Laboratory-Treated Peripheral Blood Cell Infusion After Donor Stem Cell Transplant in Treating Patients With Hematologic Cancers or Other Diseases - Full Text View

Sponsors and Collaborators:	Dana-Farber Cancer Institute National Cancer Institute (NCI)
Information provided by:	National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:	NCT00376480

Purpose

RATIONALE: Giving total-body irradiation and chemotherapy, such as thiotepa and fludarabine, before a donor stem cell transplant helps stop the growth of cancer or abnormal cells. It also helps stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving methylprednisolone and antithymocyte globulin before transplant and peripheral blood cells that have been treated in the laboratory after transplant may stop this from happening.

PURPOSE: This phase I trial is studying the side effects and best dose of laboratory-treated peripheral blood cell infusion after donor stem cell transplant in treating patients with hematologic cancers or other diseases.

Condition	Intervention	Phase
Leukemia Myelodysplastic Syndromes	Drug: anti-thymocyte globulin Drug: fludarabine phosphate Drug: methylprednisolone Drug: thiotepa Procedure: allogeneic hematopoietic stem cell transplantation Procedure: in vitro-treated peripheral blood stem cell transplantation Procedure: peripheral blood lymphocyte therapy Procedure: total-body irradiation	Phase I

MedlinePlus related topics: Anemia Cancer Leukemia, Adult Acute Leukemia, Adult Chronic Leukemia, Childhood

Drug Information available for: Methylprednisolone Thiotepa Fludarabine Fludarabine monophosphate

U.S. FDA Resources

Study Type:	Interventional
Study Design:	Treatment
Official Title:	Delayed Infusion of Ex Vivo Anergized Peripheral Blood Mononuclear Cells Following CD34 Selected Peripheral Blood Stem Cell Transplantation From a Haploidentical Donor for Patients With Acute Leukemia and Myelodysplasia

Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:

Feasibility [ Designated as safety issue: No ]
Safety [ Designated as safety issue: Yes ]
Alloreactivity [ Designated as safety issue: No ]
Rate of acute graft-versus-host disease [ Designated as safety issue: No ]

Secondary Outcome Measures:

Hyporesponsiveness by donor T cells [ Designated as safety issue: No ]
Immune cell function [ Designated as safety issue: No ]
Pathogen-specific immunity [ Designated as safety issue: No ]
Rate of recovery [ Designated as safety issue: No ]
Opportunistic infection patterns [ Designated as safety issue: No ]

Estimated Enrollment:	40
Study Start Date:	March 2005
Estimated Primary Completion Date:	December 2008 (Final data collection date for primary outcome measure)

Detailed Description:

OBJECTIVES:

Primary

Establish the feasibility of delayed infusion of ex vivo anergized donor peripheral blood mononuclear cells (PBMC) after CD34-selected megadose haploidentical hematopoietic stem cell transplantation (HSCT) in patients with hematopoietic cancers or other diseases.
Determine the feasibility of collecting parental allogeneic stimulator cells to induce anergy to the nonshared donor-recipient haplotype in these patients.
Determine the feasibility of collecting donor PBMC as a source of T cells for ex vivo anergization.
Determine the number of transplanted individuals who meet the criteria for proceeding to delayed infusion of ex vivo anergized donor PBMC.
Establish the safety of delayed infusion of ex vivo anergized donor PBMC by establishing the maximum number of donor T cells that can be infused without unacceptable graft-versus-host disease.

Secondary

Evaluate, in vitro, the induction and specificity of alloantigen hyporesponsiveness in donor PBMC after ex vivo anergization.
Assess, in vitro, the function of immune cells engrafted in these patients.
Assess, in vitro, whether alloantigen hyporesponsive donor T cells are present in these patients.
Develop, preliminarily, in vitro data on the extent of pathogen-specific immunity and its rate of recovery.
Describe the patterns of opportunistic infections in these patients.

OUTLINE: This is a multicenter, dose-escalation study of ex vivo anergized allogeneic peripheral blood mononuclear cells (PBMC). Patients who are treated on any dose level except dose level 1 are stratified according to age (under 17 [pediatric] vs 17 and over [adult]).

