Biparental HLA Haplotype Disparate T-cell Depleted Transplants for Patients Lacking an HLACompatible Donor
Study Details
Study Description
Brief Summary
Approximately 30% of patients who are candidates for bone marrow transplants do not have an HLA-matched, or close to matched, donor available. For this reason, doctors have been testing ways to make transplants from HLA-partially matched donors as safe and effective as transplants from HLA-matched donors.
This study is being done to test the safety and the treatment results of a specific kind of transplant. In this transplant, blood from two donors will be used. Each donor will share one half of your HLA type. Blood from both donors will be transplanted at the same time.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
N/A |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: REGIMEN 1 REGIMEN 1: Patients undergo hyperfractionated TBI TID for a total of 11-12 doses on days -10 to -7 and receive thiotepa IV over 4 hours QD on days -6 and -5, fludarabine phosphate IV over 30 minutes QD on days -6 to -2, and anti-thymocyte globulin IV on days -4 to -2. TRANSPLANTATION: Patients undergo CD34-selected allogeneic PBSCT on day 0. |
Radiation: total-body irradiation (TBI)
Drug: thiotepa
Drug: fludarabine phosphate
Biological: anti-thymocyte globulin
Procedure: allogeneic hematopoietic stem cell transplantation
Biological: peripheral blood stem cell transplantation
Other: laboratory biomarker analysis
|
| Experimental: Regimen 2 To be given to patients non-malignant, life-threatening diseases and patients with hematologic malignancies, with extensive prior therapy and comorbidities who are unable to receive TBI, consists of Melphalan 70mg/m2 IV x 2 days, thiotepa 5mg/kg IV x 2 days (or 10mg/kg x 1 day), and fludarabine 25 mg/m2 IV x 5 days. TRANSPLANTATION: Patients undergo CD34-selected allogeneic PBSCT on day 0. |
Drug: thiotepa
Drug: fludarabine phosphate
Drug: melphalan
Biological: anti-thymocyte globulin
Procedure: allogeneic hematopoietic stem cell transplantation
Biological: peripheral blood stem cell transplantation
Other: laboratory biomarker analysis
|
Outcome Measures
Primary Outcome Measures
- Efficacy of HLA-haploidentical Biparental T-cell Depleted CD34+ Peripheral Blood Stem Cell Transplants [1 year]
Efficacy is measured by: incidence of transplant-related mortality, overall survival and disease-free survival at 1 year post transplant. incidence, tempo and complications of engraftment and hematopoietic reconstitutions and conversely, the risk of graft failure incidence and severity of acute and/or chronic GVHD incidence and severity of opportunistic infections developing following engraftment
Secondary Outcome Measures
- Evaluation of Recipients Post Transplant [1 year]
The levels of engraftment and persistence of hematopoietic cells and their myeloid and lymphoid progressing from each donor post transplant. The tolerance or reactivity of engrafted T cells from each donor detected in the blood at 3, 6, and thereafter every 3-6 months until normal, post transplant against host cells and cells derived from the other parent as measured by standard mixed lymphocyte culture and cell mediated cytolysis assays.
Eligibility Criteria
Criteria
Inclusion Criteria:
- Malignant conditions for which CD34+ selected, T-cell depleted allogeneic hematopoietic stem cell transplantation is indicated such as:
AML in 1st remission - for patients whose AML does not have 'good risk' cytogenetic features (i.e. t 8;21, t15;17, inv 16).
-
Secondary AML in 1st remission
-
AML in 1st relapse or > 2nd remission
-
ALL/LL in 1st remission clinical or molecular features indicating a high risk for relapse; or ALL > 2nd remission
-
CML failing to respond to or not tolerating Imatinib, dasatinib, or nilotinib in first chronic phase of disease; or CML in accelerated phase or second chronic phase.
-
Non-Hodgkins lymphoma with chemoresponsive disease in any of the following categories:
- intermediate or high grade lymphomas who have failed to achieve a first CR or have relapsed following a 1st remission who are not candidates for autologous transplants.
-
any NHL in remission which is considered not curable with chemotherapy alone and not eligible/appropriate for autologous transplant. Myelodysplastic syndrome (MDS): RA/RCMD with high risk cytogenetic features or transfusion dependence, RAEB-1 and RAEB-2 and Acute myelogenous leukemia (AML) evolved from MDS, who are not eligible for transplantation under protocol IRB 08-008.
-
Chronic myelomonocytic leukemia: CMML-1 and CMML-2.
