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

Purpose

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 69 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.

...

Condition	Intervention	Phase
Myelodysplastic Syndrome Hodgkin's Lymphoma Non-Hodgkin's Disease Acute Leukemia Multiple Myeloma	Drug: Cyclophosphamide Biological: rituximab Drug: Methotrexate Drug: Sirolimus Drug: Cyclosporine Drug: Doxorubicin hydrochloride Drug: Etoposide Drug: Fludarabine phosphate Drug: Prednisone Drug: Vincristine sulfate Drug: Cytarabine Drug: Tacrolimus Biological: Alemtuzumab	Phase 1 Phase 2

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	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

Resource links provided by NLM:

MedlinePlus related topics: Blood Disorders Cancer Hodgkin Disease Leukemia Lymphoma Multiple Myeloma Myelodysplastic Syndromes Steroids

Drug Information available for: Cyclophosphamide Prednisone Methotrexate Cytarabine Vincristine sulfate Methotrexate sodium Fludarabine Doxorubicin Doxorubicin hydrochloride Etoposide Sirolimus Cyclosporine Fludarabine phosphate Tacrolimus Etoposide phosphate Everolimus Temsirolimus Rituximab Alemtuzumab

U.S. FDA Resources

Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:

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 o... [ Time Frame: 1year ] [ Designated as safety issue: No ]
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. [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]
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 pr... [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:

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. [ Designated as safety issue: Yes ]
Study of engraftment kinetics [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]
Long and short term toxicities [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]

Estimated Enrollment:	105
Study Start Date:	July 2007
Estimated Study Completion Date:	June 2016
Estimated Primary Completion Date:	June 2016 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: EPOCH-F/R Patients receive induction chemotherapy comprising fludarabine phosphate IV over 30 minutes once daily; etoposide IV continuously, doxorubicin hydrochloride IV continuously, and vincristine IV continuously on days 1-4; cyclophosphamide IV over 30 minutes on day 5; and oral prednisone on days 1-5. Patients with CD20+ disease also receive rituximab IV on day 1. All patients receive filgrastim (G-CSF) subcutaneously (SC) beginning on day 6 and continuing until blood counts recover. Treatment repeats every 21 days for up to 3 courses in the absence of disease progression or unacceptable toxicity.	Drug: Cyclophosphamide Given IV Biological: rituximab Given IV for patients with CD20-positive disease Drug: Doxorubicin hydrochloride Given by IV continuously Drug: Etoposide Given by IV continuously Drug: Fludarabine phosphate Given IV Drug: Prednisone Given orally Drug: Vincristine sulfate Given by IV continuously
Experimental: FLAG Patients receive induction chemotherapy comprising fludarabine phosphate IV over 30 minutes and cytarabine IV over 4 hours on days 1-5. Patients also receive G-CSF SC beginning on day 0 and continuing until blood counts recover. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity.	Drug: Fludarabine phosphate Given IV Drug: Cytarabine Given IV
Experimental: Arm I (TMS) Patients receive tacrolimus IV continuously or orally and oral sirolimus on days -3 to 63, followed by a taper if GVHD does not develop. Patients also receive methotrexate IV over 15 minutes on days 1, 3, 6, and 11.	Drug: Methotrexate Given IV Drug: Sirolimus Given orally Drug: Tacrolimus Given by IV continuously or orally
Experimental: Arm II (CA) Patients receive alemtuzumab IV over 8 hours on days -8 to -4. Patients also receive 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: Cyclosporine Given IV Biological: Alemtuzumab Given IV

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Eligibility

Ages Eligible for Study:	18 Years to 74 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

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.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00520130

Contacts

Contact: Ashley E Carpenter	(301) 594-5525	carpentera@mail.nih.gov
Contact: Steven Z Pavletic, M.D.	(301) 402-4899	sp326h@nih.gov

Locations

United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike	Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office (888) NCI-1937

Sponsors and Collaborators

National Cancer Institute (NCI)

Investigators

Principal Investigator:

Steven Z Pavletic, M.D.

National Cancer Institute (NCI)

More Information

Additional Information:

NIH Clinical Center Detailed Web Page This link exits the ClinicalTrials.gov site

Publications:

Champlin RE. T-cell depletion for bone marrow transplantation: effects on graft rejection, graft-versus-host disease, graft-versus-leukemia, and survival. Cancer Treat Res. 1990;50:99-111. Review.

Giralt SA, Kolb HJ. Donor lymphocyte infusions. Curr Opin Oncol. 1996 Mar;8(2):96-102. Review.

Martin PJ, Hansen JA, Torok-Storb B, Durnam D, Przepiorka D, O'Quigley J, Sanders J, Sullivan KM, Witherspoon RP, Deeg HJ, et al. Graft failure in patients receiving T cell-depleted HLA-identical allogeneic marrow transplants. Bone Marrow Transplant. 1988 Sep;3(5):445-56.

Responsible Party:	National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier:	NCT00520130 History of Changes
Other Study ID Numbers:	070195, 07-C-0195
Study First Received:	August 21, 2007
Last Updated:	May 21, 2013
Health Authority:	United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):

Unrelated Donors
Reduced Intensity Stem Cell Transplant
Leukemia
Lymphoma

Allogeneic Stem Cell Transplant
Myelodysplastic Syndrome
Multiple Myeloma

Additional relevant MeSH terms:

Hodgkin Disease
Leukemia
Lymphoma
Multiple Myeloma
Neoplasms, Plasma Cell
Myelodysplastic Syndromes
Preleukemia
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
Cyclophosphamide
Cyclosporins
Cyclosporine
Cytarabine
Methotrexate
Fludarabine monophosphate
Sirolimus
Everolimus

ClinicalTrials.gov processed this record on May 23, 2013