Lymphoma, Non-Hodgkin
Conditions
Keywords
Non-Hodgkin's lymphoma, Stem cell mobilization
Brief summary
The purpose of this study is to determine whether the combination of AMD3100 (plerixafor) and granulocyte colony-stimulating factor (G-CSF or generic name filgrastim) is better than G-CSF alone to mobilize and collect the optimal number of stem cells in non-Hodgkin's lymphoma patients for autologous transplantation.
Detailed description
A peripheral stem cell transplant may be able to replace blood-forming cells that were destroyed by chemotherapy. Currently filgrastim (G-CSF), a colony stimulating factor, is used to cause the growth and mobilization of stem cells from bone marrow to peripheral blood, which can then be collected from the peripheral blood by a process called apheresis. Plerixafor aids in the release of the stem cells from the bone marrow into the peripheral blood, possibly allowing for a more rapid collection of a larger number of stem cells from the peripheral blood. Larger stem cell doses for transplantation correlate to faster recovery times after high dose chemotherapy followed with stem cell transplantation. This study is intended to determine whether the combination of plerixafor with filgrastim is better than filgrastim alone in helping non-Hodgkin's lymphoma patients collect at least 5 million stem cells in four or less apheresis sessions. 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.
Interventions
Participants underwent mobilization with granulocyte colony-stimulating factor (G-CSF) (10 µg/kg/day) for 4 days, administered by subcutaneous (SC) injection. On the evening of Day 4, participants received plerixafor (240 µg/kg), administered by SC injection. On Day 5, participants received a morning dose of G-CSF (10 µg/kg) and underwent apheresis approx. 10 to 11 hours after the dose of plerixafor (within 60 minutes of G-CSF administration). Participants continued to receive an evening dose of plerixafor followed by a morning dose of G-CSF and apheresis for up to 4 aphereses or until ≥ 5\*10\^6 CD34+ cells/kg were collected. Participants who participated in the rescue procedure underwent an additional daily treatment with plerixafor (240 µg/kg) and apheresis for up to 4 days.
Participants underwent mobilization with granulocyte colony-stimulating factor (G-CSF) (10 µg/kg/day) for 4 days, administered by subcutaneous (SC) injection. On the evening of Day 4, participants received placebo, administered by SC injection. On Day 5, participants received a morning dose of G-CSF (10 µg/kg) and underwent apheresis approx. 10 to 11 hours after the dose of placebo (within 60 minutes of G-CSF administration). Participants continued to receive an evening dose of placebo followed by a morning dose of G-CSF and apheresis for up to 4 aphereses or until ≥ 5\*10\^6 CD34+ cells/kg were collected. Participants who participated in the rescue procedure underwent an additional daily treatment with plerixafor (240 µg/kg) and apheresis for up to 4 days.
Sponsors
Genzyme, a Sanofi Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 78 Years
Healthy volunteers
No
Inclusion criteria
(Abbreviated List): * Non-Hodgkin's lymphoma in first or second complete or partial remission * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 * White Blood Cell count (WBC) \> 2.5\*10\^9/L * Platelet (PLT) \> 100\*10\^9/L
Exclusion criteria
(Abbreviated List): * Failed previous stem cell collection * Prior autologous or allogeneic transplant * Brain metastases or bone marrow involvement \> 20% * Radiation to pelvis * Abnormal electrocardiogram (ECG) with rhythm disturbance (ventricular arrhythmias) or other conduction abnormality
