HLA-Compatible Related or Unrelated Donors With CD34+ Enriched, T-cell Depleted Peripheral Blood Stem Cells Isolated by the CliniMACS System in the Treatment of Patients With Hematologic Malignancies

This study is currently recruiting participants.
Verified March 2014 by Memorial Sloan-Kettering Cancer Center
Sponsor:
Information provided by (Responsible Party):
Memorial Sloan-Kettering Cancer Center
ClinicalTrials.gov Identifier:
NCT01119066
First received: May 4, 2010
Last updated: March 13, 2014
Last verified: March 2014
  Purpose

The purpose of this study is to find out the effects of using a system called CliniMACS to remove Tcells from blood stem cells. Removing T-cells may help stop a side effect called Graft-Versus-Host Disease (GVHD). Some studies have been done with CliniMACS, but the Food and Drug Administration (FDA) has not yet approved it.


Condition Intervention Phase
Acute Lymphoblastic Leukemia
Acute Myelogenous Leukemia
Myelodysplastic Syndrome
Multiple Myeloma
Device: CliniMACS Fractionation system
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase II Trial of Transplants From HLA-Compatible Related or Unrelated Donors With CD34+ Enriched, T-cell Depleted Peripheral Blood Stem Cells Isolated by the CliniMACS System in the Treatment of Patients With Hematologic Malignancies and Other Lethal Hematologic Disorders

Resource links provided by NLM:


Further study details as provided by Memorial Sloan-Kettering Cancer Center:

Primary Outcome Measures:
  • To assess the incidence of durable hematopoietic engraftment for T-cell depleted transplants fractionated by the CliniMACS system administered after each of the four disease targeted cytoreduction regimens. [ Time Frame: 3 years ] [ Designated as safety issue: No ]
  • To assess the incidence and severity of acute and chronic GVHD following T-cell depleted, CD34+ progenitor cell enriched transplants fractionated by the CliniMACS system. [ Time Frame: 3 years ] [ Designated as safety issue: Yes ]
  • To assess the incidence of non-relapse mortality (transplant-related mortality) following each cytoreduction regimen and a transplant fractionated by the CliniMACS system. [ Time Frame: 3 years ] [ Designated as safety issue: No ]
  • To estimate the probability of survival and disease-free survival (DFS) [ Time Frame: at 6 months post transplant ] [ Designated as safety issue: No ]
  • To estimate the probability of survival and disease-free survival (DFS) [ Time Frame: 1 year post transplant ] [ Designated as safety issue: No ]
  • To estimate the probability of survival and disease-free survival (DFS) [ Time Frame: 2 years post transplant ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • To determine the proportion of patients receiving optimal CD34+ (> 5x106/kg) and CD3+ (<1x105/kg) cell doses the proportion recurring suboptimal doses (< 2x106/kg) CD34+ cells; and the proportion of patients receiving CD3+ T-cell doses > 1x105/kg. [ Time Frame: 3 years ] [ Designated as safety issue: No ]
  • To correlate doses of CD34+ progenitors and CD3+ T cells with engraftment, graft vs. host disease and non-relapse mortality. [ Time Frame: 3 years ] [ Designated as safety issue: No ]

