Busulfan, Melphalan, Fludarabine and T-Cell Depleted Allogeneic Hematopoietic Stem Cell Transplantation Followed by Post Transplantation Donor Lymphocyte Infusions
Study Details
Study Description
Brief Summary
The patients are being offered a stem cell transplant. Stem cells are very early blood cells. They have not yet matured to become red or white blood cells or platelets. They have already received the standard treatment of chemotherapy and an autologous stem cell transplant. An autologous stem cell transplant is when the patient receives their infusion of their own cells. Thi will give the patient a better chance of curing the disease, this protocol includes an infusion of stem cells from the blood (or the bone marrow) of another person. This is called an allogeneic stem cell transplant. The stem cells will begin to grow in the bone marrow and produce new blood cells.
Allogeneic stem cell transplants can cause a condition called graft-versus-host disease or GVHD. In GVHD, a kind of white blood cell from the donor (graft) begins to attack the body (host). That blood cell is called a T-cell. It is a cell that normally helps to protects against things like bacteria and viruses. In this case, the donor's T-cells see the body as foreign in the same way they would see bacteria as foreign. GVHD can be fatal. In order to lower the chance that the patient will get GVHD this protocol treatment will remove the T-cells from the donor's cells. This is called T-cell depletion. The T cells are removed by a system called "Clinimacs". This method is still being evaluated through clinical trials and not been approved by the Federal Drug Administration (FDA) at this time.
Before the transplant, the physician will treat the bone marrow to get rid of the cancer. The physician uses three chemotherapy drugs plus ATG. The chemotherapy drugs (Busulfan, Melphalan and Fludarabine) kills the cancer. ATG gets rid of any of the patients T cells that survive the chemotherapy. This ensures that the donor stem cells are not rejected. The patient will also receive additional white blood cells called lymphocytes from the donor. This is called a donor lymphocyte infusion or DLI. These additional infusions will help cause a graft-versus-myeloma effect and can help the donor stem cells grow.
Condition or Disease | Intervention/Treatment | Phase |
---|---|---|
|
Phase 2 |
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
---|---|
Experimental: relapsed multiple myeloma This is a two arm phase II trial to assess the progression-free and overall survival as well as the safety and efficacy of allogeneic hematopoietic stem cell transplantation using a preparative regimen with busulfan, melphalan, fludarabine, and anti-thymocyte globulin (ATG), and a T cell depleted stem cell transplant from a histocompatible related or unrelated donor in patients with relapsed or high-risk multiple myeloma. |
Drug: busulfan, melphalan and fludarabine
Patients will be cytoreduced with IV busulfan, melphalan and fludarabine. Busulfan will be administered at a dose of 0.8mg/Kg q6hrs for 10 doses on days -9, -8, -7. Doses for busulfan should be adjusted according to pharmacokinetic studies. Melphalan will be administered at a dose of 70 mg/m2/day for 2 days on days -7, -6. Fludarabine will be administered at a dose of 25 mg/m2/day for 5 days on days -6, -5, -4, -3, -2. Patients will also receive rabbit anti-thymocyte globulin (ATG) to prevent immune mediated graft rejection. The ATG will be administered at a dose of 2.5 mg/Kg/day IV on days -3 and -2. Doses for busulfan, melphalan and ATG should be adjusted if patient is > 125% ideal body weight and should be calculated on adjusted ideal body weight.
Other Names:
|
Experimental: high-risk multiple myeloma This is a two arm phase II trial to assess the progression-free and overall survival as well as the safety and efficacy of allogeneic hematopoietic stem cell transplantation using a preparative regimen with busulfan, melphalan, fludarabine, and anti-thymocyte globulin (ATG), and a T cell depleted stem cell transplant from a histocompatible related or unrelated donor in patients with relapsed or high-risk multiple myeloma. |
Drug: busulfan, melphalan and fludarabine
Patients will be cytoreduced with IV busulfan, melphalan and fludarabine. Busulfan will be administered at a dose of 0.8mg/Kg q6hrs for 10 doses on days -9, -8, -7. Doses for busulfan should be adjusted according to pharmacokinetic studies. Melphalan will be administered at a dose of 70 mg/m2/day for 2 days on days -7, -6. Fludarabine will be administered at a dose of 25 mg/m2/day for 5 days on days -6, -5, -4, -3, -2. Patients will also receive rabbit anti-thymocyte globulin (ATG) to prevent immune mediated graft rejection. The ATG will be administered at a dose of 2.5 mg/Kg/day IV on days -3 and -2. Doses for busulfan, melphalan and ATG should be adjusted if patient is > 125% ideal body weight and should be calculated on adjusted ideal body weight.
