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No prospective randomized trials have evaluated the most efficacious dose of cyclophosphamide to mobilize autologous stem cells. We previously demonstrated that the time to collection of autologous hematopoietic stem cells is 10-12 days following the one dose of cyclophosphamide and daily G-CSF (granulocyte-colony stimulating factor).9 This prospective randomized trial is designed to determine if a lower dose of cyclophosphamide (1.5 gm/m2) will be as efficacious as the intermediate dose (3 gm/m2), based on cell number collected, number of apheresis required and resource utilization.
This prospective randomized trial is designed to determine if a lower dose of cyclophosphamide (1.5 gm/m2) will be as efficacious as the intermediate dose (3 gm/m2), based on cell number collected, number of apheresis required and resource utilization.
The time to collection of autologous hematopoietic stem cells was ten to twelve days following cyclophosphamide and daily filgrastim. Peripheral blood CD34+ cell numbers were examined beginning ten days after cyclophosphamide administration. Leukapheresis began once the blood CD34+ number reached 10 cells/mcl. Patients received consecutive days of leukapheresis, with the goal of collecting > 5 x 106 CD34+cells/kg. The collection process, concentration and storage of PBSC were similar for all patients. Briefly, a 4-blood volume leukapheresis PBSC collection was performed daily using a COBE Spectra cell separator (COBE BCT, Lakewood, CO). Collected cells were concentrated and cryopreserved. Cells were frozen in Cryocyte freezing bags (Nexell Therapeutics Inc.) in a controlled rate freezer (Custom BioGenic Systems, Shelby Township, MI). At the conclusion of this freezing, the cells were transferred to the vapor phase of a monitored liquid nitrogen freezer (CryoPlus III, Forma Scientific, Marietta, OH) at a temperature of -120 0C or below.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Arm 2: Cyclophosphamide 3 gms/m(2) | Active Comparator | Patients will receive intravenous mesna 15 minutes prior to cyclophosphamide and again at 4 and 8 hours afterwards. Each infusion will be given over 15 minutes. Oral mesna can be substituted for the two post-cyclophosphamide doses. Oral mesna will be administered at 2 and 6 hours after the start of cyclophosphamide. Cyclophosphamide will be administered intravenously over one hour at the dose of 3 gms/m(2). |
|
| Arm 1: 1.5 gms/m(2) Cyclophosphamide | Experimental | Patients will receive intravenous mesna 15 minutes prior to cyclophosphamide and again at 4 and 8 hours afterwards. Each infusion will be given over 15 minutes. Oral mesna can be substituted for the two post-cyclophosphamide doses. Oral mesna will be administered at 2 and 6 hours after the start of cyclophosphamide. Cyclophosphamide will be administered intravenously over one hour at the dose of 1.5 gms/m(2). |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Cyclophosphamide | Drug | Mechanism of action: Cyclophosphamide is a pro drug that requires activation. Following hepatic and cellular activation, phosphoramide mustard and acrolein are formed. Phosphoramide mustard is the alkylating agent that demonstrates cytotoxic effects. Acrolein binds to proteins but does not contribute to the anti-tumor effects. |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Nucleated Cells Collected Within the Apheresis Products | the investigator will identify the number of cells collected within the apheresis products | 6 weeks |
| Number of CD34+ Cells Collected Within the Apheresis Products | the investigator will identify the number of CD34+ cells collected within the apheresis products | 6 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Resource Utilization - Transfusions of Red Blood Cells | Resources used during the mobilization and apheresis processes will be captured. | participants will be followed approximately 6 weeks following initiation of treatment |
| Resource Utilization- Transfusion of Platelets |
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Inclusion Criteria:
Non-Hodgkin's Lymphoma, including B- and T-cell lymphoma Multiple Myeloma or another plasma cell dyscrasia (Waldenstrom, Amyloidosis)
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Kenneth Meehan, MD | Dartmouth-Hitchcock Medical Center | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Dartmouth Hitchcock Medical Center | Lebanon | New Hampshire | 03756 | United States |