-
Other rare lethal disorders of Hematopoiesis and Lymphopoiesis for which a T-cell depleted transplant is indicated (e.g. hemophagocytic lymphohistiocytosis; refractory aplastic anemia or conjugated cytopenias; non-SCID lethal genetic immunodeficiencies such as Wiskott Aldrich Syndrome, CD40 ligand deficiency, ALPS).
-
Patients may be of either gender and of any racial or ethnic background.
-
Patients must have a Karnofsky (adult) or Lansky (pediatric) 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 < 2.0x ULN 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)
-
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:
-
Female patients who are pregnant or breast-feeding
-
Uncontrolled viral, bacterial or fungal infection
-
Patient seropositive for HIV-I/II; HTLV -I/II
-
Presence of leukemia in the CNS.
Donor Inclusion Criteria:
-
Each donor must meet criteria outlined by institutional policies
-
Donor must have adequate peripheral venous catheter access for leukapheresis or must agree to placement of a central catheter.
Donor Exclusion Criteria:
-
Evidence of active infection (including urinary tract infection, or upper respiratory tract infection), viral hepatitis exposure (on screening), unless only HBS Ab+ and HBV DNA negative, or serologic evidence of exposure or infection with HIV-I/II or HTLV-I/II
-
If donors do not meet institutional guidelines, exclusion will be considered.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Memorial Sloan Kettering Cancer Center | New York | New York | United States | 10065-0009 |
Sponsors and Collaborators
- Memorial Sloan Kettering Cancer Center
Investigators
- Principal Investigator: Richard O'Reilly, MD, Memorial Sloan Kettering Cancer Center
Study Documents (Full-Text)
More Information
Additional Information:
Publications
None provided.- 12-053
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | REGIMEN 1 | Regimen 2 |
|---|---|---|
| Arm/Group Description | REGIMEN 1: Patients undergo hyperfractionated TBI TID for a total of 11-12 doses on days -10 to -7 and receive thiotepa IV over 4 hours QD on days -6 and -5, fludarabine phosphate IV over 30 minutes QD on days -6 to -2, and anti-thymocyte globulin IV on days -4 to -2. TRANSPLANTATION: Patients undergo CD34-selected allogeneic PBSCT on day 0. total-body irradiation (TBI) thiotepa fludarabine phosphate anti-thymocyte globulin allogeneic hematopoietic stem cell transplantation peripheral blood stem cell transplantation laboratory biomarker analysis | To be given to patients non-malignant, life-threatening diseases and patients with hematologic malignancies, with extensive prior therapy and comorbidities who are unable to receive TBI, consists of Melphalan 70mg/m2 IV x 2 days, thiotepa 5mg/kg IV x 2 days (or 10mg/kg x 1 day), and fludarabine 25 mg/m2 IV x 5 days. TRANSPLANTATION: Patients undergo CD34-selected allogeneic PBSCT on day 0. thiotepa fludarabine phosphate melphalan anti-thymocyte globulin allogeneic hematopoietic stem cell transplantation peripheral blood stem cell transplantation laboratory biomarker analysis |
| Period Title: Overall Study | ||
| STARTED | 0 | 3 |
| COMPLETED | 0 | 0 |
| NOT COMPLETED | 0 | 3 |
Baseline Characteristics
| Arm/Group Title | REGIMEN 1 | Regimen 2 | Total |
|---|---|---|---|
| Arm/Group Description | REGIMEN 1: Patients undergo hyperfractionated TBI TID for a total of 11-12 doses on days -10 to -7 and receive thiotepa IV over 4 hours QD on days -6 and -5, fludarabine phosphate IV over 30 minutes QD on days -6 to -2, and anti-thymocyte globulin IV on days -4 to -2. TRANSPLANTATION: Patients undergo CD34-selected allogeneic PBSCT on day 0. total-body irradiation (TBI) thiotepa fludarabine phosphate anti-thymocyte globulin allogeneic hematopoietic stem cell transplantation peripheral blood stem cell transplantation laboratory biomarker analysis | To be given to patients non-malignant, life-threatening diseases and patients with hematologic malignancies, with extensive prior therapy and comorbidities who are unable to receive TBI, consists of Melphalan 70mg/m2 IV x 2 days, thiotepa 5mg/kg IV x 2 days (or 10mg/kg x 1 day), and fludarabine 25 mg/m2 IV x 5 days. TRANSPLANTATION: Patients undergo CD34-selected allogeneic PBSCT on day 0. thiotepa fludarabine phosphate melphalan anti-thymocyte globulin allogeneic hematopoietic stem cell transplantation peripheral blood stem cell transplantation laboratory biomarker analysis | Total of all reporting groups |
