Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Trial Contact Information
Related Information
Registry Information

Alternate Title

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

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase II	Supportive care, Treatment	Active	18 to 75	NCI	NCI-04-C-0055 NCT00077480

Special Category: NIH Clinical Center trial, NCI Web site featured trial

Objectives

Primary

1. 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.)
2. Evaluate 6-day cultured Th2 cells in these patients (group 4B).
3. Determine the alloengraftment in patients treated with this regimen (group 4B).
4. 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.)
5. Determine, in a preliminary manner, whether low acute GVHD rate observed in group 4A can be maintained in group 4B.

Secondary

1. 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.)
2. 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.)
3. Determine, preliminarily, whether T cells collected after transplantation have increased reactivity to patient tumor cells relative to donor T cells collected before transplantation.
4. 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.)
5. 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.

Entry 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

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

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

Expected Enrollment

Approximately 230 patients will be accrued for this study.

Outcomes

Safety and feasibility
Graft-versus-host disease rate

Pattern of post-transplantation CD4+ and CD8+ T-cell production of Th1- and Th2-type cytokines
Kinetics of alloengraftment
Incidence of opportunistic infection
Incidence of malignant disease in complete remission
Reactivity of T cells collected after transplantation
Pattern of post-transplantation CD14+ monocyte production of inflammatory cytokines, interleukin-1-alpha, and tumor necrosis factor alpha

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.

Trial Contact Information

Trial Lead Organizations

NCI - Center for Cancer Research

Daniel Fowler, MD, Protocol chair		Ph: 301-435-8641 Email: dhfowler@helix.nih.gov

U.S.A.
Maryland
	Bethesda
	NCI - Center for Cancer Research
		Clinical Trials Office - NCI - Center for Cancer Research	Ph:  888-624-1937
	Warren Grant Magnuson Clinical Center - NCI Clinical Trials Referral Office
		Clinical Trials Office - Warren Grant Magnusen Clinical Center - NCI Clinical Trials Referral Office	Ph:  888-NCI-1937
New Jersey
	Hackensack
	Hackensack University Medical Center Cancer Center
		Clinical Trials Office - Hackensack University Medical Center Cancer Center	Ph:  201-996-2879

Related Information

Featured trial article

Registry Information
Official Title		Pilot Study Of Sirolimus (Rapamycin) Generated Donor Th2 Cells And In Vivo Sirolimus For GVHD Prevention After Allogeneic HSCT For Hematologic Malignancy
Trial Start Date		2003-12-30
Trial Completion Date		2009-12-01 (estimated)
Registered in ClinicalTrials.gov		NCT00077480
Date Submitted to PDQ		2003-12-30
Information Last Verified		2007-11-26

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