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Proportion of Participants With Relapsed Multiple Myeloma With Progression-free (PFS) [2 years]
Secondary Outcome Measures
- Proportion of Participants With Relapsed Multiple Myeloma Alive at 2 Years [2 years]
- Number of Participants Who Relapse That Are Restored to Remission (CR) [3 years]
To compute the current multiple myeloma free survival curve in order to account for patients who relapse and are restored to remission through DLI.
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Patient must have multiple myeloma that has either relapsed or has high risk cytogenetics.
-
Patients with relapsed multiple myeloma following autologous stem cell transplantation must have achieved at least partial response following additional chemotherapy (cohort 1):
-
Patients are eligible if relapse occurs with complex/high-risk cytogenetics or occurs with normal cytogenetics but within 15 months following the autologous transplant.
-
Patients with high risk cytogenetics at diagnosis must have achieved at least very good partial response following autologous stem cell transplantation (cohort 2):
-
Patients must have complex karyotype, 1q25, del17p, t4;14 and/or t14;16 by FISH and/or del13 by karyotyping.
DONOR: Patients must have a healthy HLA matched or mismatched related or unrelated donor who is willing to receive G-CSF injections and undergo apheresis for PBSC collection, or undergo a marrow harvesting procedure.
-
HLA-matched related and unrelated donors Patients who have an HLA-matched related or unrelated donor are eligible for entry on this protocol. This will include a healthy donor who is genotypically matched at all A, B, C, DRB1 and DQB1 locus, loci, as tested by DNA analysis.
-
HLA- mismatched related and unrelated donors Patients who do not have an HLA-matched donor but have a related or unrelated donor who have one antigen or one allele mismatch at the HLA A, B, C, DRB1 or DQB1 loci; or who have two mismatches, at HLA-DQB1 and at one other locus, will be eligible for entry on this protocol.
The following inclusion criteria are also required:
-
Patients should be ≥ 21, < 73 years old.
-
Patients may be of either gender or any ethnic background.
-
Patients must have a Karnofsky (adult) or Performance Status ≥ 70%
-
Patients must have adequate organ function measured by:
Cardiac: asymptomatic or if symptomatic then LVEF at rest must be ≥ 50% and must improve with exercise. Hepatic: < 3x ULN ALT and ≤ 1.5 total serum bilirubin, unless there is congenital benign hyperbilirubinemia.
Renal: serum creatinine <1.2 mg/dl or if serum creatinine is outside the normal range, then CrCl > 40 ml/min (measured or calculated/estimated) with dose adjustment of Fludarabine for <70ml/min.
Pulmonary: asymptomatic or if symptomatic, DLCO > 50% of predicted (corrected for hemoglobin)
- Each patient must be willing to participate as a research subject and must sign an informed consent form.
Exclusion Criteria:
-
Patients achieving < Partial Response following preceding chemotherapy (cohort 1) or < Very Good Partial Response following autologous stem cell transplantation (cohort 2).
-
Patients with Plasma Cell Leukemia.
-
Female patients who are pregnant or breast-feeding
-
Active viral, bacterial or fungal infection
-
Patient seropositive for HIV-I/II; HTLV -I/II
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Patients who have undergone prior allogeneic hematopoietic stem cell transplantation.
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Patients who have had a previous malignancy that is not in remission.
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Patients with known hypersensitivity to mouse proteins (murine antibodies in ISOLEX) if receiving SBA-E- bone marrow, or chicken egg products.
