Sirolimus in Preventing Graft-Versus-Host Disease in Patients With Hematologic Malignancies Who Are Undergoing Allogeneic Hematopoietic Stem Cell Transplantation - Full Text View

Sponsor:	National Cancer Institute (NCI)
Information provided by:	National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:	NCT00077480

Purpose

RATIONALE: Sirolimus may be effective in preventing graft-versus-host disease in patients who are undergoing allogeneic stem cell transplantation.

PURPOSE: This phase II trial is studying four different regimens of sirolimus-treated T cells and/or sirolimus by mouth and comparing how well they work in preventing graft-versus-host disease in patients who are undergoing allogeneic hematopoietic stem cell transplantation for hematologic malignancies .

Condition	Intervention	Phase
Chronic Myeloproliferative Disorders Graft Versus Host Disease Leukemia Lymphoma Multiple Myeloma and Plasma Cell Neoplasm Myelodysplastic Syndromes Myelodysplastic/Myeloproliferative Diseases	Biological: therapeutic allogeneic lymphocytes Drug: sirolimus	Phase II

Study Type:	Interventional
Study Design:	Supportive Care, Active Control
Official Title:	Pilot Study Of Sirolimus (Rapamycin) Generated Donor Th2 Cells And In Vivo Sirolimus For GVHD Prevention After Allogeneic HSCT For Hematologic Malignancy

Resource links provided by NLM:

Genetics Home Reference related topics: aceruloplasminemia hemophilia

MedlinePlus related topics: Cancer Leukemia, Adult Acute Leukemia, Adult Chronic Lymphoma Multiple Myeloma

Drug Information available for: Sirolimus

U.S. FDA Resources

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

Primary Outcome Measures:

Safety and feasibility [ Designated as safety issue: Yes ]
Graft-versus-host disease rate [ Designated as safety issue: Yes ]

Secondary Outcome Measures:

Pattern of post-transplantation CD4+ and CD8+ T-cell production of Th1- and Th2-type cytokines [ Designated as safety issue: No ]
Kinetics of alloengraftment [ Designated as safety issue: No ]
Incidence of opportunistic infection [ Designated as safety issue: Yes ]
Incidence of malignant disease in complete remission [ Designated as safety issue: No ]
Reactivity of T cells collected after transplantation [ Designated as safety issue: No ]
Pattern of post-transplantation CD14+ monocyte production of inflammatory cytokines, interleukin-1-alpha, and tumor necrosis factor alpha [ Designated as safety issue: No ]

Estimated Enrollment:	230
Study Start Date:	December 2003
Estimated Primary Completion Date:	December 2009 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Group 1 (allogeneic transplantation): Experimental Patients receive donor 12-day cultured Th2 cells IV on day 1.	Biological: therapeutic allogeneic lymphocytes Given IV
Group 2 (allogeneic transplantation): Experimental Patients receive donor 12-day cultured Th2 cells IV on day 14. Patients also receive an initial loading dose of oral sirolimus once on day -2 and then oral sirolimus once daily on days -1 to 14.	Biological: therapeutic allogeneic lymphocytes Given IV Drug: sirolimus Given orally
Group 3 (allogeneic transplantation): Experimental Patients receive oral sirolimus as in group 2.	Drug: sirolimus Given orally
Group 4 (allogeneic transplantation): Experimental Patients receive donor 12-day or 6-day cultured Th2 cells and sirolimus as in group 2.	Biological: therapeutic allogeneic lymphocytes Given IV Drug: sirolimus Given orally
Group 5 (allogeneic transplantation): Experimental Patients receive donor 12-day cultured Th2 cells IV on day 0. Patients also receive sirolimus as in group 2.	Biological: therapeutic allogeneic lymphocytes Given IV Drug: sirolimus Given orally

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Detailed Description:

OBJECTIVES:

Primary

Determine the safety and feasibility of donor 12-day and 6-day cultured Th2 cells generated in vitro by sirolimus treatment with or without oral sirolimus vs oral sirolimus alone for graft-versus-host disease (GVHD) prevention after allogeneic hematopoietic stem cell transplantation in patients with hematologic malignancies. (Groups 1 and 3 closed to accrual as of 6/27/05 and 12/15/05, respectively; group 2 also closed to accrual; group 5 closed to accrual as of 9/22/08.)
Evaluate 6-day cultured Th2 cells in these patients (group 4B).
Determine the alloengraftment in patients treated with this regimen (group 4B).
Determine the GVHD rate in patients treated with these regimens. (Groups 1 and 3 closed to accrual as of 6/27/05 and 12/15/05, respectively; group 2 also closed to accrual; group 5 closed to accrual as of 9/22/08.)
Determine, in a preliminary manner, whether low acute GVHD rate observed in group 4A can be maintained in group 4B.

Secondary

Determine the pattern of post-transplantation CD4+ and CD8+ T-cell production of Th1- and Th2-type cytokines in patients treated with these regimens. (Groups 1 and 3 closed to accrual as of 6/27/05 and 12/15/05, respectively; group 2 also closed to accrual; group 5 closed to accrual as of 9/22/08.)
Determine the kinetics of alloengraftment, incidence of opportunistic infection, and incidence of malignant disease in complete remission in patients treated with these regimens. (Groups 1 and 3 closed to accrual as of 6/27/05 and 12/15/05, respectively; group 2 also closed to accrual; group 5 closed to accrual as of 9/22/08.)
Determine, preliminarily, whether T cells collected after transplantation have increased reactivity to patient tumor cells relative to donor T cells collected before transplantation.
Determine the pattern of post-transplantation CD14+ monocyte production of inflammatory cytokines interleukin-1-alpha and tumor necrosis factor alpha in patients treated with these regimens. (Groups 1 and 3 closed to accrual as of 6/27/05 and 12/15/05, respectively; group 2 also closed to accrual; group 5 closed to accrual as of 9/22/08.)
Evaluate, in a preliminary manner, whether patients treated on group 4B might have higher levels of donor T cell chimerism post-transplant compared to patients treated on group 4A.

OUTLINE: This is a pilot study. Patients are stratified according to age (18 to 45 vs 46 to 75).

Induction chemotherapy: Patients with CD20+ B-cell malignancies receive rituximab IV on day 1. All patients receive fludarabine IV over 30 minutes and etoposide, doxorubicin, and vincristine IV continuously on days 1-4; cyclophosphamide IV over 30 minutes on day 5; oral prednisone on days 1-5; and filgrastim (G-CSF) subcutaneously (SC) beginning on day 6 and continuing until blood counts recover. Treatment repeats every 21 days for 1-3 courses depending on the quantity of host immune T cells remaining after each course. Patients, including those who develop progressive disease during induction chemotherapy, proceed to transplantation chemotherapy*.

NOTE: *Patients assigned to group 5 (see below [closed to accrual as of 9/22/08]) do not receive transplantation chemotherapy; these patients proceed directly to allogeneic transplantation after induction chemotherapy.

Transplantation chemotherapy: Patients receive fludarabine IV over 30 minutes and cyclophosphamide IV over 2 hours on days -6 to -3.
Allogeneic transplantation: Patients undergo allogeneic peripheral blood stem cell transplantation or bone marrow transplantation on day 0. Patients receive G-CSF SC beginning on day 0 and continuing until blood counts recover. Patients also receive cyclosporine orally or IV over 2 hours twice daily beginning on day -1 and continuing until approximately day 100 followed by a taper until day 180. Patients are sequentially assigned to 1 of 5 groups (groups 1, 2, and 3 are closed to accrual).
- Group 1 (closed to accrual as of 6/27/05): Patients receive donor 12- day cultured Th2 cells IV on day 1.
- Group 2 (closed to accrual): Patients receive donor 12- day cultured Th2 cells IV on day 14. Patients also receive an initial loading dose of oral sirolimus once on day -2 and then oral sirolimus once daily on days -1 to 14.
- Group 3 (closed to accrual as of 12/15/05): Patients receive oral sirolimus as in group 2.
- Group 4A: Patients receive donor 12-day cultured Th2 cells and sirolimus as in group 2.
- Group 4B: Patients receive donor 6-day cultured Th2 cells IV on day 12. Patients also receive sirolimus as in group 2.
- Group 5 (closed to accrual as of 9/22/08): Patients receive donor 12-day cultured Th2 cells IV on day 0. Patients also receive sirolimus as in group 2.
Donor lymphocyte infusion (DLI): Patients with persistent or progressive malignant disease after transplantation may receive DLI. DLI may be administered alone or in combination with chemotherapy.

