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

Alternate Title

Alemtuzumab, Total-Body Irradiation, and Fludarabine Followed By Donor Peripheral Stem Cell Transplant in Treating Patients With Hematologic Cancer

Basic Trial Information

Phase Type Status Age Sponsor Protocol IDs Phase II Treatment Active Under 75 NCI FHCRC-1591.00 5275, NCI-H02-0089, NCT00040846

Objectives

Primary

1. Determine the optimum dose of alemtuzumab administered with low-dose total body irradiation and fludarabine followed by HLA class I mismatched allogeneic peripheral blood stem cell transplantation in patients with hematologic malignancies.
2. Determine whether stable allogeneic engraftment can be safely achieved in patients treated with this regimen.

Secondary

1. Determine the risk of occurrence of acute and chronic graft-vs-host disease in patients treated with this regimen.
2. Determine the risk and incidence of infections in patients treated with this regimen.
3. Determine whether engraftment can be maintained in patients treated with fludarabine, mycophenolate mofetil, and cyclosporine.
4. Determine the risk of disease progression and relapse in patients treated with this regimen.

Entry Criteria

Disease Characteristics:

• Diagnosis of hematologic malignancy that is ineligible for (or patient refused) conventional transplantation and expected to be stable for at least 100 days without chemotherapy
  • Diffuse large B-cell non-Hodgkin's lymphoma (NHL), meeting 1 of the following criteria:
    • Ineligible for autologous stem cell transplantation (SCT)
    • Ineligible for conventional myeloablative SCT
    • Failed prior autologous SCT
  • Low-grade NHL
    • Less than 6 months duration of complete remission between courses of prior conventional therapy
  • Mantle cell lymphoma
    • First complete remission allowed
  • Chronic lymphocytic leukemia
    • Failed 2 lines of prior conventional therapy
    • Refractory to fludarabine
  • Hodgkin's lymphoma
    • Failed prior frontline therapy
    • Failed or ineligible for prior autologous transplantation
  • Multiple myeloma, meeting 1 of the following criteria:
    • Received prior chemotherapy
    • Failed prior autografting
      • No autografting immediately prior to nonmyeloablative SCT
  • Acute myeloid leukemia
    • Less than 5% marrow blasts
    • No circulating leukemic blasts in the peripheral blood
  • Acute lymphoblastic leukemia
    • Less than 5% blasts
    • No circulating leukemic blasts in the peripheral blood
  • Chronic myelogenous leukemia
    • Beyond first chronic phase if failed prior therapy with myelosuppressive chemotherapy or SCT and less than 5% blasts
    • No circulating leukemic blasts in the peripheral blood
  • Myelodysplastic syndromes/myeloproliferative disorders
    • Failed prior myelosuppressive chemotherapy
    • Less than 5% marrow blasts
  • Waldenstrom's macroglobulinemia
    • Failed 2 prior courses of therapy



• No rapidly progressive intermediate- or high-grade NHL



• Related or unrelated donor available
  • Best available match is an HLA class II DRB1 and DQB1 matched donor who is incompatible for 1 of the following:
    • Any single serologically detectable class I HLA-A, -B, or -C mismatch
      • Patient and donor must not be homozygous at the mismatched MHC class I locus
      • One additional allele level class I mismatch allowed
    • Any combination of 2 allele level mismatches
  • Likelihood of rapid disease progression during HLA typing exists and a completely matched unrelated donor is not found
  • No HLA-A, -B, or -C single locus allelic mismatched related donor available
  • No positive crossmatch between donor and patient



• No indication for autologous transplantation as a treatment option OR patient refused treatment on a conventional SCT protocol



• No CNS involvement with disease refractory to intrathecal chemotherapy

 [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
• No concurrent post-transplantation growth factors during the first 28 days of mycophenolate mofetil administration

Chemotherapy:

• See Disease Characteristics
• At least 3 weeks since prior intensive chemotherapy

Endocrine therapy:

• Not specified

Radiotherapy:

• Not specified

Surgery:

• Not specified

Patient Characteristics:

Age:

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

Performance status:

• Karnofsky 70-100% (adults)

  OR

• Lansky 50-100% (children)

Life expectancy:

• Not severely limited by diseases other than malignancy

Hematopoietic:

• See Disease Characteristics

Hepatic:

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

Renal:

• Not specified

Cardiovascular:

• No symptomatic coronary artery disease
• No poorly controlled hypertension despite multiple antihypertensives
• No other cardiac failure requiring therapy
• Ejection fraction at least 35% (required if patient is > 50 years of age, received prior anthracyclines, or had prior cardiac disease)

Pulmonary:

• No requirement for supplementary continuous oxygen
• DLCO at least 35%
• Total lung capacity at least 35%
• FEV₁ at least 35%

Other:

• HIV negative
• No severe limitation of life expectancy due to diseases other than malignancy
• No fungal infections with radiological progression after amphotericin B or active triazole for more than 1 month
• No active bacterial or fungal infections unresponsive to medical therapy
• No active nonhematologic malignancy except nonmelanoma skin cancer
  • Patients with a history of a nonhematologic malignancy (except nonmelanoma skin cancer) currently in complete remission, who are < 5 years from the time of complete remission, and have a > 20% risk of disease recurrence are not eligible
• Not pregnant or nursing
• Fertile patients must use effective contraception during and for up to 1 year after study treatment

Expected Enrollment

A total of 60 patients will be accrued for this study within 4 years.

Outcomes

Safety

Risk of acute graft-vs-host disease (aGVHD) and chronic graft-vs-host disease (cGVHD)
Risk of infections
Engraftment maintenance on day 28 post-transplant
Risk of progression and relapse as assessed by nonrelapse-related mortality on day 100 post-transplant

Outline

This is a multicenter, dose-escalation study of alemtuzumab*.

Patients receive alemtuzumab* IV over 2 hours on days -8 to -5 and fludarabine IV on days -4 to -2. Patients undergo low-dose total body irradiation followed by allogeneic peripheral blood stem cell transplantation (PBSCT) on day 0. Patients receive graft-vs-host disease (GVHD) prophylaxis comprising oral cyclosporine twice daily on days -3 to 180 followed by a taper until day 365 and oral mycophenolate mofetil three times daily on days 0 to 100 followed by a taper until day 156.

Cohorts of 7-14 patients receive escalating doses of alemtuzumab* until the optimum dose is determined. The optimum dose is defined as the dose at which no more than 2 of 14 patients (1 in each of 2 cohorts of 7 patients) experience graft rejection or unacceptable toxicity.

 [Note: *Alemtuzumab is only added after the first cohort of patients experiences a rejection rate of > 20%.]

After completion of PBSCT, patients are followed monthly for 4 months, at 6 months, every 6 months until year 2, and then annually for 3 years.

Trial Contact Information

Trial Lead Organizations

Fred Hutchinson Cancer Research Center

Brenda Sandmaier, MD, Protocol chair		Ph: 206-667-4961 Email: bsandmai@fhcrc.org

U.S.A.
Colorado
	Denver
	Rocky Mountain Cancer Centers - Denver Midtown
		Peter McSweeney, MD	Ph:  303-388-4876
Utah
	Salt Lake City
	Huntsman Cancer Institute at University of Utah
		Michael Pulsipher, MD	Ph:  801-581-2121
			Email: michael.pulsipher@hsc.utah.edu
	LDS Hospital
		Finn Petersen, MD	Ph:  801-408-3800
			Email: ldfpeter@ihc.com
Washington
	Seattle
	Fred Hutchinson Cancer Research Center
		Brenda Sandmaier, MD	Ph:  206-667-4961
	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
Italy
	Turin
	Universita di Torino
		Benedetto Bruno, MD, PhD	Ph:  39-0339-112-9064

Registry Information
Official Title		Campath [Alemtuzumab] Dose Escalation, Low-Dose TBI and Fludarabine Followed by HLA Class I Mismatched Donor Stem Cell Transplantation for Patients with Hematologic Malignancies - A Multi-Center Trial
Trial Start Date		2001-11-07
Trial Completion Date		2008-11-07 (estimated)
Registered in ClinicalTrials.gov		NCT00040846
Date Submitted to PDQ		2002-05-31
Information Last Verified		2008-12-28
NCI Grant/Contract Number		CA18029, CA15704, CA920508

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