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
---|---|---|---|---|---|
1 | Memorial Sloan Kettering Cancer Center | New York | New York | United States | 10065 |
Sponsors and Collaborators
- Memorial Sloan Kettering Cancer Center
- Otsuka America Pharmaceutical
- Ludwig Institute for Cancer Research
Investigators
- Principal Investigator: Sergio Giralt, MD, Memorial Sloan Kettering Cancer Center
Study Documents (Full-Text)
More Information
Additional Information:
Publications
None provided.- 10-051
Study Results
Participant Flow
Recruitment Details | |
---|---|
Pre-assignment Detail |
Arm/Group Title | Relapsed Multiple Myeloma | High-risk Multiple Myeloma |
---|---|---|
Arm/Group Description | This is a two arm phase II trial to assess the progression-free and overall survival as well as the safety and efficacy of allogeneic hematopoietic stem cell transplantation using a preparative regimen with busulfan, melphalan, fludarabine, and anti-thymocyte globulin (ATG), and a T cell depleted stem cell transplant from a histocompatible related or unrelated donor in patients with relapsed or high-risk multiple myeloma | This is a two arm phase II trial to assess the progression-free and overall survival as well as the safety and efficacy of allogeneic hematopoietic stem cell transplantation using a preparative regimen with busulfan, melphalan, fludarabine, and anti-thymocyte globulin (ATG), and a T cell depleted stem cell transplant from a histocompatible related or unrelated donor in patients with relapsed or high-risk multiple myeloma. |
Period Title: Overall Study | ||
STARTED | 47 | 19 |
COMPLETED | 47 | 19 |
NOT COMPLETED | 0 | 0 |
Baseline Characteristics
Arm/Group Title | Relapsed Multiple Myeloma | High-risk Multiple Myeloma | Total |
---|---|---|---|
Arm/Group Description | This is a two arm phase II trial to assess the progression-free and overall survival as well as the safety and efficacy of allogeneic hematopoietic stem cell transplantation using a preparative regimen with busulfan, melphalan, fludarabine, and anti-thymocyte globulin (ATG), and a T cell depleted stem cell transplant from a histocompatible related or unrelated donor in patients with relapsed or high-risk multiple myeloma | This is a two arm phase II trial to assess the progression-free and overall survival as well as the safety and efficacy of allogeneic hematopoietic stem cell transplantation using a preparative regimen with busulfan, melphalan, fludarabine, and anti-thymocyte globulin (ATG), and a T cell depleted stem cell transplant from a histocompatible related or unrelated donor in patients with relapsed or high-risk multiple myeloma. | Total of all reporting groups |
Overall Participants | 47 | 19 | 66 |
Age (years) [Mean (Full Range) ] | |||
Mean (Full Range) [years] |
55.3
|
49.5
|
54
|
Sex: Female, Male (Count of Participants) | |||
Female |
12
25.5%
|
5
26.3%
|
17
25.8%
|
Male |
35
74.5%
|
14
73.7%
|
49
74.2%
|
Ethnicity (NIH/OMB) (Count of Participants) | |||
Hispanic or Latino |
5
10.6%
|
2
10.5%
|
7
10.6%
|
Not Hispanic or Latino |
42
89.4%
|
17
89.5%
|
59
89.4%
|
Unknown or Not Reported |
0
0%
|
0
0%
|
0
0%
|
Race (NIH/OMB) (Count of Participants) | |||
American Indian or Alaska Native |
0
0%
|
0
0%
|
0
0%
|
Asian |
4
8.5%
|
0
0%
|
4
6.1%
|
Native Hawaiian or Other Pacific Islander |
0
0%
|
0
0%
|
0
0%
|
Black or African American |
8
17%
|
2
10.5%
|
10
15.2%
|
White |
34
72.3%