Myeloablative conditioning regimen: Patients undergo total-body irradiation twice daily on days -11 to -9. Patients also receive thiotepa IV over 4 hours on days -8 and -7, fludarabine phosphate IV over 30 minutes on days -7 to -3, and anti-thymocyte globulin IV over 8 hours and methylprednisolone IV over 15-30 minutes on days -6 to -3.
Allogeneic peripheral blood stem cell transplantation (PBSCT): Patients undergo CD34-selected PBSCT on day 0.
Ex vivo anergized allogeneic PBMC infusion: If cells have engrafted and patients are free of active uncontrolled infection and graft-vs-host disease, patients undergo allogeneic or autologous PBMC infusion on day 35 or 42.

Cohorts of 3-8 patients receive escalating doses of ex vivo anergized allogeneic PBMCs until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose at which 2 of 5 or 3 of 8 patients experience dose-limiting toxicity.

After completion of study, patients are followed periodically for 2 years.

PROJECTED ACCRUAL: A total of 40 patients will be accrued for this study.

Eligibility

Ages Eligible for Study:	up to 50 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

DISEASE CHARACTERISTICS:

Diagnosis of 1 of the following:
- Acute lymphocytic leukemia
  - In ≥ second complete remission (CR), defined as < 5% blasts in bone marrow (BM) and no active extramedullary disease OR in first CR with any of the following high risk features:
    - History of induction failure
    - Philadelphia chromosome positive
    - t(4;11) by cytogenetic analysis
    - Any infant with MLL rearrangements on cytogenetic analysis
  - No relapse with isolated extramedullary disease after completion of prior treatment
- Acute myeloid leukemia
  - Failed induction therapy after < 3 courses
  - In ≥ second CR, defined as < 5% blasts in BM and no active extramedullary disease OR in first CR with any of the following high-risk features:
    - History of induction failure = 5q- or monosomy 7 cytogenetic findings
- Any of the following myelodysplastic syndromes:
  - Refractory anemia (RA) with excess blasts (RAEB) with a high International Prognostic Scoring System (IPSS) score or score of intermediate-1(INT-1) or intermediate-2 (INT-2)
  - RAEB in transformation with INT-1, INT-2, or high IPSS score
  - RA with INT-2 score
Patients must have a healthy, related donor who is at least genotypically HLA-A, B, C, and DR haploidentical to the patient
- No suitably matched family donor defined by genotypic or phenotypic identity for ≥ 5/6 A, B, or DR loci
- No immediately available genotypically matched (6/6) unrelated marrow donor
- No immediately available umbilical cord blood donor with suitable cell dose after a search ≥ 2 months
- Patients whose medical condition is at high risk of deteriorating or whose disease is at high risk of progression during a donor search are eligible
Has a parent with a haplotype that is disparate from that of the donor for the haplotype shared by the patient and parent, but not shared by the patient and donor OR patient is able to donate sufficient autologous cells by peripheral blood draw or unstimulated leukapheresis
No active CNS disease

PATIENT CHARACTERISTICS:

Room air O_2 saturation > 95% unless the lungs are involved with disease
No clinical evidence of pulmonary insufficiency unless the lungs are involved with disease
AST and ALT < 3 times upper limit of normal (ULN)*
Bilirubin < 2.0 mg/dL*
Creatinine < 2 times ULN OR creatinine clearance or glomerular filtration rate > 50% of the lower limit of normal
LVEF > 45% OR shortening fraction > 20%
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception
No active infection, defined as absence of an infectious diagnosis or (in patients who have had a recent positive infectious diagnosis) the resolution of fever, documentation of negative cultures or antigen testing, continuation or completion of a course of appropriate therapy, and presence of stable to resolving clinical symptoms
No evidence of HIV infection OR known HIV positivity NOTE: *Does not apply if liver is involved with disease

PRIOR CONCURRENT THERAPY:

See Disease Characteristics
No prior stem cell transplantation
No other concurrent immunosuppressive therapy