| Overall Participants | 0 | 3 | 3 |
| Age (years) [Median (Full Range) ] | |||
| Median (Full Range) [years] |
12
|
12
|
|
| Sex: Female, Male (Count of Participants) | |||
| Female |
0
NaN
|
1
33.3%
|
1
33.3%
|
| Male |
0
NaN
|
2
66.7%
|
2
66.7%
|
| Ethnicity (NIH/OMB) (Count of Participants) | |||
| Hispanic or Latino |
0
NaN
|
0
0%
|
0
0%
|
| Not Hispanic or Latino |
0
NaN
|
3
100%
|
3
100%
|
| Unknown or Not Reported |
0
NaN
|
0
0%
|
0
0%
|
| Race (NIH/OMB) (Count of Participants) | |||
| American Indian or Alaska Native |
0
NaN
|
0
0%
|
0
0%
|
| Asian |
0
NaN
|
2
66.7%
|
2
66.7%
|
| Native Hawaiian or Other Pacific Islander |
0
NaN
|
0
0%
|
0
0%
|
| Black or African American |
0
NaN
|
0
0%
|
0
0%
|
| White |
0
NaN
|
1
33.3%
|
1
33.3%
|
| More than one race |
0
NaN
|
0
0%
|
0
0%
|
| Unknown or Not Reported |
0
NaN
|
0
0%
|
0
0%
|
| Region of Enrollment (Count of Participants) | |||
| United States |
0
NaN
|
3
100%
|
3
100%
|
Outcome Measures
| Title | Efficacy of HLA-haploidentical Biparental T-cell Depleted CD34+ Peripheral Blood Stem Cell Transplants |
|---|---|
| Description | Efficacy is measured by: incidence of transplant-related mortality, overall survival and disease-free survival at 1 year post transplant. incidence, tempo and complications of engraftment and hematopoietic reconstitutions and conversely, the risk of graft failure incidence and severity of acute and/or chronic GVHD incidence and severity of opportunistic infections developing following engraftment |
| Time Frame | 1 year |
Outcome Measure Data
| Analysis Population Description |
|---|
| Due to the small accrual on study, as well as patient course following treatment on study, the primary objectives of this study were not able to be analyzed. |
| Arm/Group Title | REGIMEN 1 | Regimen 2 |
|---|---|---|
| Arm/Group Description | REGIMEN 1: Patients undergo hyperfractionated TBI TID for a total of 11-12 doses on days -10 to -7 and receive thiotepa IV over 4 hours QD on days -6 and -5, fludarabine phosphate IV over 30 minutes QD on days -6 to -2, and anti-thymocyte globulin IV on days -4 to -2. TRANSPLANTATION: Patients undergo CD34-selected allogeneic PBSCT on day 0. total-body irradiation (TBI) thiotepa fludarabine phosphate anti-thymocyte globulin allogeneic hematopoietic stem cell transplantation peripheral blood stem cell transplantation laboratory biomarker analysis | To be given to patients non-malignant, life-threatening diseases and patients with hematologic malignancies, with extensive prior therapy and comorbidities who are unable to receive TBI, consists of Melphalan 70mg/m2 IV x 2 days, thiotepa 5mg/kg IV x 2 days (or 10mg/kg x 1 day), and fludarabine 25 mg/m2 IV x 5 days. TRANSPLANTATION: Patients undergo CD34-selected allogeneic PBSCT on day 0. thiotepa fludarabine phosphate melphalan anti-thymocyte globulin allogeneic hematopoietic stem cell transplantation peripheral blood stem cell transplantation laboratory biomarker analysis |
| Measure Participants | 0 | 0 |
| Title | Evaluation of Recipients Post Transplant |
|---|---|
| Description | The levels of engraftment and persistence of hematopoietic cells and their myeloid and lymphoid progressing from each donor post transplant. The tolerance or reactivity of engrafted T cells from each donor detected in the blood at 3, 6, and thereafter every 3-6 months until normal, post transplant against host cells and cells derived from the other parent as measured by standard mixed lymphocyte culture and cell mediated cytolysis assays. |
| Time Frame | 1 year |