|
17
89.5%
|
51
77.3%
|
More than one race |
0
0%
|
0
0%
|
0
0%
|
Unknown or Not Reported |
1
2.1%
|
0
0%
|
1
1.5%
|
Region of Enrollment (participants) [Number] | |||
United States |
46
97.9%
|
19
100%
|
65
98.5%
|
Turkey |
1
2.1%
|
0
0%
|
1
1.5%
|
Outcome Measures
Title | Proportion of Participants With Relapsed Multiple Myeloma With Progression-free (PFS) |
---|---|
Description | |
Time Frame | 2 years |
Outcome Measure Data
Analysis Population Description |
---|
This objective only applies to Arm I: Participants with Relapsed Multiple Myeloma |
Arm/Group Title | Relapsed Multiple Myeloma | High-risk Multiple Myeloma |
---|---|---|
Arm/Group Description | This is a two arm phase II trial to assess the progression-free and overall survival as well as the safety and efficacy of allogeneic hematopoietic stem cell transplantation using a preparative regimen with busulfan, melphalan, fludarabine, and anti-thymocyte globulin (ATG), and a T cell depleted stem cell transplant from a histocompatible related or unrelated donor in patients with relapsed or high-risk multiple myeloma | This is a two arm phase II trial to assess the progression-free and overall survival as well as the safety and efficacy of allogeneic hematopoietic stem cell transplantation using a preparative regimen with busulfan, melphalan, fludarabine, and anti-thymocyte globulin (ATG), and a T cell depleted stem cell transplant from a histocompatible related or unrelated donor in patients with relapsed or high-risk multiple myeloma. |
Measure Participants | 47 | 0 |
Number (95% Confidence Interval) [Proportion of participants PFS] |
0.31
0.7%
|
Title | Proportion of Participants With Relapsed Multiple Myeloma Alive at 2 Years |
---|---|
Description | |
Time Frame | 2 years |
Outcome Measure Data
Analysis Population Description |
---|
This objective is only for participants with relapsed multiple myeloma. |
Arm/Group Title | Relapsed Multiple Myeloma | High-risk Multiple Myeloma |
---|---|---|
Arm/Group Description | This is a two arm phase II trial to assess the progression-free and overall survival as well as the safety and efficacy of allogeneic hematopoietic stem cell transplantation using a preparative regimen with busulfan, melphalan, fludarabine, and anti-thymocyte globulin (ATG), and a T cell depleted stem cell transplant from a histocompatible related or unrelated donor in patients with relapsed or high-risk multiple myeloma | This is a two arm phase II trial to assess the progression-free and overall survival as well as the safety and efficacy of allogeneic hematopoietic stem cell transplantation using a preparative regimen with busulfan, melphalan, fludarabine, and anti-thymocyte globulin (ATG), and a T cell depleted stem cell transplant from a histocompatible related or unrelated donor in patients with relapsed or high-risk multiple myeloma |
Measure Participants | 44 | 0 |
Number (95% Confidence Interval) [Proportion of pts alive at 2 years] |
0.54
|
Title | Number of Participants Who Relapse That Are Restored to Remission (CR) |
---|---|
Description | To compute the current multiple myeloma free survival curve in order to account for patients who relapse and are restored to remission through DLI. |
Time Frame | 3 years |
Outcome Measure Data
Analysis Population Description |
---|
This group consists of participants with residual disease either because they did not reach CR from salvage and transplant conditioning or because they were given this dose at the time of progression |
