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

Alternate Title

Total-Body Irradiation With Or Without Fludarabine Followed By Donor Stem Cell Transplant in Treating Patients With Hematologic Cancer

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase III	Treatment	Active	Under 75	NCI	FHCRC-1813.00 5666, NCT00075478

Objectives

Primary

1. Compare the nonrelapse mortality 1 year after nonmyeloablative conditioning comprising low-dose total body irradiation (TBI) with vs without fludarabine followed by HLA-matched related allogeneic hematopoietic stem cell transplantation in patients with hematologic malignancies at low or moderate risk for graft rejection.

Secondary

1. Compare the 1-year overall survival of patients after treatment with these regimens.
2. Compare the incidence of graft rejection in patients treated with these regimens.
3. Compare the incidence of grades II-IV acute graft-versus-host disease (GVHD) and chronic extensive GVHD in patients treated with these regimens.
4. Compare the rates of disease progression and/or relapse-related mortality in patients treated with these regimens.
5. Compare the immune reconstitution and risk of infection in patients treated with these regimens.

Entry Criteria

Disease Characteristics:

• Diagnosis of a hematologic malignancy treatable with hematopoietic stem cell transplantation (HSCT) OR a B-cell malignancy, including any of the following:
  • Aggressive non-Hodgkin's lymphoma (NHL) and other histologies, such as diffuse large B-cell non-Hodgkin's lymphoma (NHL)
    • Not eligible for conventional myeloablative HSCT OR failed autologous HSCT
    • No rapidly progressive aggressive NHL, unless in minimal disease state
  • Low-grade NHL with less than 6 months duration of complete remission (CR) between courses of conventional therapy
  • Mantle cell lymphoma
    • In first CR
  • Chronic lymphocytic leukemia
    • Meets 1 of the following criteria:
      • Failed to meet NCI Working Group criteria for complete or partial response after therapy with a regimen containing fludarabine (FLU) (or another nucleoside analog, e.g., 2-CDA, pentostatin) or experience disease relapse within 12 months after completing therapy with a regimen containing FLU (or another nucleoside analog)
      • Failed FLU-CY-Rituximab (FCR) combination chemotherapy at any time point
      • Have “17p deletion” cytogenetic abnormality (patients should have received induction chemotherapy but could be transplanted in first CR)
  • Hodgkin's lymphoma
    • Received and failed front-line therapy
    • Failed or were not eligible for autologous transplantation
  • Multiple myeloma
    • Chemosensitive disease after failed autografting
    • No autografting prior (within 6 months) to nonmyeloablative hematopoietic cell transplantation (HCT)
  • Acute myeloid leukemia
    • Less then 5% marrow blasts at the time of transplantation and beyond first CR
    • No circulating leukemic blasts in the peripheral blood
  • Acute lymphoblastic leukemia
    • Less than 5% marrow blasts at the time of transplantation and beyond first CR
    • No circulating leukemic blasts in the peripheral blood
  • Chronic myelogenous leukemia
    • Chronic phase (CP) beyond CP1 allowed provided the patient is beyond the first CP and was previously treated with myelosuppressive chemotherapy or HSCT and has less than 5% marrow blasts at time of transplantation
    • No circulating leukemic blasts in the peripheral blood
  • Myelodysplastic syndromes
    • Received prior myelosuppressive chemotherapy or HSCT and less than 5% marrow blasts at time of transplantation



• Not eligible for conventional allogeneic HSCT AND must have disease that is expected to be stable for at least 100 days without chemotherapy
  • Not curable with an autologous transplantation
  • Patients who refused to be treated on a conventional HSCT study are eligible



• Not eligible for a high priority curative autologous transplantation



• No chronic myelomonocytic leukemia or myeloproliferative disorder



• No concurrent CNS involvement with disease refractory to intrathecal chemotherapy



• Available HLA-matched related donor
  • Genotypically identical in at least 1 haplotype
  • Phenotypically or genotypically identical donor at the allele level at HLA-A, -B, -C, -DRB1, and -DQB1 allowed
  • No identical twin

 [Note: A new classification scheme for adult non-Hodgkin's lymphoma has been adopted by PDQ. The terminology of "indolent" or "aggressive" lymphoma will replace the former terminology of "low", "intermediate", or "high" grade lymphoma. However, this protocol uses the former terminology.]

Prior/Concurrent Therapy:

Biologic therapy

• See Disease Characteristics
• More than 6 months since prior autograft immediately before nonmyeloablative HSCT (tandem approach)
• More than 3 weeks (from the initiation of conditioning) since prior cytotoxic agents for “cytoreduction, ” except tyrosine kinase inhibitors (e.g., imatinib mesylate), cytokine therapy, hydroxyurea, low dose cytarabine, chlorambucil, or rituxan

Chemotherapy

• See Disease Characteristics
• See Biologic therapy
• More than 3 weeks since prior myelosuppressive chemotherapy

Endocrine therapy

• Not specified

Radiotherapy

• Not specified

Surgery

• Not specified

Patient Characteristics:

Age

• Under 75
  • Patients under 12 must be approved by the principal investigator

Performance status

• Karnofsky 50-100% (adult patients)
• Lansky 50-100% (pediatric patients)

Life expectancy

• Not severely limited by disease other than malignancy

Hematopoietic

• Not specified

Hepatic

• No fulminant liver failure
• No cirrhosis of the liver with evidence of portal hypertension
• No alcoholic hepatitis
• No esophageal varices
• No history of bleeding esophageal varices
• No hepatic encephalopathy
• No uncorrectable hepatic synthetic dysfunction evidenced by prolongation of the PT
• No ascites related to portal hypertension
• No bacterial or fungal liver abscess
• No biliary obstruction
• No chronic viral hepatitis with bilirubin greater than 3 mg/dL
• No symptomatic biliary disease

Renal

• Not specified

Cardiovascular

• Ejection fraction at least 35%*
• No poorly controlled hypertension despite multiple hypertensive drugs
• No symptomatic coronary artery disease*
• No other cardiac failure requiring therapy*

 [Note: *For patients with a history of cardiac disease or anthrocycline use]

Pulmonary

• DLCO at least 30%
• Total lung capacity at least 30%
• FEV₁ at least 30%
• No concurrent supplementary continuous oxygen
• No fungal pneumonia with radiological progression after receiving amphotericin formulation or mold-active azoles for more than 1 month

Other

• Not pregnant or nursing
• Fertile patients must use effective contraception during and for up to 12 months after study participation
• HIV negative
• No active nonhematologic malignancy except localized nonmelanoma skin cancer
• No nonhematologic malignancy not in complete remission with > 20% risk of disease recurrence except nonmelanoma skin cancer

Expected Enrollment

A total of 200 patients (100 per treatment arm) will be accrued for this study within 3 years.

Outcomes

Nonrelapse mortality 1 year post-transplant

Overall survival 1 year post-transplant
Incidence of graft rejection
Incidence of acute graft-vs-host disease (GVHD) and chronic extensive GVHD
Compare rates of disease progression and/or relapse-related mortality 1 year post-transplant
Compare immune reconstitution and the risks of infections

Outline

This is a randomized, multicenter study. Patients are stratified according to participating center, disease risk (indolent vs aggressive), and prior conventional hematopoietic stem cell transplantation (yes vs no).

• Nonmyeloablative conditioning regimen: Patients are randomized to 1 of 2 treatment arms.
  • Arm I: Patients receive fludarabine IV on days -4 to -2. Patients then undergo low-dose total body irradiation (TBI) on day 0.
  
  
  
  • Arm II: Patients undergo low-dose TBI on day 0.
  
  
  



• Allogeneic peripheral blood stem cell transplantation (PBSCT): After TBI, patients undergo PBSCT on day 0.



• Immunosuppression: Patients receive oral cyclosporine twice daily on days -3 to 56 in the absence of graft-versus-host disease (GVHD). Patients with no evidence of GVHD at day 56 begin a cyclosporine taper and continue the taper until day 180. Patients with evidence of disease progression and no evidence of GVHD prior to day 56 receive tapered doses of cyclosporine for 2 weeks. Patients also receive oral mycophenolate mofetil (MMF) twice daily on days 0-27 in the absence of GVHD. If treatment for GVHD is required before day 28, MMF is continued until a steroid taper begins.

Patients are followed periodically for 1.5 years and then annually for 5 years post-transplantation.

Trial Contact Information

Trial Lead Organizations

Fred Hutchinson Cancer Research Center

Brenda Sandmaier, MD, Principal investigator		Ph: 206-667-4961

U.S.A.
Oregon
	Portland
	Knight Cancer Institute at Oregon Health and Science University
		Clinical Trials Office - Knight Cancer Institute at Oregon Health and Science University	Ph:  503-494-1080
			Email: trials@ohsu.edu
Utah
	Salt Lake City
	LDS Hospital
		Finn Petersen, MD	Ph:  801-408-1818
			Email: ldfpeter@ihc.com
Washington
	Seattle
	Fred Hutchinson Cancer Research Center
		Brenda Sandmaier, MD	Ph:  206-667-4961
	Seattle Cancer Care Alliance
		Clinical Trials Office - Seattle Cancer Care Alliance	Ph:  800-804-8824
	Veterans Affairs Medical Center - Seattle
		Thomas R. Chauncey, MD, PhD	Ph:  206-764-2709 800-329-8387
Wisconsin
	Milwaukee
	Medical College of Wisconsin Cancer Center
		Clinical Trials Office - Medical College of Wisconsin Cancer Center	Ph:  414-805-4380
Germany
	Cologne
	Medizinische Universitaetsklinik I at the University of Cologne
		Kai Huebel, MD	Ph:  49-221-478-3583
			Email: kai.huebel@uni-koeln.de
	Leipzig
	Universitaet Leipzig
		Dietger Niederwieser, MD	Ph:  49-341-971-3050
			Email: dietger@medizin.uni_leipzig.de
	Tuebingen
	Universitaetsklinikum Tuebingen
		Wolfgang Bethge, MD	Ph:  49-4707-1298-2711
Italy
	Turin
	Azienda Sanitaria Ospedale San Giovanni Battista Molinette di Torino
		Benedetto Bruno, MD, PhD	Ph:  39-339-112-9064
			Email: benedetto.bruno@unito.it

Registry Information
Official Title		A Multi-Center Phase III Study Comparing Nonmyeloablative Conditioning with TBI Versus Fludarabine/TBI for HLA-Matched Related Hematopoietic Cell Transplantation for Treatment of Hematologic Malignancies
Trial Start Date		2003-10-16
Trial Completion Date		2010-10-16 (estimated)
Registered in ClinicalTrials.gov		NCT00075478
Date Submitted to PDQ		2003-11-17
Information Last Verified		2009-07-05
NCI Grant/Contract Number		CA78902, CA15704, HL36444

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