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Participants Able to Achieve Target (≥ 5*10^6 CD34+ Cells/kg) in 4 or Fewer Days of Apheresis | Days 5 to 8 | Proportion of participants achieving a target of ≥ 5\*10\^6 CD34+ cells/kg in 4 or fewer days of apheresis. Central lab data were taken from Days 5 to 8 of the Treatment/Apheresis period. Each participant's value was calculated as the sum of all daily values collected over the 4 apheresis days. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Participants Able to Achieve Target (>=2*10^6 CD34+ Cells/kg) in 4 or Fewer Days of Apheresis | up to Day 8 | Proportion of participants achieving a target of \>=2\*10\^6 CD34+ Cells/kg in 4 or fewer days of apheresis. Central lab data were taken from Days 5 to 8 of the Treatment/Apheresis period. Each participant's value was calculated as the sum of all daily values collected over the 4 apheresis days. |
| Median Number of Days of Apheresis Required to Achieve >=5*10^6 CD34+ Cells/kg | up to Day 8 | The Kaplan Meier estimate of median number of days (number of days at which 50% of participants reached the threshold, accounting for censored values) in each treatment arm to collect the target number of cells (≥5\*10\^6 CD34+ cells/kg) for transplantation. Central laboratory values were used. |
| Median Number of Days to Polymorphonuclear (PMN) Cell Engraftment | Up to Month 13 | The Kaplan Meier estimate of median number of days to PMN engraftment (number of days at which 50% of participants have experienced the event, accounting for censored values) was a secondary efficacy endpoint. Engraftment was defined as PMN counts ≥ 0.5\*10\^9/L for 3 consecutive days or ≥ 1.0\*10\^9/L for 1 day. Time to engraftment corresponded to the first day that the criteria were met. |
| Number of Participants With Adverse Events | up to Day 38 | Number of participants with treatment emergent adverse events (AEs). The timeframe for treatment emergent AEs is defined as Day 1 (start of G-CSF Mobilization) to the day before starting chemotherapy (approximately 38 days later). AEs were reported regardless of relationship to study treatment. The investigator graded each AE using the World Health Organization (WHO) Adverse Event Grading Scale. AEs of Grade 3 were considered severe and Grade 4 were considered life-threatening. |
| Graft Durability at 100 Days Post Transplantation | approximately Day 138 | The proportion of participants maintaining a durable graft at 100 days post transplantation by at least 2 of the following criteria (without erythropoietin (EPO), G-CSF, or transfusions): (1) a platelet count \>50000/µL without transfusion for at least 2 weeks, (2) hemoglobin \>=10g/dL for at least 1 month, (3) and absolute neutrophil count \>1000/µL for at least 1 week. |
| Graft Durability at 6 Months Post Transplantation | approximately Month 7 | The proportion of participants maintaining a durable graft at 6 months post transplantation by at least 2 of the following criteria (without erythropoietin (EPO), G-CSF, or transfusions): (1) a platelet count \>50000/µL without transfusion for at least 2 weeks, (2) hemoglobin \>=10g/dL for at least 1 month, (3) and absolute neutrophil count \>1000/µL for at least 1 week. |
| Graft Durability at 12 Months Post Transplantation | approximately Month 13 | The proportion of participants maintaining a durable graft 12 months post-transplantation by at least 2 of the following criteria (without erythropoietin (EPO), G-CSF, or transfusions): (1) a platelet count \>50000/µL without transfusion for at least 2 weeks, (2) hemoglobin \>=10g/dL for at least 1 month, (3) and absolute neutrophil count \>1000/µL for at least 1 week. |
| Median Number of Days to Platelet (PLT) Engraftment | Up to Month 13 | The Kaplan Meier estimate of median number of days to PLT engraftment (number of days at which 50% of participants have experienced the event, accounting for censored values) was a secondary efficacy endpoint. Engraftment was defined as ≥ 20\*10\^9/L without transfusion for the preceding 7 days. Time to engraftment corresponded to the first day that the criteria were met. |
Countries
Canada, United States
Participant flow
Recruitment details
Participants with non-Hodgkin's lymphoma (NHL) eligible for autologous hematopoietic stem cell transplant were recruited from 31 centers in the U.S. and 1 in Canada. The first participant was randomized on 18 January 2005 and the last participant's last study visit occurred on 20 December 2007. A total of 298 participants were randomized.
