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View Clinical Trial (Medical Research Study)
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Most Closely HLA Matched Allogeneic Virus Specific Cytotoxic T-Lymphocytes (CTL) to Treat Persistent Reactivation Or Infection With Adenovirus, CMV and EBV After Hemopoietic Stem Cell Transplantation (HSCT) - NCT00711035-02115 (Clinical Trial 230229)
Permalink: http://www.ClinicalConnection.com/exp/ExpandedPatientViewStudy230229.aspx
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| City: |
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Boston |
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State:
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MA |
| Zip Code: |
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02115 |
| Conditions: |
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Allogeneic Transplant - Cytomegalovirus - Adenovirus Infection - EBV Infection |
| Purpose: |
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This trial is designed to evaluate the feasibility, safety and efficacy of most closely
HLA-matched multivirus specific CTL lines (CHM-CTLs) in HSCT patients with EBV, CMV or
adenovirus infections that are persistent despite standard therapy.
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| Study summary: |
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Patients may be screened for study entry when they have persistent disease despite standard
therapy for 5 days. At that stage a search will be done of the available lines. Lines were
generated from HSCT donors who consented to the use of CTLs not required for their recipient
for research or from normal donors. All donors were screened and deemed to be eligible as
transplant donors. We will also manufacture additional lines with the goal of covering
common HLA types and will consult with the NMDP to determine what HLA types would be
desirable. Additional donors will be screened by a transplant donor center physician and
must be deemed eligible before a line can be manufactured.
CTL Lines: We will use trivirus specific CTL lines generated as described previously.
Generation of trivirus-specific CTL lines requires the generation of several different
components from PBMC. The CTL line will be derived from donor peripheral blood T cells, by
multiple stimulations with antigen-presenting cells (APCs) presenting CMV, EBV and
adenovirus antigens and expansion with interleukin-2 (IL-2). The APCs used to stimulate and
expand the CMV-specific T cells will be derived from patient mononuclear cells and B
lymphocytes.
To initiate the trivirus-specific CTL line, PBMC will be transduced with an adenovirus
vector (Ad5f35-pp65) expressing the immunodominant antigen of CMV, pp65. The monocyte
fraction of PBMC expressed and presented CMV-pp65 peptide epitopes to the CMV-specific T
cell fraction of the PBMC, while the virion proteins from the adenovirus vector were
processed and presented to the adenovirus-specific T cell fraction.
To expand trivirus -specific T cells we used EBV-transformed B lymphoblastoid cell lines
(EBV-LCLs) transduced with Ad5f35-pp65. This transduction allows the EBV-LCLs to present
CMV-pp65 and adenovirus virion peptides to the T cells as well as endogenously expressed EBV
antigens.
EBV-LCLs are derived from PBMC-B lymphocytes by infection with a clinical grade, laboratory
strain of Epstein-Barr virus (EBV). About 5 x 106 PBMC, or 5 to 10 mLs of blood is required
to generate the EBV-LCL
At the end of the CTL culture period, the frequency of T cells specific for each virus were
determined using tetramer reagents if available. To test the functional antigen specificity
of the CTL we will use overlapping peptide libraries for pp65 and adenovirus hexon and
autologous and allogeneic LCLs in Elispot assays and we will perform cytotoxicity assays
using unmodified PHA blasts and LCLs untransduced or transduced with Ad5f35-null and
Ad5f35-pp65.
The CTL lines will also be checked for identity, phenotype and sterility, and cryopreserved
prior to administration according to SOP. Release criteria for administering the CTL to
patients include viability >70%, negative culture for bacteria and fungi for at least 7
days, endotoxin testing less than or equal to 5EU/ml, negative result for Mycoplasma, <2%
CD19 positive B cells, <2% CD14 positive monocytes (or <2% CD83 positive cells if Dendritic
cells were used as stimulators) and HLA identity.
No Matched CTL Line Available: If no matched line is available the patient will be
registered so that the feasibility of the approach can be assessed and the eventual outcome
will also be collected.