Arm/Group Title | Relapsed Multiple Myeloma |
---|---|
Arm/Group Description | This is a two arm phase II trial to assess the progression-free and overall survival as well as the safety and efficacy of allogeneic hematopoietic stem cell transplantation using a preparative regimen with busulfan, melphalan, fludarabine, and anti-thymocyte globulin (ATG), and a T cell depleted stem cell transplant from a histocompatible related or unrelated donor in patients with relapsed or high-risk multiple myeloma |
Measure Participants | 18 |
Restored to CR, did not develop GVHD |
4
8.5%
|
Were not restored to CR, did not develop GVHD |
14
29.8%
|
Adverse Events
Time Frame | Through study completion, an average of 3 years | |||
---|---|---|---|---|
Adverse Event Reporting Description | ||||
Arm/Group Title | Relapsed Multiple Myeloma | High-risk Multiple Myeloma | ||
Arm/Group Description | This is a two arm phase II trial to assess the progression-free and overall survival as well as the safety and efficacy of allogeneic hematopoietic stem cell transplantation using a preparative regimen with busulfan, melphalan, fludarabine, and anti-thymocyte globulin (ATG), and a T cell depleted stem cell transplant from a histocompatible related or unrelated donor in patients with relapsed or high-risk multiple myeloma | This is a two arm phase II trial to assess the progression-free and overall survival as well as the safety and efficacy of allogeneic hematopoietic stem cell transplantation using a preparative regimen with busulfan, melphalan, fludarabine, and anti-thymocyte globulin (ATG), and a T cell depleted stem cell transplant from a histocompatible related or unrelated donor in patients with relapsed or high-risk multiple myeloma. | ||
All Cause Mortality |
||||
Relapsed Multiple Myeloma | High-risk Multiple Myeloma | |||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 17/47 (36.2%) | 9/19 (47.4%) | ||
Serious Adverse Events |
||||
Relapsed Multiple Myeloma | High-risk Multiple Myeloma | |||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 29/47 (61.7%) | 11/19 (57.9%) | ||
Blood and lymphatic system disorders | ||||
Anemia | 2/47 (4.3%) | 2/19 (10.5%) | ||
Febrile neutropenia | 2/47 (4.3%) | 0/19 (0%) | ||
Cardiac disorders | ||||
Cardiac disorders - Other, specify | 1/47 (2.1%) | 0/19 (0%) | ||
Ventricular tachycardia | 1/47 (2.1%) | 0/19 (0%) | ||
Eye disorders | ||||
Uveitis | 1/47 (2.1%) | 0/19 (0%) | ||
Gastrointestinal disorders | ||||
Abdominal pain | 2/47 (4.3%) | 1/19 (5.3%) | ||
Diarrhea | 3/47 (6.4%) | 4/19 (21.1%) | ||
Nausea | 6/47 (12.8%) | 3/19 (15.8%) | ||
Vomiting | 3/47 (6.4%) | 1/19 (5.3%) | ||
General disorders | ||||
Death NOS | 9/47 (19.1%) | 2/19 (10.5%) | ||
Death not assoc w CTCAE term-Disease prog NOS | 1/47 (2.1%) | 0/19 (0%) | ||
Fatigue | 1/47 (2.1%) | 0/19 (0%) | ||
Fever | 4/47 (8.5%) | 0/19 (0%) | ||
Gen disorders & admin site conditions Other, spec | 1/47 (2.1%) | 0/19 (0%) | ||
Non-cardiac chest pain | 1/47 (2.1%) | 0/19 (0%) | ||
Infections and infestations | ||||
Catheter related infection | 2/47 (4.3%) | 0/19 (0%) | ||
Inf norm ANC/gr1/2 neut-Pneumonia(lung) | 1/47 (2.1%) | 2/19 (10.5%) | ||
Infection, other | 1/47 (2.1%) | 1/19 (5.3%) | ||
Infections and infestations - Other, specify | 17/47 (36.2%) | 4/19 (21.1%) | ||
Lung infection | 7/47 (14.9%) | 0/19 (0%) | ||
