Melphalan, Fludarabine, and Alemtuzumab Followed by Peripheral Stem Cell Transplant in Treating Patients With Hematologic Cancer

Lymphoma Clinical Trial

Official title:

Phase II Trial Of Non-Myeloablative Regimen Combining Melphalan, Fludarabine, And Anti-CD52 Monoclonal Antibody (CAMPATH-1H) Followed By An Unmodified Hematopoietic Cell Transplant From An HLA Compatible Related Or Unrelated Donor For Treatment Of Lymphohematopoietic Malignancies

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00027560
• Other study ID #: 01-092
• Secondary ID: MSKCC-01092NCI-G
• Status: Completed
• Phase: Phase 2
• First received: December 7, 2001
• Last updated: December 3, 2012
• Start date: July 2001
• Est. completion date: April 2009

Study information

• Verified date: December 2012
• Source: Memorial Sloan Kettering Cancer Center
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial Summary

RATIONALE: Giving low doses of chemotherapy, such as melphalan and fludarabine, and a monoclonal antibody, such as alemtuzumab, before a donor bone marrow or peripheral blood stem cell transplant helps stop the growth of cancer cells. It also stops the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune system and help destroy any remaining cancer cells (graft-versus-tumor effect). Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving cyclosporine after the transplant may stop this from happening.

PURPOSE: This phase II trial is studying how well fludarabine, melphalan, alemtuzumab, and peripheral stem cell transplant work in treating patients with hematologic cancer.

Description:

OBJECTIVES:

Overall survival-12 months

Overall survival-24 months

Acute Graft-versus-Host Disease Matched Related patients-up to 4 months post transplant

Acute Graft-versus-Host Disease Unrelated and Mismatched related patients- up to 4 months post transplant

Chronic Graft-versus-Host Disease Matched Related patients- up to 2 years post transplant

Chronic Graft-versus-host disease Unrelated and Mismatched related patients- up to 2 years post transplant

• OUTLINE: Patients are stratified according to donor type (HLA-matched related vs HLA-matched unrelated, single HLA-allele disparate related, or unmatched) (HLA-mismatched related or matched unrelated donor stratum closed to accrual as of 1/11/06).

Patients receive a nonmyeloablative regimen comprising alemtuzumab IV over 8 hours on days -8 to -5, fludarabine IV over 30 minutes on days -8 to -4, and melphalan IV over 30 minutes on days -3 and -2. Allogeneic peripheral blood stem cells or bone marrow is infused on day 0.

Patients receive graft-versus host disease prophylaxis comprising cyclosporine IV every 12 hours beginning on day -1 and continuing orally as tolerated until day 100.

Patients are followed every 6 weeks for 6 months, every 3 months for 6 months, every 3-6 months for 1 year, and then annually thereafter or as clinically indicated.

PROJECTED ACCRUAL: A maximum of 50 patients (25 HLA-matched related and 25 HLA-mismatched related or matched unrelated) will be accrued for this study within 2 years (HLA-mismatched related or matched unrelated donor stratum closed to accrual as of 1/11/06).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 51
• Est. completion date: April 2009
• Est. primary completion date: April 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A to 70 Years

Eligibility

INCLUSION CRITERIA:

• Disease criteria: This trial is primarily designed for: 1) patients with relapsed or primary refractory non-Hodgkin's lymphoma, 2) chemosensitive relapsed or refractory acute and chronic lymphocytic leukemias, 3) relapsed or primary refractory Hodgkin's Disease, or advanced (Durie-Salmon stage II or III) multiple myeloma, advanced Waldenstrom macroglobulinemia, who, by virtue of advanced age, intensity of prior radiation and/or chemotherapy, history of prior toxicity associated with chemo/radiotherapy or existing organ dysfunction, would be at undue risk of regimen associated mortality if transplanted according to protocols involving myeloablative conditioning regimens.

• Patients with aggressive NHL histologies must have chemo/radiosensitive disease, or have non-progressive disease, or have stable disease on therapy, and be ineligible for an autologous HSC transplant because of disease in the marrow.

• Patients with chronic myeloid leukemia and high risk forms of acute myelogenous leukemia or myelodysplastic syndromes are also eligible in the absence of an alternative active higher priority allogeneic transplant protocol for which they are eligible.