Criteria for Selection of CTL Line: In general the line matching at the highest number of
HLA loci will be selected. Matching at the allele level will be preferred but antigen level
will be accepted. However consideration will also be given to the type of infection and
activity of the line against that virus. For example for a patient with adenovirus infection
a line that matches at 2 loci but that has recognition of adenovirus mediated through those
antigens would be preferable to a line matched at 3 loci but with no demonstrated activity
against adenovirus. The protocol chair will discuss each case with the principal
investigators at each center to determine the optimal CTL line for each patient. If more
than one line matches and there are insufficient cells to cover additional infusions a
second CTL line will be reserved in the event that additional infusions are warranted.
Patients with a partial response are eligible to receive an additional dose.
Premedications: Patients will be premedicated with Benadryl 1mg/kg (max 50 mg) IV and
Tylenol 10 mg/kg (max 650 mg) PO.
Patients will be monitored according to institutional standards for administration of blood
products with the exception that the injection will be given by a physician or a BMT team
physician's assistant or nurse practitioner.
Supportive Care: Patients will receive supportive care for acute or chronic toxicity,
including blood components or antibiotics, and other intervention as appropriate.
If a patient has a partial response they are eligible to receive up to 4 additional doses at
biweekly intervals. These doses would come from the original infused line if sufficient
vials were available but may come from another line if there are insufficient cells in the
original line.
Follow-up Assessments: The timing of follow-up visits is based on the date of CTL infusion.
If a patient has multiple CTL doses the schedule resets again at the beginning so follow up
relates to the last CTL dose.
Follow up will occur at 7 days, 14 days, 21 days, 28 days, 42 days, 90 days, 180 days, and
365 days post enrollment.
The following assessments are considered standard-of-care unless identified below by " * ":
Pre-Infusion: 1. History and physical exam including height and weight 2. Viral loads for
EBV, adenovirus, CMV 3. Biopsy disease site, if appropriate 4. Imaging studies, if
appropriate 5. Complete acute GVHD staging and grading information including assessments of
rash, diarrhea, nausea/vomiting, weight and liver function tests 6. CBC with differential,
platelet count 7. Liver function tests (bilirubin, alkaline phosphatase, AST, ALT) plus
creatinine 8. Tacrolimus/cyclosporine level 9. * Samples for laboratory studies
Post-Infusion: 1. Viral loads for CMV, EBV, adenovirus weekly until Day 42, and 3, 6 and 12
months. 2. Complete acute GVHD staging and grading information including assessments of
rash, diarrhea, nausea/vomiting, weight and liver function tests weekly until Day 42, and 3,
6 and 12 months 3. Chronic GVHD evaluation (if present) 3, 6 and 9 months 4. CBC with
differential and platelet count weekly until Day 42 5. Toxicity evaluation weekly until Day
42 6. Steroid dose weekly until Day 42, and 3, 6 and 9 months 7. * Samples for laboratory
studies on Days 0, 14, 28 and 90 8. Infections through Day 42 and at 3, 6 and 12 months
Ancillary laboratory studies will include: 1) Assessment of virus-specific immunity based on
CTL levels as measured by ELISPOT assays or tetramer assays. 2) Persistence of infused T
cells based on PCR for non-shared antigen |
| Criteria: |
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Inclusion Criteria:
1. Prior allogeneic hematopoietic stem cell transplant using either bone marrow,
peripheral blood stem cells or cord blood. Recipients of non-myeloablative
transplants are also eligible.
2. CMV, adenovirus or EBV infection persistent despite standard therapy
1. CMV infection defined as: i.Patients with CMV disease: defined as the
demonstration of CMV by biopsy specimen from visceral sites (by culture or
histology) or the detection of CMV by culture or direct fluorescent antibody
stain in bronchoalveolar lavage fluid in the presence of new or changing
pulmonary infiltrates OR ii. Failure of antiviral therapy: defined as the
continued presence of pp65 antigenemia (>1+ cell/100,000 cells) or DNAemia (as
defined by reference lab performing PCR assay but usually >400 copies/ml) after
at least 7 days of antiviral therapy OR iii. Relapse after antiviral therapy
defined as recurrence of either pp65 antigenemia or DNAemia after at least 2
weeks of antiviral therapy
2. EBV infection is defined as: i. Biopsy proven lymphoma with EBV genomes detected
in tumor cells by immunocytochemistry or in situ PCR ii. Or clinical or imaging
findings consistent with EBV lymphoma and elevated EBV viral load in peripheral
blood.