Participants by arm
| Arm | Count |
|---|---|
| G-CSF Plus Plerixafor Participants underwent mobilization with G-CSF for 4 days. On the evening of Day 4, participants received a dose of plerixafor. On each subsequent day, participants received a morning dose of G-CSF followed by apheresis and an evening dose of plerixafor for a maximum of 4 aphereses or until ≥ 5\*10\^6 CD34+ cells/kg were collected. | 150 |
| G-CSF Plus Placebo Participants underwent mobilization with G-CSF for 4 days. On the evening of Day 4, participants received a dose of placebo. On each subsequent day, participants received a morning dose of G-CSF followed by apheresis and an evening dose of placebo for a maximum of 4 aphereses or until ≥ 5\*10\^6 CD34+ cells/kg were collected. | 148 |
| Total | 298 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 2 |
| Overall Study | Death | 16 | 12 |
| Overall Study | Elective Withdrawal | 4 | 0 |
| Overall Study | Entered Rescue Procedure | 10 | 52 |
| Overall Study | Failed mobilization | 1 | 5 |
| Overall Study | Lost to Follow-up | 3 | 1 |
| Overall Study | Noncompliance | 0 | 1 |
| Overall Study | Other | 2 | 7 |
Baseline characteristics
| Characteristic | G-CSF Plus Plerixafor | G-CSF Plus Placebo | Total |
|---|---|---|---|
| Age, Continuous | 55.1 years STANDARD_DEVIATION 10.9 | 57.5 years STANDARD_DEVIATION 10.3 | 56.3 years STANDARD_DEVIATION 10.7 |
| Race/Ethnicity, Customized African-American | 6 participants | 1 participants | 7 participants |
| Race/Ethnicity, Customized Asian | 2 participants | 2 participants | 4 participants |
| Race/Ethnicity, Customized Caucasian | 136 participants | 140 participants | 276 participants |
| Race/Ethnicity, Customized Hispanic/Latino | 5 participants | 4 participants | 9 participants |
| Race/Ethnicity, Customized Other | 1 participants | 1 participants | 2 participants |
| Sex: Female, Male Female | 50 Participants | 46 Participants | 96 Participants |
| Sex: Female, Male Male | 100 Participants | 102 Participants | 202 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 145 / 150 | 136 / 145 |
| serious Total, serious adverse events | 8 / 150 | 10 / 145 |
Outcome results
Primary
Proportion of Participants Able to Achieve Target (≥ 5*10^6 CD34+ Cells/kg) in 4 or Fewer Days of Apheresis
Proportion of participants achieving a target of ≥ 5\*10\^6 CD34+ cells/kg in 4 or fewer days of apheresis. Central lab data were taken from Days 5 to 8 of the Treatment/Apheresis period. Each participant's value was calculated as the sum of all daily values collected over the 4 apheresis days.
Time frame: Days 5 to 8
Population: Intent-to-Treat Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| G-CSF Plus Plerixafor | Proportion of Participants Able to Achieve Target (≥ 5*10^6 CD34+ Cells/kg) in 4 or Fewer Days of Apheresis | Proportion achieving target in ≤4 days | 0.593 proportion of participants |
| G-CSF Plus Plerixafor | Proportion of Participants Able to Achieve Target (≥ 5*10^6 CD34+ Cells/kg) in 4 or Fewer Days of Apheresis | Proportion not achieving target in ≤4 days | 0.407 proportion of participants |
| G-CSF Plus Placebo | Proportion of Participants Able to Achieve Target (≥ 5*10^6 CD34+ Cells/kg) in 4 or Fewer Days of Apheresis | Proportion achieving target in ≤4 days | 0.196 proportion of participants |
| G-CSF Plus Placebo | Proportion of Participants Able to Achieve Target (≥ 5*10^6 CD34+ Cells/kg) in 4 or Fewer Days of Apheresis | Proportion not achieving target in ≤4 days | 0.804 proportion of participants |
Secondary
Graft Durability at 100 Days Post Transplantation
The proportion of participants maintaining a durable graft at 100 days post transplantation by at least 2 of the following criteria (without erythropoietin (EPO), G-CSF, or transfusions): (1) a platelet count \>50000/µL without transfusion for at least 2 weeks, (2) hemoglobin \>=10g/dL for at least 1 month, (3) and absolute neutrophil count \>1000/µL for at least 1 week.