Treatment continues in the absence of disease progression or unacceptable toxicity.

Patients are followed weekly for 6 weeks post-transplantation, at 3 months, every 3 months for 1 year, every 6 months for 1 year, and then annually thereafter.

PROJECTED ACCRUAL: Approximately 230 patients will be accrued for this study.

Eligibility

Ages Eligible for Study:	18 Years to 75 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

DISEASE CHARACTERISTICS:

Histological diagnosis of 1 of the following hematologic malignancies, myelodysplasia, or myeloproliferative disorders:
- Chronic lymphocytic leukemia
  - Relapsed after fludarabine
  - Non-complete remission (CR) after salvage regimen
- Hodgkin's or non-Hodgkin's lymphoma (all types, including mantle cell lymphoma)
  - Primary treatment failure
  - Relapsed after autologous stem cell transplantation (SCT)
  - Non-CR after salvage regimen
- High-risk lymphoma including, but not limited to, plasma dendritic cell type, hepato-splenic T cell type, gamma delta pinniculitic T cell type, muco-cutaneous NK cell type, or stage III-IV nasal NK cell type
  - Primary treatment failure
  - Relapsed after autologous SCT
  - Non-CR after salvage regimen
  - In first CR or any later CR
- Multiple myeloma
  - Primary treatment failure
  - Relapsed after autologous SCT or for consolidation therapy after autologous SCT AND not yet relapsed
  - Non-CR after salvage regimen
- Acute myeloid leukemia
  - In first CR (CR1) and at high risk [excludes t(8;21), t(15;17), or inv(16)]
  - In second CR (CR2) or greater
- Acute lymphoblastic leukemia
  - In CR1 and at high risk [t(9;22) or bcr-abl+; t(4;11), 1(1;19), t(8;14)]
  - In CR2 or greater
- Myelodysplastic syndromes
  - Refractory anemia with excess blasts (RAEB)
  - RAEB in transformation (requires bone marrow and blood blasts of less than 10% after induction chemotherapy)
- Myeloproliferative disorders*
  - Idiopathic myelofibrosis
  - Polycythemia vera
  - Essential thrombocythemia
  - Chronic myelomonocytic leukemia NOTE: *Patients must be end-stage, primarily defined as disease severity refractory to splenectomy
- Chronic myelogenous leukemia
  - Chronic phase refractory to imatinib mesylate
  - Accelerated phase
Acute leukemia must be in hematologic remission (less than 5% of blood or marrow blasts)
Must have a first-degree relative donor matched at 6/6 HLA antigens (A, B, and DR)
No active CNS involvement by malignancy

PATIENT CHARACTERISTICS:

Age

18 to 75

Performance status

ECOG 0-1

Life expectancy

At least 3 months

Hematopoietic

Not specified

Hepatic

ALT and AST no greater than 2.5 times upper limit of normal*
Bilirubin less than 2.5 mg/dL* NOTE: *Values above these levels may be accepted, at the discretion of the principal investigator or study chairman, if the elevations are due to liver involvement

Renal

Creatinine no greater than 1.5 mg/dL
Creatinine clearance at least 50 mL/min

Cardiovascular

LVEF ≥ 45% by 2-dimensional ECHO or MUGA
- Patients with LVEF between 35% and 44% are eligible provided they are cleared by a cardiology consultation that must include a cardiac stress test