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00376480

Locations

United States, California
Childrens Hospital Los Angeles	Recruiting
Los Angeles, California, United States, 90027-0700
Contact: Neena Kapoor, MD 323-669-2434 nkapoor@chla.usc.edu
United States, Massachusetts
Children's Hospital Boston	Recruiting
Boston, Massachusetts, United States, 02115
Contact: Eva Guinan, MD 617-632-4932
Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute	Recruiting
Boston, Massachusetts, United States, 02115
Contact: Eva Guinan, MD 617-632-4932 eva_guinan@dfci.harvard.edu
Massachusetts General Hospital	Recruiting
Boston, Massachusetts, United States, 02114
Contact: Clinical Trials Office - Massachusetts General Hospital 877-726-5130
United States, Texas
M. D. Anderson Cancer Center at University of Texas	Recruiting
Houston, Texas, United States, 77030-4009
Contact: Clinical Trials Office - M. D. Anderson Cancer Center at the U 713-792-3245

Sponsors and Collaborators

Dana-Farber Cancer Institute

National Cancer Institute (NCI)

Investigators

Study Chair:

Eva Guinan, MD

Dana-Farber Cancer Institute

More Information

Clinical trial summary from the National Cancer Institute's PDQ® database This link exits the ClinicalTrials.gov site

Study ID Numbers:	CDR0000491633, DFCI-05030, MDA-2005-0695
Study First Received:	September 13, 2006
Last Updated:	December 2, 2008
ClinicalTrials.gov Identifier:	NCT00376480
Health Authority:	Unspecified

Keywords provided by National Cancer Institute (NCI):

refractory anemia with excess blasts in transformation
adult acute lymphoblastic leukemia in remission
refractory anemia with excess blasts
refractory anemia
adult acute myeloid leukemia in remission
childhood acute lymphoblastic leukemia in remission
childhood acute myeloid leukemia in remission
de novo myelodysplastic syndromes
previously treated myelodysplastic syndromes

secondary acute myeloid leukemia
adult acute myeloid leukemia with 11q23 (MLL) abnormalities
adult acute myeloid leukemia with inv(16)(p13;q22)
adult acute myeloid leukemia with t(15;17)(q22;q12)
adult acute myeloid leukemia with t(16;16)(p13;q22)
adult acute myeloid leukemia with t(8;21)(q22;q22)
secondary myelodysplastic syndromes
childhood myelodysplastic syndromes

Study placed in the following topic categories:

Leukemia, Lymphoid
Hematologic Neoplasms
Precancerous Conditions
Methylprednisolone
Refractory anemia
Prednisolone acetate
Leukemia, Myeloid, Acute
Acute lymphoblastic leukemia, adult
Leukemia
Preleukemia
Anemia, Refractory
Neoplasm Metastasis
Acute myeloid leukemia, adult
Congenital Abnormalities
Acute myelocytic leukemia

Methylprednisolone Hemisuccinate
Myelodysplastic syndromes
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Hematologic Diseases
Myelodysplastic Syndromes
Myelodysplasia
Anemia
Acute myelogenous leukemia
Methylprednisolone acetate
Leukemia, Myeloid
Fludarabine monophosphate
Thiotepa
Antilymphocyte Serum
Prednisolone
Anemia, Refractory, with Excess of Blasts

Additional relevant MeSH terms:

Anti-Inflammatory Agents
Antimetabolites
Antimetabolites, Antineoplastic
Molecular Mechanisms of Pharmacological Action
Immunologic Factors
Antineoplastic Agents
Physiological Effects of Drugs
Hormones, Hormone Substitutes, and Hormone Antagonists
Antiemetics
Neuroprotective Agents
Hormones
Pathologic Processes
Therapeutic Uses

Syndrome
Disease
Neoplasms by Histologic Type
Antineoplastic Agents, Hormonal
Gastrointestinal Agents
Immunosuppressive Agents
Protective Agents
Glucocorticoids
Pharmacologic Actions
Neoplasms
Autonomic Agents
Peripheral Nervous System Agents
Central Nervous System Agents

ClinicalTrials.gov processed this record on January 15, 2009