Time frame: approximately Day 138
Population: Participants who received a stem cell transplant and were evaluable at 100 days post-transplant
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| G-CSF Plus Plerixafor | Graft Durability at 100 Days Post Transplantation | Proportion of participants with durable graft | 0.948 proportion of participants |
| G-CSF Plus Plerixafor | Graft Durability at 100 Days Post Transplantation | Proportion of participants without durable graft | 0.052 proportion of participants |
| G-CSF Plus Placebo | Graft Durability at 100 Days Post Transplantation | Proportion of participants with durable graft | 0.951 proportion of participants |
| G-CSF Plus Placebo | Graft Durability at 100 Days Post Transplantation | Proportion of participants without durable graft | 0.049 proportion of participants |
Secondary
Graft Durability at 12 Months Post Transplantation
The proportion of participants maintaining a durable graft 12 months post-transplantation by at least 2 of the following criteria (without erythropoietin (EPO), G-CSF, or transfusions): (1) a platelet count \>50000/µL without transfusion for at least 2 weeks, (2) hemoglobin \>=10g/dL for at least 1 month, (3) and absolute neutrophil count \>1000/µL for at least 1 week.
Time frame: approximately Month 13
Population: Participants who received a stem cell transplant and were evaluable at 12 months post-transplant
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| G-CSF Plus Plerixafor | Graft Durability at 12 Months Post Transplantation | Proportion of participants with a durable graft | 0.982 proportion of participants |
| G-CSF Plus Plerixafor | Graft Durability at 12 Months Post Transplantation | Proportion of participants without a durable graft | 0.018 proportion of participants |
| G-CSF Plus Placebo | Graft Durability at 12 Months Post Transplantation | Proportion of participants with a durable graft | 1.0 proportion of participants |
| G-CSF Plus Placebo | Graft Durability at 12 Months Post Transplantation | Proportion of participants without a durable graft | 0.0 proportion of participants |
Secondary
Graft Durability at 6 Months Post Transplantation
The proportion of participants maintaining a durable graft at 6 months post transplantation by at least 2 of the following criteria (without erythropoietin (EPO), G-CSF, or transfusions): (1) a platelet count \>50000/µL without transfusion for at least 2 weeks, (2) hemoglobin \>=10g/dL for at least 1 month, (3) and absolute neutrophil count \>1000/µL for at least 1 week.
Time frame: approximately Month 7
Population: Participants who received a stem cell transplant and were evaluable at 6 months post-transplant
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| G-CSF Plus Plerixafor | Graft Durability at 6 Months Post Transplantation | Proportion of participants without a durable graft | 0.024 proportion of participants |
| G-CSF Plus Plerixafor | Graft Durability at 6 Months Post Transplantation | Proportion of participants with a durable graft | 0.976 proportion of participants |
| G-CSF Plus Placebo | Graft Durability at 6 Months Post Transplantation | Proportion of participants with a durable graft | 0.987 proportion of participants |
| G-CSF Plus Placebo | Graft Durability at 6 Months Post Transplantation | Proportion of participants without a durable graft | 0.013 proportion of participants |
Secondary
Median Number of Days of Apheresis Required to Achieve >=5*10^6 CD34+ Cells/kg
The Kaplan Meier estimate of median number of days (number of days at which 50% of participants reached the threshold, accounting for censored values) in each treatment arm to collect the target number of cells (≥5\*10\^6 CD34+ cells/kg) for transplantation. Central laboratory values were used.
Time frame: up to Day 8
Population: Intent-to-Treat Population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| G-CSF Plus Plerixafor | Median Number of Days of Apheresis Required to Achieve >=5*10^6 CD34+ Cells/kg | 3.0 Days |
| G-CSF Plus Placebo | Median Number of Days of Apheresis Required to Achieve >=5*10^6 CD34+ Cells/kg | NA Days |
Secondary
Median Number of Days to Platelet (PLT) Engraftment
The Kaplan Meier estimate of median number of days to PLT engraftment (number of days at which 50% of participants have experienced the event, accounting for censored values) was a secondary efficacy endpoint. Engraftment was defined as ≥ 20\*10\^9/L without transfusion for the preceding 7 days. Time to engraftment corresponded to the first day that the criteria were met.
Time frame: Up to Month 13
Population: Participants who received a stem cell transplant
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| G-CSF Plus Plerixafor | Median Number of Days to Platelet (PLT) Engraftment | 20.0 Days |
| G-CSF Plus Placebo | Median Number of Days to Platelet (PLT) Engraftment | 20.0 Days |
Secondary
Median Number of Days to Polymorphonuclear (PMN) Cell Engraftment
The Kaplan Meier estimate of median number of days to PMN engraftment (number of days at which 50% of participants have experienced the event, accounting for censored values) was a secondary efficacy endpoint. Engraftment was defined as PMN counts ≥ 0.5\*10\^9/L for 3 consecutive days or ≥ 1.0\*10\^9/L for 1 day. Time to engraftment corresponded to the first day that the criteria were met.