Sepsis | 4/47 (8.5%) | 0/19 (0%) | ||
Sinusitis | 1/47 (2.1%) | 1/19 (5.3%) | ||
Upper respiratory infection | 1/47 (2.1%) | 0/19 (0%) | ||
Investigations | ||||
Alanine aminotransferase increased | 0/47 (0%) | 1/19 (5.3%) | ||
Alkaline phosphatase increased | 0/47 (0%) | 1/19 (5.3%) | ||
Aspartate aminotransferase increased | 0/47 (0%) | 1/19 (5.3%) | ||
Blood bilirubin increased | 0/47 (0%) | 1/19 (5.3%) | ||
Creatinine increased | 0/47 (0%) | 1/19 (5.3%) | ||
Platelet count decreased | 0/47 (0%) | 2/19 (10.5%) | ||
Metabolism and nutrition disorders | ||||
Dehydration | 2/47 (4.3%) | 0/19 (0%) | ||
Musculoskeletal and connective tissue disorders | ||||
Back pain | 1/47 (2.1%) | 0/19 (0%) | ||
Generalized muscle weakness | 1/47 (2.1%) | 0/19 (0%) | ||
Neck pain | 1/47 (2.1%) | 0/19 (0%) | ||
Pain in extremity | 1/47 (2.1%) | 0/19 (0%) | ||
Nervous system disorders | ||||
Dizziness | 0/47 (0%) | 1/19 (5.3%) | ||
Lethargy | 1/47 (2.1%) | 0/19 (0%) | ||
Nervous system disorders - Other, specify | 1/47 (2.1%) | 0/19 (0%) | ||
Neurology - Other (specify) | 1/47 (2.1%) | 0/19 (0%) | ||
Vasovagal reaction | 1/47 (2.1%) | 0/19 (0%) | ||
Psychiatric disorders | ||||
Confusion | 1/47 (2.1%) | 0/19 (0%) | ||
Renal and urinary disorders | ||||
Acute kidney injury | 1/47 (2.1%) | 0/19 (0%) | ||
Hematuria | 1/47 (2.1%) | 1/19 (5.3%) | ||
Urinary tract pain | 1/47 (2.1%) | 1/19 (5.3%) | ||
Urinary urgency | 1/47 (2.1%) | 0/19 (0%) | ||
Respiratory, thoracic and mediastinal disorders | ||||
Dyspnea | 3/47 (6.4%) | 1/19 (5.3%) | ||
Hypoxia | 3/47 (6.4%) | 0/19 (0%) | ||
Pneumonitis | 1/47 (2.1%) | 0/19 (0%) | ||
Resp, thoracic & mediastinal disorder Other, spec | 0/47 (0%) | 1/19 (5.3%) | ||
Sore throat | 1/47 (2.1%) | 0/19 (0%) | ||
Skin and subcutaneous tissue disorders | ||||
Rash maculo-papular | 2/47 (4.3%) | 1/19 (5.3%) | ||
Vascular disorders | ||||
Hypotension | 2/47 (4.3%) | 0/19 (0%) | ||
Thromboembolic event | 2/47 (4.3%) | 0/19 (0%) | ||
Other (Not Including Serious) Adverse Events |
||||
Relapsed Multiple Myeloma | High-risk Multiple Myeloma | |||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 47/47 (100%) | 19/19 (100%) | ||
Gastrointestinal disorders | ||||
Mucositis oral | 5/47 (10.6%) | 6/19 (31.6%) | ||
General disorders | ||||
Pain | 3/47 (6.4%) | 0/19 (0%) | ||
Fatigue | 4/47 (8.5%) | 3/19 (15.8%) | ||
Investigations | ||||
Weight loss | 5/47 (10.6%) | 5/19 (26.3%) | ||
Activated partial thromboplastin time prolonged | 7/47 (14.9%) | 3/19 (15.8%) | ||
Alanine aminotransferase increased | 33/47 (70.2%) | 12/19 (63.2%) | ||
Alkaline phosphatase increased | 22/47 (46.8%) | 7/19 (36.8%) | ||
Aspartate aminotransferase increased | 30/47 (63.8%) | 10/19 (52.6%) | ||
Metabolism and nutrition disorders | ||||
Hypomagnesemia | 3/47 (6.4%) | 0/19 (0%) | ||
Hypoglycemia | 5/47 (10.6%) | 3/19 (15.8%) | ||
Hypertriglyceridemia | 5/47 (10.6%) | 0/19 (0%) | ||
Hypermagnesemia | 6/47 (12.8%) | 4/19 (21.1%) | ||
Anorexia | 6/47 (12.8%) | 6/19 (31.6%) | ||
Renal and urinary disorders | ||||
Renal and urinary disorders - Other, specify | 3/47 (6.4%) | 0/19 (0%) | ||
Vascular disorders | ||||
Hypotension | 3/47 (6.4%) | 0/19 (0%) |
Limitations/Caveats
More Information
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Name/Title | Sergio Giralt, MD |
---|---|
Organization | Memorial Sloan Kettering Cancer Center |
Phone | 646-608-3731 |
GiraltS@mskcc.org |
- 10-051