Pulmonary

DLCO greater than 50% of expected

Other

Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception during and for at least 1 year after study participation
HIV negative
No active infection that is not responding to antimicrobial therapy
No psychiatric illness that would preclude study compliance or informed consent

PRIOR CONCURRENT THERAPY:

Biologic therapy

See Disease Characteristics

Chemotherapy

See Disease Characteristics

Endocrine therapy

No concurrent steroids as antiemetics during chemotherapy
No concurrent steroids during transplantation

Surgery

See Disease Characteristics

Other

At least 2 weeks since prior therapy and recovered

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00077480

Locations

United States, Maryland
NCI - Center for Cancer Research	Recruiting
Bethesda, Maryland, United States, 20892
Contact: Clinical Trials Office - NCI - Center for Cancer Research 888-624-1937
Warren Grant Magnuson Clinical Center - NCI Clinical Trials Referral Office	Recruiting
Bethesda, Maryland, United States, 20892-1182
Contact: Clinical Trials Office - Warren Grant Magnusen Clinical Center 888-NCI-1937
United States, New Jersey
Hackensack University Medical Center Cancer Center	Recruiting
Hackensack, New Jersey, United States, 07601
Contact: Clinical Trials Office - Hackensack University Medical Center 201-996-2879

Sponsors and Collaborators

National Cancer Institute (NCI)

Investigators

Study Chair:

Daniel Fowler, MD

National Cancer Institute (NCI)

More Information

Additional Information:

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

Featured trial article This link exits the ClinicalTrials.gov site

No publications provided

Responsible Party:	NCI - Center for Cancer Research ( Daniel Fowler )
Study ID Numbers:	CDR0000350350, NCI-04-C-0055
Study First Received:	February 10, 2004
Last Updated:	October 10, 2009
ClinicalTrials.gov Identifier:	NCT00077480 History of Changes
Health Authority:	Unspecified

Keywords provided by National Cancer Institute (NCI):

graft versus host disease
refractory chronic lymphocytic leukemia
accelerated phase chronic myelogenous leukemia
chronic phase chronic myelogenous leukemia
refractory anemia with excess blasts in transformation
refractory anemia with excess blasts
relapsing chronic myelogenous leukemia
recurrent adult Hodgkin lymphoma
refractory multiple myeloma
chronic idiopathic myelofibrosis
recurrent adult Burkitt lymphoma
recurrent adult diffuse large cell lymphoma
recurrent adult diffuse mixed cell lymphoma
recurrent adult diffuse small cleaved cell lymphoma
recurrent adult immunoblastic large cell lymphoma

recurrent mantle cell lymphoma
recurrent grade 1 follicular lymphoma
recurrent grade 2 follicular lymphoma
recurrent grade 3 follicular lymphoma
recurrent adult lymphoblastic lymphoma
secondary myelodysplastic syndromes
adult acute lymphoblastic leukemia in remission
adult acute myeloid leukemia in remission
de novo myelodysplastic syndromes
previously treated myelodysplastic syndromes
chronic myelomonocytic leukemia
polycythemia vera
essential thrombocythemia
myelodysplastic/myeloproliferative disease, unclassifiable
recurrent marginal zone lymphoma

Additional relevant MeSH terms:

Sirolimus
Anti-Infective Agents
Immunologic Factors
Precancerous Conditions
Hematologic Neoplasms
Antineoplastic Agents
Blood Protein Disorders
Physiological Effects of Drugs
Paraproteinemias
Antibiotics, Antineoplastic
Hemostatic Disorders
Anti-Bacterial Agents
Leukemia
Preleukemia
Neoplasms by Site

Pathologic Processes
Hemorrhagic Disorders
Antifungal Agents
Therapeutic Uses
Syndrome
Cardiovascular Diseases
Lymphoma
Disease
Neoplasms by Histologic Type
Immunoproliferative Disorders
Immune System Diseases
Hematologic Diseases
Myelodysplastic Syndromes
Myeloproliferative Disorders
Vascular Diseases

ClinicalTrials.gov processed this record on November 25, 2009