Time frame: Up to Month 13
Population: Participants who received a stem cell transplant.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| G-CSF Plus Plerixafor | Median Number of Days to Polymorphonuclear (PMN) Cell Engraftment | 10.0 Days |
| G-CSF Plus Placebo | Median Number of Days to Polymorphonuclear (PMN) Cell Engraftment | 10.0 Days |
Secondary
Number of Participants With Adverse Events
Number of participants with treatment emergent adverse events (AEs). The timeframe for treatment emergent AEs is defined as Day 1 (start of G-CSF Mobilization) to the day before starting chemotherapy (approximately 38 days later). AEs were reported regardless of relationship to study treatment. The investigator graded each AE using the World Health Organization (WHO) Adverse Event Grading Scale. AEs of Grade 3 were considered severe and Grade 4 were considered life-threatening.
Time frame: up to Day 38
Population: Safety population of all participants who received at least 1 mobilization dose of G-CSF or study treatment (plerixafor or placebo). Three participants did not receive G-CSF or any study treatment and were excluded from the safety analyses.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| G-CSF Plus Plerixafor | Number of Participants With Adverse Events | Adverse Events (AEs) | 146 participants |
| G-CSF Plus Plerixafor | Number of Participants With Adverse Events | Related AEs | 98 participants |
| G-CSF Plus Plerixafor | Number of Participants With Adverse Events | AEs Leading to early treatment termination | 3 participants |
| G-CSF Plus Plerixafor | Number of Participants With Adverse Events | AEs Leading to early study termination | 2 participants |
| G-CSF Plus Plerixafor | Number of Participants With Adverse Events | Grade 3 (severe) or 4 (life-threatening) AEs | 11 participants |
| G-CSF Plus Plerixafor | Number of Participants With Adverse Events | SAEs | 8 participants |
| G-CSF Plus Placebo | Number of Participants With Adverse Events | Grade 3 (severe) or 4 (life-threatening) AEs | 14 participants |
| G-CSF Plus Placebo | Number of Participants With Adverse Events | Adverse Events (AEs) | 138 participants |
| G-CSF Plus Placebo | Number of Participants With Adverse Events | AEs Leading to early study termination | 4 participants |
| G-CSF Plus Placebo | Number of Participants With Adverse Events | Related AEs | 60 participants |
| G-CSF Plus Placebo | Number of Participants With Adverse Events | SAEs | 10 participants |
| G-CSF Plus Placebo | Number of Participants With Adverse Events | AEs Leading to early treatment termination | 3 participants |
Secondary
Proportion of Participants Able to Achieve Target (>=2*10^6 CD34+ Cells/kg) in 4 or Fewer Days of Apheresis
Proportion of participants achieving a target of \>=2\*10\^6 CD34+ Cells/kg in 4 or fewer days of apheresis. Central lab data were taken from Days 5 to 8 of the Treatment/Apheresis period. Each participant's value was calculated as the sum of all daily values collected over the 4 apheresis days.
Time frame: up to Day 8
Population: Intent-to-treat Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| G-CSF Plus Plerixafor | Proportion of Participants Able to Achieve Target (>=2*10^6 CD34+ Cells/kg) in 4 or Fewer Days of Apheresis | Proportion achieving target in ≤4 days | 0.867 proportion of participants |
| G-CSF Plus Plerixafor | Proportion of Participants Able to Achieve Target (>=2*10^6 CD34+ Cells/kg) in 4 or Fewer Days of Apheresis | Proportion not achieving target in ≤4 days | 0.133 proportion of participants |
| G-CSF Plus Placebo | Proportion of Participants Able to Achieve Target (>=2*10^6 CD34+ Cells/kg) in 4 or Fewer Days of Apheresis | Proportion achieving target in ≤4 days | 0.473 proportion of participants |
| G-CSF Plus Placebo | Proportion of Participants Able to Achieve Target (>=2*10^6 CD34+ Cells/kg) in 4 or Fewer Days of Apheresis | Proportion not achieving target in ≤4 days | 0.527 proportion of participants |