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Chemotherapy and Unrelated Donor Stem Cell Transplantation for Patients With Cancers of the Blood and Immune System

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier:
NCT00520130
First received: August 21, 2007
Last updated: May 11, 2016
Last verified: March 2016

August 21, 2007
May 11, 2016
July 2007
October 2015   (final data collection date for primary outcome measure)
  • To assess the effects of two biologically distinct GVHD prophylaxis regimens [ Time Frame: 1year ] [ Designated as safety issue: No ]
  • To determine and monitor incidence, organ severity and overall severity of chronic GVHD [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
  • Change in the CD4+ T-cell repertoire diversity determined by spectratype complexity index within a Vβ family at 3 months post-transplant
  • Overall safety
  • Graft rejection based on CD3+ chimerism
  • Acute graft-vs-host disease
  • Treatment-related mortality (early and at 1 year)
  • Overall survival at 1 year
Complete list of historical versions of study NCT00520130 on ClinicalTrials.gov Archive Site
  • To assess overall safety of these two regimens in this setting, and overall survival. [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]
  • Study of engraftment kinetics [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]
  • Toxicities [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]
Immune reconstitution parameters
Not Provided
Not Provided
 
Chemotherapy and Unrelated Donor Stem Cell Transplantation for Patients With Cancers of the Blood and Immune System
Phase II Trial of Targeted Immune-Depleting Chemotherapy and Reduced-Intensity Allogeneic Hematopoietic Stem Cell Transplantation Using 8/8 and 7/8 HLA-matched Unrelated Donors and Utilizing Two Graft-versus-Host Disease Prophylaxis Regimens for the Treatment of Leukemias, Lymphomas, and Pre-malignant Blood Disorders

Background:

Major problems with stem cell transplantation (SCT) for cancer treatment are a lack of suitable donors for patients without an HLA tissue-matched sibling and graft-versus-host disease (GVHD), a serious side effects of immune-suppressing chemotherapy that is given to bring the cancer under control before SCT. In GVHD, the patient s immune system attacks the transplanted donor cells.

This study will try to improve the results of SCT from unrelated HLA-matched donors using targeted immune-depleting chemotherapy to bring the cancer under control before transplantation and to lower the chance of graft rejection, followed by reduced-intensity transplant chemotherapy to make the procedure less toxic.

Objectives:

To evaluate the safety and effectiveness of targeted immune-depleting chemotherapy followed by reduced-intensity transplant chemotherapy in patients with advanced cancers of the blood and immune system.

To evaluate the safety and effectiveness of two different drug combinations to prevent GVHD. Both regimens have been successful in preventing GVHD, but they work by different mechanisms and affect the rebuilding of the immune system after the transplant.

Eligibility:

People 18 to 74 years of age with advanced or high-risk cancers of the blood and immune system who do not have a suitable HLA-matched sibling.

Design:

All patients receive chemotherapy before transplant to treat the cancer and suppress immune function.

All patients receive a conditioning regimen of cyclophosphamide for 4 days and fludarabine for 4 days before SCT to prepare for the transplant.

Patients are randomly assigned to one of two combination drug treatments to prevent GHVD as follows:

  • Group 1: Tacrolimus starting 3 days before SCT and continuing for 6 months, plus methotrexate on days 1, 3, 6, and 11 post-SCT, plus sirolimus starting 3 days before the SCT and continuing through day 14 following SCT.
  • Group 2: Alemtuzumab for 4 days starting 8 days before SCT, plus cyclosporine starting 1 day before SCT and continuing for 6 months.

Patients receive the donor s stem cells and immune cells 2 days after the conditioning regimen.

Patients are followed at the clinic regularly for the first 6 months after SCT, and then less often for at least 5 years. Some visits may include bone marrow aspirates and biopsies, blood draws, and other tests to monitor disease status.

A skin biopsy, oral mucosa biopsy, and saliva collection are done to study chronic GVHD.