58 Individuals provided informed consent. Of those. four (4) participants were screen failures.
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| ID | Title | Description |
|---|---|---|
| FG000 | Arm 1: 1.5 Gms/m(2) Cyclophosphamide | Patients will receive intravenous mesna 15 minutes prior to cyclophosphamide and again at 4 and 8 hours afterwards. Each infusion will be given over 15 minutes. Oral mesna can be substituted for the two post-cyclophosphamide doses. Oral mesna will be administered at 2 and 6 hours after the start of cyclophosphamide. Cyclophosphamide will be administered intravenously over one hour at the dose of 1.5 gms/m(2). Cyclophosphamide: Mechanism of action: Cyclophosphamide is a pro drug that requires activation. Following hepatic and cellular activation, phosphoramide mustard and acrolein are formed. Phosphoramide mustard is the alkylating agent that demonstrates cytotoxic effects. Acrolein binds to proteins but does not contribute to the anti-tumor effects. |
| FG001 | Arm 2: Cyclophosphamide 3 Gms/m(2) | Patients will receive intravenous mesna 15 minutes prior to cyclophosphamide and again at 4 and 8 hours afterwards. Each infusion will be given over 15 minutes. Oral mesna can be substituted for the two post-cyclophosphamide doses. Oral mesna will be administered at 2 and 6 hours after the start of cyclophosphamide. Cyclophosphamide will be administered intravenously over one hour at the dose of 3 gms/m(2). Cyclophosphamide: Mechanism of action: Cyclophosphamide is a pro drug that requires activation. Following hepatic and cellular activation, phosphoramide mustard and acrolein are formed. Phosphoramide mustard is the alkylating agent that demonstrates cytotoxic effects. Acrolein binds to proteins but does not contribute to the anti-tumor effects. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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|
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| ID | Title | Description |
|---|---|---|
| BG000 | Arm 1: 1.5 Gms/m(2) Cyclophosphamide | Patients will receive intravenous mesna 15 minutes prior to cyclophosphamide and again at 4 and 8 hours afterwards. Each infusion will be given over 15 minutes. Oral mesna can be substituted for the two post-cyclophosphamide doses. Oral mesna will be administered at 2 and 6 hours after the start of cyclophosphamide. Cyclophosphamide will be administered intravenously over one hour at the dose of 1.5 gms/m(2). Cyclophosphamide: Mechanism of action: Cyclophosphamide is a pro drug that requires activation. Following hepatic and cellular activation, phosphoramide mustard and acrolein are formed. Phosphoramide mustard is the alkylating agent that demonstrates cytotoxic effects. Acrolein binds to proteins but does not contribute to the anti-tumor effects. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Median |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Number of Nucleated Cells Collected Within the Apheresis Products | the investigator will identify the number of cells collected within the apheresis products | Posted | Median | Full Range | cells x10e10 | 6 weeks |
|
Monitoring of toxicities will terminate on the last day of collection, since treatment-related toxicities occur during this time period. Patients who complete mobilization will be considered "off treatment" on the date of the last mobilization. There will be no specified follow up beyond the off treatment period other than following for engraftment. Average period of data collection was 10 days
Evaluation of toxicities (other than Hematologic) will be graded using National Cancer Institute Common Toxicity Criteria, specifically CTC AE 4.0.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Arm 1: 1.5 Gms/m(2) Cyclophosphamide | Patients will receive intravenous mesna 15 minutes prior to cyclophosphamide and again at 4 and 8 hours afterwards. Each infusion will be given over 15 minutes. Oral mesna can be substituted for the two post-cyclophosphamide doses. Oral mesna will be administered at 2 and 6 hours after the start of cyclophosphamide. Cyclophosphamide will be administered intravenously over one hour at the dose of 1.5 gms/m(2). Cyclophosphamide: Mechanism of action: Cyclophosphamide is a pro drug that requires activation. Following hepatic and cellular activation, phosphoramide mustard and acrolein are formed. Phosphoramide mustard is the alkylating agent that demonstrates cytotoxic effects. Acrolein binds to proteins but does not contribute to the anti-tumor effects. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Infection | Infections and infestations | Systematic Assessment | Febrile neutropenia (fever of unknown origin without clinically or microbiologically documented infection)(ANC <1.0 x 10e9/L, fever >=38.5 degrees C) |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Platelets | Blood and lymphatic system disorders | Systematic Assessment | BLOOD/BONE MARROW: Platelets |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Kenneth Meehan, MD | Dartmouth-Hitchcock Medical Center | 603.650.4628 | Kenneth.R.Meehan@hitchcock.org |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Oct 23, 2020 | Dec 17, 2020 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D019337 | Hematologic Neoplasms |
| ID | Term |
|---|---|
| D009371 | Neoplasms by Site |
| D009369 | Neoplasms |
| D006402 | Hematologic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
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| ID | Term |
|---|---|
| D003520 | Cyclophosphamide |
| ID | Term |
|---|---|
| D010752 | Phosphoramide Mustards |
| D009588 | Nitrogen Mustard Compounds |
| D009150 | Mustard Compounds |
| D006846 | Hydrocarbons, Halogenated |
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|
|
Resources used during the mobilization and apheresis processes will be captured. |
| participants will be followed approximately 6 weeks following initiation of treatment |
| Resource Utilization- Hospitalizations | Resources used during the mobilization and apheresis processes will be captured. | participants will be followed approximately 6 weeks following initiation of treatment |
| Resource Utilization- Incidence of Febrile Neutropenia | Resources used during the mobilization and apheresis processes will be captured. | participants will be followed approximately 6 weeks following initiation of treatment |
| Toxicities During the Mobilization and Apheresis Processes | Toxicities during the mobilization and apheresis processes Grade 3 and higher | participants will be followed approximately 6 weeks following initiation of treatment |
| BG001 | Arm 2: Cyclophosphamide 3 Gms/m(2) | Patients will receive intravenous mesna 15 minutes prior to cyclophosphamide and again at 4 and 8 hours afterwards. Each infusion will be given over 15 minutes. Oral mesna can be substituted for the two post-cyclophosphamide doses. Oral mesna will be administered at 2 and 6 hours after the start of cyclophosphamide. Cyclophosphamide will be administered intravenously over one hour at the dose of 3 gms/m(2). Cyclophosphamide: Mechanism of action: Cyclophosphamide is a pro drug that requires activation. Following hepatic and cellular activation, phosphoramide mustard and acrolein are formed. Phosphoramide mustard is the alkylating agent that demonstrates cytotoxic effects. Acrolein binds to proteins but does not contribute to the anti-tumor effects. |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| OG001 | Arm 2: Cyclophosphamide 3 Gms/m(2) | Patients will receive intravenous mesna 15 minutes prior to cyclophosphamide and again at 4 and 8 hours afterwards. Each infusion will be given over 15 minutes. Oral mesna can be substituted for the two post-cyclophosphamide doses. Oral mesna will be administered at 2 and 6 hours after the start of cyclophosphamide. Cyclophosphamide will be administered intravenously over one hour at the dose of 3 gms/m(2). Cyclophosphamide: Mechanism of action: Cyclophosphamide is a pro drug that requires activation. Following hepatic and cellular activation, phosphoramide mustard and acrolein are formed. Phosphoramide mustard is the alkylating agent that demonstrates cytotoxic effects. Acrolein binds to proteins but does not contribute to the anti-tumor effects. |
|
|
| Primary | Number of CD34+ Cells Collected Within the Apheresis Products | the investigator will identify the number of CD34+ cells collected within the apheresis products | Posted | Median | Full Range | cells x10e8 | 6 weeks |
|
|
|
| Secondary | Resource Utilization - Transfusions of Red Blood Cells | Resources used during the mobilization and apheresis processes will be captured. | Data was not collected due to the large geographic areas of the patient residence. It was too difficult to collect the date from multiple physicians from multiple states. | Posted | participants will be followed approximately 6 weeks following initiation of treatment |
|
|
| Secondary | Resource Utilization- Transfusion of Platelets | Resources used during the mobilization and apheresis processes will be captured. | Data was not collected due to the large geographic areas of the patient residence. It was too difficult to collect the date from multiple physicians from multiple states. | Posted | participants will be followed approximately 6 weeks following initiation of treatment |
|
|
| Secondary | Resource Utilization- Hospitalizations | Resources used during the mobilization and apheresis processes will be captured. | Posted | Count of Participants | Participants | participants will be followed approximately 6 weeks following initiation of treatment |
|
|
|
| Secondary | Resource Utilization- Incidence of Febrile Neutropenia | Resources used during the mobilization and apheresis processes will be captured. | Posted | Count of Participants | Participants | participants will be followed approximately 6 weeks following initiation of treatment |
|
|
|
| Secondary | Toxicities During the Mobilization and Apheresis Processes | Toxicities during the mobilization and apheresis processes Grade 3 and higher | Number of participants who experienced a grade 3 or higher adverse event | Posted | Count of Participants | Participants | participants will be followed approximately 6 weeks following initiation of treatment |
|
|
|
| 0 |
| 33 |
| 1 |
| 33 |
| 16 |
| 33 |
| EG001 | Arm 2: Cyclophosphamide 3 Gms/m(2) | Patients will receive intravenous mesna 15 minutes prior to cyclophosphamide and again at 4 and 8 hours afterwards. Each infusion will be given over 15 minutes. Oral mesna can be substituted for the two post-cyclophosphamide doses. Oral mesna will be administered at 2 and 6 hours after the start of cyclophosphamide. Cyclophosphamide will be administered intravenously over one hour at the dose of 3 gms/m(2). Cyclophosphamide: Mechanism of action: Cyclophosphamide is a pro drug that requires activation. Following hepatic and cellular activation, phosphoramide mustard and acrolein are formed. Phosphoramide mustard is the alkylating agent that demonstrates cytotoxic effects. Acrolein binds to proteins but does not contribute to the anti-tumor effects. | 0 | 20 | 2 | 20 | 8 | 20 |
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| Nausea | Gastrointestinal disorders | Systematic Assessment |
|
| Edema: limb | Blood and lymphatic system disorders | Systematic Assessment |
|
| Pain: Back | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Cough | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Sinus tachycardia | Cardiac disorders | Systematic Assessment | CARDIAC ARRHYTHMIA: Supraventricular and nodal arrhythmia - Sinus tachycardia |
|
| Hypotension | Cardiac disorders | Systematic Assessment |
|
| Pruritus/itching | Skin and subcutaneous tissue disorders | Systematic Assessment | DERMATOLOGY/SKIN: Pruritus/itching: Vaginal pruritus |
|
| Diarrhea | Gastrointestinal disorders | Systematic Assessment |
|
| Pain: Abdomen NOS | Gastrointestinal disorders | Systematic Assessment |
|
| Pain: Bone | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Pain: Extremity-limb | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Pain NOS | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
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| D006838 | Hydrocarbons |
| D009930 | Organic Chemicals |
| D063088 | Phosphoramides |
| D009943 | Organophosphorus Compounds |