3. Adenovirus infection is defined as the presence of adenoviral positivity as
detected by PCR, DAA or culture from ONE site such as stool or blood or urine or
nasopharynx. Adenovirus disease will be defined as the presence of adenoviral
positivity as detected by culture from more than two sites such as stool or
blood or urine or nasopharynx
4. Standard therapy is defined as: i.For CMV infection, 7 days therapy with
Ganciclovir, Foscarnet or Cidofovir for patients with disease (see 2.a.i) or
recurrence after 14 days therapy (see 2.a.iii) ii. For EBV infection, rituximab
given at 375mg/m2 in patients with a CD20+ve tumor iii. For adenovirus
infection, 7 days therapy with Cidofovir (if renal function permits this agent
to be given)
5. The virus infection would be defined as progressive if: i. There was a rise or a
fall of less than 50% in viral load in peripheral blood or any site of disease
as measured by PCR for adenovirus, CMV or EBV (or in antigenemia levels for CMV
or any other quantitative assay) ii. There was an increase or less than 50%
response at sites of disease for EBV lymphoma
3. Clinical status at enrollment to allow tapering of steroids to less than 0.5
mg/kg/day prednisone.
4. Absolute neutrophil count (ANC) greater than 500/µL.
5. Written informed consent from patient, parent or guardian.
6. Education materials have been provided to, and reviewed with, patients under the age
of 18.
Donors will be eligible if they meet eligibility criteria for blood donors on history and
exam by a transplant donor physician and have negative infectious diseases testing for
HIV-1 antibody, HIV-2 antibody, HIV NAT, HTLV-1/2 antibodies, HBs antigen, HBc antibody,
HCV NAT, RPR, West Nile virus NAT, and Chagas testing
Exclusion Criteria:
1. Patients receiving ATG, or Campath or other immunosuppressive monoclonal antibodies
within 28 days of screening for enrollment.
2. Patients with other uncontrolled infections. For bacterial infections, patients must
be receiving definitive therapy and have no signs of progressing infection for 72
hours prior to enrollment. For fungal infections patients must be receiving
definitive systemic anti-fungal therapy and have no signs of progressing infection
for 1 week prior to enrollment.
Progressing infection is defined as hemodynamic instability attributable to sepsis or
new symptoms, worsening physical signs or radiographic findings attributable to
infection. Persisting fever without other signs or symptoms will not be interpreted
as progressing infection.
3. Patients who have received DLI within 28 days.
4. Patients with active acute GVHD grades II-IV.
Donors will be ineligible if they do not meet eligibility criteria for blood donors on the
donor questionaire or have positive infectious diseases testing on any of the tests
outlined in the inclusion criteria |
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| Study is available at: |
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Dana Farber Cancer Institute
Boston, MA 02115
United States
Primary Contact:
Bimalangshu Dey, MD
Email: BDEY@partners.org
Phone: 617-724-1124
Secondary Contact:
Helen Heslop, MD
Email: hheslop@bcm.tmc.edu
Phone: 832-824-4662 |
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If you are interested in this clinical trial please use the contact information above. If you would like to get additional information about this clinical trial please visit ClinicalTrials.gov.
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| Data Source: |
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ClinicalTrials.gov |
| Date Processed: |
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November 4, 2009 |
Modifications to
this listing: |
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Only selected fields are shown, please use the link
above to view all information about this clinical trial. |
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Clinical trials are medical research studies designed to test the safety and/or
effectiveness of new drugs, devices, or treatments in humans. These studies are
conducted worldwide for a range of conditions and illnesses. Learn more about
clinical research and participating in a study at
About Clinical Trials.
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