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

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase 2, Multicenter, Open-label Study to Evaluate the Safety and Efficacy of AMD3100 (240 µg/kg) Added to a G-CSF Mobilization Regimen in Poor Mobilizing Adult Patients Who Have Previously Failed Stem Cell Collection/Attempts

Conditions
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Autologous Stem Cell Transplantation

Intervention / Treatment
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* Drug: G-CSF plus plerixafor


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 78 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: G-CSF plus Plerixafor<br> | Drug: G-CSF plus plerixafor<br>* Participants underwent mobilization with granulocyte colony-stimulating factor (G-CSF) 10 µg/kg/day for 4 days, administered by subcutaneous injection (SC) injection each morning. On the evening of Day 4, participants received a dose of plerixafor 240 µg/kg, administered by SC injection. On Day 5, participants returned to the clinic and received a morning dose of G-CSF 10 µg/kg and underwent apheresis approximately 10 to 11 hours after the dose of plerixafor (within 60 minutes after administration of G-CSF). Participants continued to receive an evening dose of plerixafor followed the next day by a morning dose of G-CSF and apheresis for up to a maximum of 7 aphereses or until ≥ 2*10^6 CD34+ cells/kg were collected.<br>* Other names: Mozobil;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Participant Counts Summarizing Adverse Events (AEs) During the Treatment Period | 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'). | Day 1 to approximately day 38 | 
| Proportion of Participants Who Achieved ≥2*10^6 CD34+ Cells/kg Following Treatment With Plerixafor and G-CSF | Proportion of participants who reached the target of at least 2*10^6 CD34+ cells/kg collected during up to 7 aphereses. | Day 5 to Day 11 (up to 7 apheresis) | 
| Proportion of Participants Who Achieved ≥5*10^6 CD34+ Cells/kg Following Treatment With Plerixafor and G-CSF | Proportion of participants who reached the target of at least 5*10^6 CD34+ cells/kg collected during up to 7 apheresis. | Day 5 to Day 11 (up to 7 aphereses) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Number of Days to Polymorphonuclear Leukocyte (PMN) Engraftment | 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. | approximately 2 months (1 month post transplant) | 
| Median Number of Days to Platelet (PLT) Engraftment | The number of days from transplantation to successful engraftment as measured by platelet value of >=20*10^9/L for 7 days without transfusion. | Approximately 2 months (1 month post transplant) | 
| Number of Participants With Durable Engraftment 12 Months After Autologous Transplantation | 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. | Approximately 13 months (12 months post transplant ) | 
| Number of Participants With Non-Hodgkin's Lymphoma (NHL) Who Had Evidence of Tumor Cell Mobilization After G-CSF or Plerixafor Administration | The number of participants with Bcl2 translocation in post-treatment samples. | Up to Day 7 | 
| Number of Participants Who Achieved ≥2*10^6 CD34+ Cells/kg Collected During Both Courses of Treatment With Plerixafor and G-CSF | 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. | Day 5 up to Month 6 (up to 7 aphereses in each course of treatment) | 
| Number of Participants Who Achieved ≥5*10^6 CD34+ Cells/kg Collected During Both Courses of Treatment With Plerixafor and G-CSF | 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. | Day 5 up to Month 6 (up to 7 aphereses in each course of treatment) | 
| Maximum Observed Plasma Concentration (Cmax) on Day 4 | Maximum plasma concentration (Cmax) of plerixafor following daily doses of 240 µg/kg plerixafor, determined directly from the concentration-time data. | Day 4 (following first plerixafor administration) | 
| Maximum Observed Plasma Concentration (Cmax) on Day 7 | Maximum plasma concentration (Cmax) of plerixafor following daily doses of 240 µg/kg plerixafor, determined directly from the concentration-time data. | Day 7 (following fourth plerixafor administration) | 
| Time to Maximum Plasma Concentration (Tmax) on Day 4 | Time to maximum plasma concentration (Tmax) of plerixafor following daily doses of 240 µg/kg plerixafor, determined directly from the concentration-time data | Day 4 (following first plerixafor administration) | 
| Time to Maximum Plasma Concentration (Tmax) on Day 7 | Time to maximum plasma concentration (Tmax) of plerixafor following daily doses of 240 µg/kg plerixafor, determined directly from the concentration-time data | Day 7 (following fourth plerixafor administration) | 
| Area Under the Steady-state Plasma Concentration Time Curve From Time Zero to the Last Quantifiable Sample (AUC0-last) on Day 4 | 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. | Days 4 -5 (following first plerixafor administration) | 
| Area Under the Steady-state Plasma Concentration Time Curve From Time Zero to the Last Quantifiable Sample (AUC0-last) on Day 7 | 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. | Days 7-8 (following fourth plerixafor administration) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Multiple Myeloma, Non-Hodgkin's Lymphoma, autologous transplantation, AMD3100, stem cell mobilization, plerixafor