Estimated Enrollment: 370
Study Start Date: May 2010
Estimated Study Completion Date: May 2017
Estimated Primary Completion Date: May 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Total Body Irradiation, Thiotepa and Cyclophosphamide
Hyperfractionated total body irradiation to a dose of 1375-1500 cGy (depending on age, stage of disease and requirement of general anesthesia) ) with lung shielding, thiotepa (5 mg/kg day x 2 or 10 mg/kg/day x 1), cyclophosphamide (60 mg/m2/day x 2) (or fludarabine 25mg/m2 x 5 if cyclophosphamide is contraindicated).
Device: CliniMACS Fractionation system
The patient will receive total body irradiation (TBI) for 11 or 12 doses over 4 days. The number of doses is based on their age and the disease being treated. Next, the patient will get 2 doses of a chemotherapy drug called thiotepa for 2 days. After thiotepa, the patient will receive a chemotherapy drug called cyclophosphamide for 2 days.
Other Names:
  • All patients (with the exception of patients ≤ 18 who receive transplants from HLA-matched
  • related siblings) will also receive antithymocyte globulin (ATG) (thymoglobulin 2.5 mg/kg/day
  • x 2 or equine ATG 15 mg/kg/day x 2 or 30mg/kg/day x 1 if thymoglobulin is not tolerated) during pre-transplant
  • conditioning to deplete radiation or chemotherapy resistant host T-cells that
  • could hamper engraftment. If patient is receiving a second transplant from the same donor,
  • ATG administration will be at the discretion of the physician.
  • Following preparative cytoreduction, all patients will receive a GCSF mobilized
  • PBSC transplant depleted of T-cells by positive selection of CD34+ progenitor
  • cells with the CliniMACS system. The targeted dose progenitor cells will be
  • > 5 x 106 CD34+ cells/kg with the dose of T-cells limited to < 1.0 x 105CD3+
  • cells/kg.
Experimental: Busulfan, Melphalan and Fludarabine
Busulfan (0.8 mg/kg/ every 6 hours x 10 or 12 doses, (depending on disease) with dose modified according to pharmacokinetics Melphalan (70mg/m2/day x 2) Melphalan will be administered on Days - 7 and -6 for multiple myeloma patients. and Fludarabine (25mg/m2/ day x 5).
Device: CliniMACS Fractionation system
The patient will get 3 chemotherapy drugs to prepare for transplant: Busulfan every 6 hours for about 3 days, Melphalan once a day for 2 days, and Fludarabine once a day for 5 days. The number of Busulfan doses is 10 for patients with multiple myeloma and 12 for other diseases. The chemotherapy treatments for each day of the regimen.
Other Names:
  • All patients will also receive antithymocyte globulin (ATG) (thymoglobulin 2.5 mg/m2/day x 2 or equine
  • ATG 15 mg/kg/day x 2 if thymoglobulin is not tolerated) during pre-transplant
  • conditioning to deplete radiation or chemotherapy resistant host T-cells that
  • could hamper engraftment. If patient is receiving a second transplant from the same donor, ATG administration will be at the discretion of the physician.
  • Following preparative cytoreduction, all patients will receive a GCSF mobilized
  • PBSC transplant depleted of T-cells by positive selection of CD34+ progenitor
  • cells with the CliniMACS system. The targeted dose progenitor cells will be
  • > 5 x 106 CD34+ cells/kg with the dose of T-cells limited to < 1.0 x 105CD3+
  • cells/kg.
Experimental: Clofarabine, Melphalan and Thiotepa
Clofarabine (20mg/m2/ day x 5) Patients < 18 years of age deemed suitable may receive Clofarabine at 30mg/m2/day with PI approval. Melphalan (70 mg/m2/day x 2)( or, for children < 18 yrs of age, 30mg/m2/day x 5 if deemed suitable and with PI approval) and Thiotepa (5 mg/kg/day x 2 or 10mg/kg/day x1).
Device: CliniMACS Fractionation system
The patient will receive 3 chemotherapy drugs. They will get Clofarabine once a day for 5 days, Melphalan once a day for 2 days, and Thiotepa on the sixth day of treatment.
Other Names:
  • All patients will also receive antithymocyte globulin (ATG) (thymoglobulin 2.5 mg/m2/day
  • x 2 or equine ATG 15 mg/kg/day x 2 if thymoglobulin is not tolerated) during pre-transplant
  • conditioning to deplete radiation or chemotherapy resistant host T-cells that
  • could hamper engraftment. If patient is receiving a second transplant from the same donor,
  • ATG administration will be at the discretion of the physician.
  • Following preparative cytoreduction, all patients will receive a GCSF mobilized
  • PBSC transplant depleted of T-cells by positive selection of CD34+ progenitor
  • cells with the CliniMACS system. The targeted dose progenitor cells will be
  • > 5 x 106 CD34+ cells/kg with the dose of T-cells limited to < 1.0 x 105CD3+
  • cells/kg.
Experimental: Fludarabine, Melphalan and Thiotepa
The combination of Fludarabine 25 mg/m2/day x 5, Melphalan 70 mg/m2/day x 2 and Thiotepa 5 mg/kg/day x 2 (or 10mg/kg/day x 1).
Device: CliniMACS Fractionation system
Fludarabine will be administered via a 30 minute infusion at a dose of 25 mg/m2/day for 5 days (day -6 through day -2). Fludarabine may be adjusted in the case of renal toxicity. Melphalan will be administered via a 30 minute infusion at a dose of 70mg/m2/day for 2 doses (days -8, and -7). Thiotepa will be administered via a 4 hour intravenous infusion at a dose of 5mg/kg/day IV over approximately 4 hr daily x 2 days (Day-6 and Day -5).
Other Names:
  • All patients will also receive antithymocyte globulin (ATG) (thymoglobulin 2.5 mg/m2/day
  • x 2 or equine ATG 15 mg/kg/day x 2 if thymoglobulin is not tolerated) during pre-transplant
  • conditioning to deplete radiation or chemotherapy resistant host T-cells that
  • could hamper engraftment. If patient is receiving a second transplant from the same donor,
  • ATG administration will be at the discretion of the physician.
  • Following preparative cytoreduction, all patients will receive a GCSF mobilized
  • PBSC transplant depleted of T-cells by positive selection of CD34+ progenitor
  • cells with the CliniMACS system. The targeted dose progenitor cells will be
  • > 5 x 106 CD34+ cells/kg with the dose of T-cells limited to < 1.0 x 105CD3+
  • cells/kg.