Outcome Measure Data
| Analysis Population Description |
|---|
| Due to the small accrual on study, as well as patient course following treatment on study, the primary objectives of this study were not able to be analyzed. |
| Arm/Group Title | REGIMEN 1 | Regimen 2 |
|---|---|---|
| Arm/Group Description | REGIMEN 1: Patients undergo hyperfractionated TBI TID for a total of 11-12 doses on days -10 to -7 and receive thiotepa IV over 4 hours QD on days -6 and -5, fludarabine phosphate IV over 30 minutes QD on days -6 to -2, and anti-thymocyte globulin IV on days -4 to -2. TRANSPLANTATION: Patients undergo CD34-selected allogeneic PBSCT on day 0. total-body irradiation (TBI) thiotepa fludarabine phosphate anti-thymocyte globulin allogeneic hematopoietic stem cell transplantation peripheral blood stem cell transplantation laboratory biomarker analysis | To be given to patients non-malignant, life-threatening diseases and patients with hematologic malignancies, with extensive prior therapy and comorbidities who are unable to receive TBI, consists of Melphalan 70mg/m2 IV x 2 days, thiotepa 5mg/kg IV x 2 days (or 10mg/kg x 1 day), and fludarabine 25 mg/m2 IV x 5 days. TRANSPLANTATION: Patients undergo CD34-selected allogeneic PBSCT on day 0. thiotepa fludarabine phosphate melphalan anti-thymocyte globulin allogeneic hematopoietic stem cell transplantation peripheral blood stem cell transplantation laboratory biomarker analysis |
| Measure Participants | 0 | 0 |
Adverse Events
| Time Frame | Up to 24 months after transplant | |
|---|---|---|
| Adverse Event Reporting Description | ||
| Arm/Group Title | Regimen 2 | |
| Arm/Group Description | To be given to patients non-malignant, life-threatening diseases and patients with hematologic malignancies, with extensive prior therapy and comorbidities who are unable to receive TBI, consists of Melphalan 70mg/m2 IV x 2 days, thiotepa 5mg/kg IV x 2 days (or 10mg/kg x 1 day), and fludarabine 25 mg/m2 IV x 5 days. TRANSPLANTATION: Patients undergo CD34-selected allogeneic PBSCT on day 0. | |
All Cause Mortality |
||
| Regimen 2 | ||
| Affected / at Risk (%) | # Events | |
| Total | 3/3 (100%) | |
Serious Adverse Events |
||
| Regimen 2 | ||
| Affected / at Risk (%) | # Events | |
| Total | 2/3 (66.7%) | |
| Cardiac disorders | ||
| Sinus tachycardia | 1/3 (33.3%) | |
| Gastrointestinal disorders | ||
| Pancreatitis | 1/3 (33.3%) | |
| General disorders | ||
| Multi-organ failure | 1/3 (33.3%) | |
| Infections and infestations | ||
| Myelitis | 1/3 (33.3%) | |
| Metabolism and nutrition disorders | ||
| Acidosis | 1/3 (33.3%) | |
| Nervous system disorders | ||
| Nervous system disorders - Other, specify | 1/3 (33.3%) | |
| Renal and urinary disorders | ||
| Renal and urinary disorders - Other, specify | 1/3 (33.3%) | |
| Reproductive system and breast disorders | ||
| Hypoxia | 2/3 (66.7%) | |
| Respiratory, thoracic and mediastinal disorders | ||
| Bronchopulmonary hemorrhage | 2/3 (66.7%) | |
| Vascular disorders | ||
| Hypotension | 1/3 (33.3%) | |
Other (Not Including Serious) Adverse Events |
||
| Regimen 2 | ||
| Affected / at Risk (%) | # Events | |
| Total | 3/3 (100%) | |
| Blood and lymphatic system disorders | ||
| Anemia | 2/3 (66.7%) | |
| Investigations | ||
| Lymphocyte count decreased | 3/3 (100%) | |
| Platelet count decreased | 3/3 (100%) | |
| White blood cell decreased | 3/3 (100%) | |
| Neutrophil count decreased | 2/3 (66.7%) | |
| Activated partial thromboplastin time prolonged | 1/3 (33.3%) | |
| Lipase increased | 1/3 (33.3%) | |
| Serum amylase increased | 1/3 (33.3%) | |
| Metabolism and nutrition disorders | ||
| Hypokalemia | 2/3 (66.7%) | |
| Hyperglycemia | 1/3 (33.3%) | |
| Hyperkalemia | 1/3 (33.3%) | |
| Hypocalcemia | 1/3 (33.3%) | |
| Hypophosphatemia | 1/3 (33.3%) | |
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 | Dr. Richard O'Reilly, MD |
|---|---|
| Organization | Memorial Sloan Kettering Cancer Center |
| Phone | 646-888-2157 |
| oreillyr@mskcc.org |
- 12-053