Background:

  • The major limitations to the broader applicability of allogeneic hematopoietic stem cell transplantation (HSCT) for the treatment of malignancies are lack of suitable donors and therapy-related toxicities which include delayed and incomplete immune reconstitution and graft-versus-host disease (GVHD). Based on the theory that the rapid establishment of donor chimerism was essential for an optimal graft-versus-tumor effect, we have employed a strategy of targeted immunedepleting chemotherapy prior to reduced-intensity allogeneic HSCT. It is our intent to investigate this approach in the setting of HLA-matched unrelated donors in a pilot manner.
  • A clearly superior GVHD prophylaxis regimen has not been established in the unrelated donor transplant setting. The best results that have been reported are with the combination of alemtuzumab plus cyclosporine [AC] and the combination of tacrolimus, methotrexate, and sirolimus [TMS]. These two regimens work by mechanisms which are biologically distinct and potentially have markedly different effects upon immune reconstitution that have not been well studied. In addition neither of these regimens has been assessed for their affects on chronic GVHD using the NIH Consensus Conference Criteria. It is our intent to study the effects that these two regimens have on immune reconstitution and chronic GVHD in the setting sequential targeted immune-depleting chemotherapy and reduced-intensity allogeneic HSCT from HLA-matched unrelated donors.

Objectives:

  • Primary objectives:

    1. to assess the effects of two biologically distinct GVHD prophylaxis regimens, TMS and AC, on immune reconstitution in patients receiving targeted-immune depletion and reduced-intensity allogeneic HSCT from HLA-matched unrelated donors. As part of a comprehensive assessment of immune reconstitution, the primary immunologic endpoint will be the determination of CD4+ T cell receptor V BETA repertoire by CDR3 spectratyping at 3 months post-transplant.
    2. to assess overall safety of these two regimens in this setting, as determined by engraftment, acute GVHD, early and late treatment-related mortality, and overall survival.
    3. to determine and monitor incidence, organ severity and overall severity of chronic GVHD prospectively using the newly developed NIH Consensus Conference diagnosis and staging criteria and preliminarily validate those tools for use in clinical practice and trials (Pavletic, Imanguli, and Cowen).
  • Secondary objectives include further assessment of immune reconstitution, study of engraftment kinetics, and assessment of those patients who receive higher doses of anthracyclines for long and short term toxicities

Eligibility:

  • Adults (18 74 years) with advanced or high risk hematologic malignancies including AML, ALL, MDS, CLL, NHL, HL,CML, multiple myeloma, and MPD who lack a suitable HLA matched sibling.
  • An unrelated donor matched at a minimum of 7 of 8 alleles (HLA-A,-B,-C, and DRB1) by high resolution typing, identified through the National Marrow Donor Program.
  • Life expectancy of at least 3 months, ECOG less than or equal to 2 and relatively normal major organ functions.

Design:

  • Patients will receive disease-specific induction chemotherapy (EPOCH-F/R or FLAG) prior to transplant for disease control and immune depletion. If disease is controlled (greater than PR) and immune depletion objectives have been met, patients may forgo induction chemotherapy and move forward to the transplant conditioning regimen.
  • All patients will receive an identical conditioning regimen consisting of cyclophosphamide 1200 mg/m(2)/day IV for 4 days and fludarabine 30 mg/m(2)/day for 4 days.
  • Patients will be stratified according to degree of HLA-match and randomized at the time of enrollment to one of two GHVD prophylaxis regimens:

    • Arm A (TMS): Tacrolimus, starting day -3 before transplant, given initially at 0.02 mg/kg/day CIV and then an equivalent oral dose for six months, methotrexate 5 mg/m(2) IV on days +1, +3, +6, and +11 post-transplant, and sirolimus given as an initial loading dose of 12 mg p.o. on day -3 pre-transplant and subsequently 4 mg daily through day +63 post transplant.
    • Arm B (AC): Alemtuzumab at 20 mg/day IV over 8 h on days -8 to -4 pre-transplant and cyclosporine, starting day -1 before transplant, given initially at 2mg/kg IV every 12 hours and then an equivalent oral dose for six months and.
  • A maximum of 105 patients will be enrolled and randomly assigned to the two arms in order to yield 44 patients per arm (88 total patients) who are able to be evaluated for development of severe chronic GVHD. This represents an increase of 20 patients over the number permitted prior to this amendment: 25 patients (50 total) randomly assigned to each arm within the 8/8 match group and 13/arm (26 total) within the 7/8 match group (maximum study enrollment = 76 transplanted patients from among up to 85 patients registered).
Interventional
Phase 1
Phase 2
Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
  • Myelodysplastic Syndrome
  • Hodgkin's Lymphoma
  • Non-Hodgkin's Disease
  • Acute Leukemia
  • Multiple Myeloma
  • Biological: Rituximab
    Rituximab: 375 mg/m2 IV, day 1 for patients with CD20-positive disease
  • Drug: Cyclosporine
    Cyclosporine: IV over 2 hours or orally every 12 hours on days -1 to 100, followed by a taper if GVHD does not develop.
  • Drug: Allogenic stem cell transplant (ASCT)
    Allogenic stem cell transplant
  • Drug: Conditioning Chemotherapy
    Fludarabine:30 mg/m2 per day IV infusion over 30 minutes, daily On days -6, -5, -4, and -3 Cyclophosphamide:1200 mg/m2 per day IV infusion over 2 hours on Days 6, -5, -4, -3 Mesna: 1200 mg/m2 per day IV infusion, Daily on days 6, -5,-4, and -3
  • Drug: TMS
    Tacrolimus: 0.02 mg/kg , start day 3. Continue IV or PO. Taper will begin at day +63 if no acute GVHD then at day +119 and discontinue at day +180 as tolerated Methotrexate: 5 mg/m2 IV over 15 minutes on days 1, 3, 6, and 11. Sirolimus: 12 mg PO on days -3 to 63, followed by a taper if GVHD does not develop.
  • Drug: FLAG
    Fludarabine:25 mg/m2 per day IV over 30 minutes, Daily on days 1-5 Cytarabine: 2,000 mg/m2 IV over 4 hours,on Days 1, 2, 3, 4, 5 Filgrastim: 5 mcg/kg per day SC beginning 24 hours PRIOR to initiation of chemotherapy
  • Drug: EPOCH-F
    Fludarabine:25 mg/m2 per day IV infusion over 30 minutes, daily on days 1-4 Etoposide :50 mg/m2 per day continuous IV infusion over 24 hours on days 1-4 Doxorubicin:10 mg/m2/day CIV, days 1-4 Vincristine:0.4 mg/m2 per day continuous IV infusion over 24 hours daily on days 1-4 Cyclophosphamide:750 mg/m2 IV infusion over 30 minutes on day 5
  • Biological: Alemtuzumab
    Alemtuzumab:20 mg/day IV over 8 h on days 8 to 4 pre-transplant.
  • Experimental: A
    TMS Arm
    Interventions:
    • Biological: Rituximab
    • Drug: Allogenic stem cell transplant (ASCT)
    • Drug: Conditioning Chemotherapy
    • Drug: TMS
    • Drug: FLAG
    • Drug: EPOCH-F
  • Experimental: B
    AC Arm
    Interventions:
    • Biological: Rituximab
    • Drug: Cyclosporine
    • Drug: Allogenic stem cell transplant (ASCT)
    • Drug: Conditioning Chemotherapy
    • Drug: FLAG
    • Drug: EPOCH-F
    • Biological: Alemtuzumab

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Active, not recruiting
92
March 2017
October 2015   (final data collection date for primary outcome measure)
  • ELIGIBILITY CRITERIA RECIPIENT ON STANDARD CARE THERAPY:
  • The patient is 18 74 years of age.
  • The patient has a potentially suitable 8/8 donor if they are between the ages of 69-74 years of age or a potentially suitable 8/8 or 7/8 unrelated donor(s) in the National Marrow Registry or Other Available Registry if they are between the ages of 18-74.
  • The patient currently does not meet the protocol s eligibility/enrollment criteria for any reason.
  • There is a high likelihood that the patient, in the opinion of the PI or LAI, will meet the protocol s eligibility/enrollment criteria to proceed to transplant after standard therapy is completed.
  • The patient or legal guardian is able to give informed consent.

EXCLUSION CRITERIA RECIPIENT ON STANDARD CARE THERAPY:

  • HIV infection. There is theoretical concern that the degree of immune suppression associated with the treatment may result in progression of HIV infection.
  • Pregnant or lactating. Patients of childbearing potential must use an effective method of contraception. The effects of the chemotherapy, the subsequent transplant and the medications used after the transplant are highly likely to be harmful to a fetus. The effects upon breast milk are also unknown and may be harmful to the infant.
Both
18 Years to 74 Years   (Adult, Senior)
No
Contact information is only displayed when the study is recruiting subjects
United States
 
NCT00520130
070195, 07-C-0195
Not Provided
Not Provided
Not Provided
National Cancer Institute (NCI)
National Cancer Institute (NCI)
Not Provided
Principal Investigator: Lauren M Curtis, M.D. National Cancer Institute (NCI)
National Institutes of Health Clinical Center (CC)
March 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP