^9/L
Serum creatinine ≤1.5 mg/dl
Creatinine clearance >60 ml/min
Aspartate aminotransferase (AST), alanine transaminase (ALT) and total bilirubin <2x upper limit of normal (ULN)
Left ventricle ejection fraction >45% (by normal echocardiogram (ECHO) or multiple gated acquisition (MUGA) scan)
Forced expiratory volume in one minute (FEV1) >60% of predicted or diffusion lung capacity for carbon monoxide (DLCO) ≥45% of predicted
No active infection of hepatitis B or C
Negative for HIV
Signed informed consent
Women of child-bearing potential agree to use an approved form of contraception

Exclusion Criteria

Once 70 patients have enrolled, patients with diagnoses other than lymphoma are not eligible (eg, acute myeloid leukemia, chronic lymphocytic leukemia, or multiple myeloma).
A co-morbid condition which, in the view of the investigators, renders the patient at high risk from treatment complications
A residual acute medical condition resulting from prior chemotherapy
Received Neupogen™, thalidomide, dexamethasone, and/or Velcade™ within 7 days prior to the first dose of G-CSF
Brain metastases or carcinomatous meningitis
Acute infection
Fever (temperature >38°C/100.4°F)
Hypercalcaemia (>1 mg/dL above the ULN)
Positive pregnancy test in female patients
Lactating females
Patients of child-bearing potential unwilling to implement adequate birth control
Patients whose actual body weight exceeds 175% of their ideal body weight
Patients who previously received experimental therapy within 4 weeks of enrolling in this protocol or who are currently enrolled in another experimental protocol during the Mobilization phase

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
G-CSF plus Plerixafor	G-CSF plus plerixafor	-

Primary Outcome Measures

Name	Time	Method
Overall Participant Counts Summarizing Adverse Events (AEs) During the Treatment Period	Day 1 to approximately day 38	Number of participants with adverse events (AEs) collected from Day 1 (start of G-CSF mobilization) to the day before starting chemotherapy. AEs were graded by the investigator using the World Health Organization (WHO) Adverse Event Grading Scale and were assessed for severity (mild, moderate, severe, life-threatening) and relatedness to study treatment (5 point scale from 'not related' to 'definitely related').
Proportion of Participants Who Achieved ≥2*10^6 CD34+ Cells/kg Following Treatment With Plerixafor and G-CSF	Day 5 to Day 11 (up to 7 apheresis)	Proportion of participants who reached the target of at least 2\*10\^6 CD34+ cells/kg collected during up to 7 aphereses.
Proportion of Participants Who Achieved ≥5*10^6 CD34+ Cells/kg Following Treatment With Plerixafor and G-CSF	Day 5 to Day 11 (up to 7 aphereses)	Proportion of participants who reached the target of at least 5\*10\^6 CD34+ cells/kg collected during up to 7 apheresis.

Secondary Outcome Measures

Name	Time	Method
Median Number of Days to Polymorphonuclear Leukocyte (PMN) Engraftment	approximately 2 months (1 month post transplant)	The number of days from transplantation to successful engraftment as measured by PMN \>=0.5\10\^9 /L for 3 days or \>=1.0\10\^9 /L for 1 day.
Median Number of Days to Platelet (PLT) Engraftment	Approximately 2 months (1 month post transplant)	The number of days from transplantation to successful engraftment as measured by platelet value of \>=20\*10\^9/L for 7 days without transfusion.
Number of Participants With Durable Engraftment 12 Months After Autologous Transplantation	Approximately 13 months (12 months post transplant )	The number of participants maintaining a durable graft 12 months after transplantation. A durable graft was defined as maintenance of normal blood counts: PLT \>50\10\^9/L without transfusion for at least 2 weeks prior to the visit; hemoglobin level \>= 10 g/dL with no erythropoietin or transfusions for at least 1 month prior to the visit; and absolute neutrophil count (ANC) \> 1,000 (1\10\^9/L) with no G-CSF for at least 1 week prior to the visit.
Number of Participants With Non-Hodgkin's Lymphoma (NHL) Who Had Evidence of Tumor Cell Mobilization After G-CSF or Plerixafor Administration	Up to Day 7	The number of participants with Bcl2 translocation in post-treatment samples.
Number of Participants Who Achieved ≥2*10^6 CD34+ Cells/kg Collected During Both Courses of Treatment With Plerixafor and G-CSF	Day 5 up to Month 6 (up to 7 aphereses in each course of treatment)	Number of participants who had at least 2\*10\^6 CD34+ cells/kg collected by apheresis during both the first and the second courses of treatment together.
Number of Participants Who Achieved ≥5*10^6 CD34+ Cells/kg Collected During Both Courses of Treatment With Plerixafor and G-CSF	Day 5 up to Month 6 (up to 7 aphereses in each course of treatment)	Number of participants who had at least 5\*10\^6 CD34+ cells/kg collected by apheresis during both the first and the second courses of treatment together.
Maximum Observed Plasma Concentration (Cmax) on Day 4	Day 4 (following first plerixafor administration)	Maximum plasma concentration (Cmax) of plerixafor following daily doses of 240 µg/kg plerixafor, determined directly from the concentration-time data.
Maximum Observed Plasma Concentration (Cmax) on Day 7	Day 7 (following fourth plerixafor administration)	Maximum plasma concentration (Cmax) of plerixafor following daily doses of 240 µg/kg plerixafor, determined directly from the concentration-time data.
Time to Maximum Plasma Concentration (Tmax) on Day 4	Day 4 (following first plerixafor administration)	Time to maximum plasma concentration (Tmax) of plerixafor following daily doses of 240 µg/kg plerixafor, determined directly from the concentration-time data
Time to Maximum Plasma Concentration (Tmax) on Day 7	Day 7 (following fourth plerixafor administration)	Time to maximum plasma concentration (Tmax) of plerixafor following daily doses of 240 µg/kg plerixafor, determined directly from the concentration-time data
Area Under the Steady-state Plasma Concentration Time Curve From Time Zero to the Last Quantifiable Sample (AUC0-last) on Day 4	Days 4 -5 (following first plerixafor administration)	Area under the steady-state plasma concentration time curve from time zero to the last quantifiable sample after each plerixafor daily dose of 240 µg/kg, determined using the linear trapezoidal rule.
Area Under the Steady-state Plasma Concentration Time Curve From Time Zero to the Last Quantifiable Sample (AUC0-last) on Day 7	Days 7-8 (following fourth plerixafor administration)	Area under the steady-state plasma concentration time curve from time zero to the last quantifiable sample after each plerixafor daily dose of 240 µg/kg, determined using the linear trapezoidal rule.

Trial Locations

Locations (8): City of Hope National Medical Center'
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Duarte, California, United States
Kansas City Cancer Centers
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Kansas City, Missouri, United States
University of Mississippi Medical Center, Div of Hematology
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Jackson, Mississippi, United States
H. Lee Moffitt Cancer Center
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Tampa, Florida, United States
Blood & Marrow Transplant Group of Georgia
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Atlanta, Georgia, United States
Virginia Commonwealth University - Massey Cancer Center
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Richmond, Virginia, United States
Hackensack University Medical Center
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Hackensack, New Jersey, United States
University of Wisconsin, Blood and Bone Marrow Transplant
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Madison, Wisconsin, United States