  Eligibility

Ages Eligible for Study:   up to 69 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Malignant conditions or other life threatening disorders correctable by transplant 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 > than or = to 2nd remission
  • ALL/CLL in 1st remission clinical or molecular features indicating a high risk for relapse; or ALL/CLL > than or = to 2nd remission
  • CML failing to respond to or not tolerating Imatinib or dasatinib in first chronic phase of disease; CML in accelerated phase second chronic phase or in CR after accelerated phase or blast crisis.
  • Non-Hodgkins lymphoma with chemoresponsive disease in any of the following categories:

    1. 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.
    2. 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 as well as RAEB-1 and RAEB-2 and Acute myelogenous leukemia (AML) evolved from MDS, who are not eligible for transplantation and/or unable to enroll onto protocol IRB 08-008.
  • Chronic myelomonocytic leukemia: CMML-1 and CMML-2.
  • Multiple Myeloma with disease in the following categories:

    1. Patients with relapsed multiple myeloma following autologous stem cell transplantation who have achieved at least partial response following additional chemotherapy.
    2. Patients with high risk cytogenetics at diagnosis must have achieved a partial response following autologous stem cell transplantation. Patients must have complex karyotype, del17p, t4;14 and/or t14;16 by FISH and/or del13 by karyotyping.
  • 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 congenital cytopenias; non-SCID lethal genetic immunodeficiencies such as Wiskott Aldrich Syndrome, CD40 ligand deficiency, or ALPS, as well as refractory autoimmune cytopenias, PNH, metabolic storage diseases or heavily transfused congenital hemoglobinopathies).
  • Accrual to each treatment arm will include up to 30 standard risk and 30 poor risk patients (60 patients/treatment arm) except for Regimen D, which will include 30 patients/treatment arm, all of which will be poor risk by virtue of risks of relapse and/or transplant related mortality.
  • Standard risk patients will include eligible patients, as defined above, who are receiving transplants as treatment for MDS in RA/RCMD, AML in 1st or 2nd remission, ALL in 1st CR, NHL in 1st remission, MM in 1st remission, Very Good Partial Response, or 1st Partial Response or CML in the first chronic phase or 1st remission.
  • All other patients, including those with treatment related malignancies and/or those who have AML derived from MDS, will have received extensive prior chemo/radiotherapy and, therefore, will be considered to be at poor risk of conditioning and transplant related morbidities, and potentially transplant related mortality. Patients with life threatening non-malignant genetic and acquired disorders will also, by virtue of their history of, optional transfusions and/or infection be considered poor risk. Stopping rules for non-relapse related mortality in these heavily treated patients are, therefore, slightly less stringent than patients in the poor risk transplant groups. Stopping rules for the principal endpoints of graft failure and GvHD are the same for all groups.

The following inclusion criteria are also required:

  • Patient's age includes from birth on to < 70 years old.
  • Patients may be of either gender or any ethnic background.
  • Patients must have a Karnofsky (adult) or Lansky (pediatric) Performance Status > or = to 70%
  • Patients must have adequate organ function measured by:

Cardiac: asymptomatic or if symptomatic then LVEF at rest must be > or = to 50% and must improve with exercise.

Hepatic: < 3x ULN ALT and < than or = to 1.5 total serum bilirubin, unless there is congenital benign hyperbilirubinemia. Patients with higher bilirubin levels due to causes other than active liver disease are also eligible with PI approval e.g. patients with PNH, Gilbert's disease or other hemolytic disorders.

Renal: serum creatinine < than or = to 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 > or = to 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
  • Active 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 guidelines
  • Donor should agree to undergo general anesthesia and bone marrow harvest collection if PBSC yield is inadequate or otherwise not transplantable for whatever reason.

Donor Exclusion Criteria

  • If donors do not meet institutional guidelines, exclusion will be considered.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01119066

Contacts
Contact: Richard O'Reilly, MD 212-639-5957
Contact: Guenther Koehne, M.D., Ph.D. 212-639-8599

Locations
United States, New York
Memorial Sloan Kettering Cancer Center Recruiting
New York, New York, United States, 10065
Contact: Richard O'Reilly, MD    212-639-5957      
Contact: Guenther Koehne, MD, PhD    212-639-8599      
Principal Investigator: Richard O'Reilly, MD         
Sponsors and Collaborators
Memorial Sloan-Kettering Cancer Center
Investigators
Principal Investigator: Richard O'Reilly, MD Memorial Sloan-Kettering Cancer Center
  More Information

Additional Information:
No publications provided

Responsible Party: Memorial Sloan-Kettering Cancer Center
ClinicalTrials.gov Identifier: NCT01119066     History of Changes
Other Study ID Numbers: 10-050
Study First Received: May 4, 2010
Last Updated: March 13, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Memorial Sloan-Kettering Cancer Center:
Leukemia
Multiple Myeloma
radiation
Thiotepa
cyclophosphamide
fludarabine
Clofarabine
CliniMACS device
GCSF
10-050

Additional relevant MeSH terms:
Leukemia
Leukemia, Lymphoid
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Myeloid, Acute
Leukemia, Myeloid
Multiple Myeloma
Neoplasms, Plasma Cell
Myelodysplastic Syndromes
Preleukemia
Hematologic Neoplasms
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Bone Marrow Diseases
Precancerous Conditions
Neoplasms by Site
Antilymphocyte Serum
Busulfan
Cyclophosphamide
Melphalan

ClinicalTrials.gov processed this record on April 23, 2014