• Age criteria: Patients may be up to 70 years of age. There is no lower age threshold. Patients above the age of 70 may also participate, after evaluation and approval by the BMT Service attendings.

• Absence of active or uncontrolled bacterial, viral, or fungal infection that would contraindicate the use of myelosuppressive chemotherapy.

• Patients must have a healthy HLA-compatible donor, either a matched or single HLA allele disparate related donor or a similarly compatible unrelated donor recruited through the National Marrow Donor Program. Related donors must be willing to participate as research subjects and be willing to receive G-CSF to mobilize PBPC and undergo leukapheresis to donate PBSC. Unrelated donors identified by the NMDP may elect to donate either PBSC after treatment with G-CSF, or bone marrow. These unrelated donors will provide informed consent and their PBSC or bone marrow donations will be obtained at a qualified donor center participating in the NMDP.

• Each patient must be willing to participate as a research subject and must sign an informed consent form after discussion of the nature and risks of the study prior to entering the protocol. Parents or legal guardians of patients who are minors will sign the consent form for these patients after discussion of the nature and risks of the study.

EXCLUSION CRITERIA:

• Female patients who are pregnant or lactating.

• Active or uncontrolled viral (including HIV-1), bacterial or fungal infection.

• Severe renal insufficiency (creatinine >2.0 or creatinine clearance < 30mL/minute)

• Severe hepatic dysfunction, as defined by: total bilirubin greater than 2.5 mg/dL and AST and ALT >3xnl, unless the liver is involved with disease.

• Severe cardiac insufficiency, defined as a resting left ventricular ejection of less than 30% as measured by echocardiography or radionuclide cardiac angiography. Patients on cardiac medications for congestive heart failure are eligible, as long as their LVEF is greater than 30% on medication.

• Severe pulmonary insufficiency, as defined by an adjusted diffusing capacity of less than 40% of predicted value.

• Karnofsky or Lansky score <40%

Study Design

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Leukemia
• Lymphoma
• Multiple Myeloma
• Multiple Myeloma and Plasma Cell Neoplasm
• Myelodysplastic Syndromes
• Myelodysplastic-Myeloproliferative Diseases
• Myelodysplastic/Myeloproliferative Neoplasms
• Myeloproliferative Disorders
• Neoplasms
• Neoplasms, Plasma Cell
• Plasmacytoma
• Preleukemia

Intervention

Biological:
• alemtuzumab
Consenting individuals will receive pretransplant immunosuppressive cytoreduction, which will consist of 4 days of Campath-1H, 5 days of fludarabine, and two days of melphalan. All therapy should be completed approximately 24-36 hours before administration of the primary allograft. Campath-1H (20mg/dose/day) will be administered for each of four days from day -8 to day -5, inclusive. Each dose will be infused intravenously over 8 hours.

Drug:
• cyclosporine
Patients will be treated with Cyclosporine as prophylaxis against GvHD. Cyclosporine will be initiated at least 1 day prior to transplant at a dose of 1.5 mg / kg IV q12h (3 mg / kg / day = total daily dose). Dose will thereafter be adjusted to maintain a trough serum level of 200-300 ng /ml. Cyclosporine will be administered intravenously until the patient tolerates full alimentation, at which time conversion to oral dosing to sustain therapeutic levels will be initiated according to standard BMT service guidelines.
• fludarabine phosphate
Fludarabine, 25mg/m2/d will be administered for each of five days from day -8 to day -4, inclusive. Each dose will be infused intravenously over 30 minutes.
• melphalan
Melphalan will be administered intravenously over 30 minutes on each of two days from day -3 to day -2, inclusive. The dose for recipients of HLA-matched related grafts will be 50 mg/m2/day x 2. The dose for recipients of HLA-matched unrelated and HLA-single allele disparate related or unrelated marrow or PBSC transplants will be 70 mg/m2/day x 2.

Procedure:
• allogeneic bone marrow transplantation

• peripheral blood stem cell transplantation

Locations

Country	Name	City	State
United States	Memorial Sloan-Kettering Cancer Center	New York	New York

Sponsors (2)

Lead Sponsor	Collaborator
Memorial Sloan Kettering Cancer Center	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall Survival		12 months post transplant	No
Primary	Overall Survival		24 months post transplant	No
Primary	Acute Graft-versus-Host Disease Matched Related Patients	Grade III-IV Acute Graft-versus-Host Disease	up to 4 months post transplant	No
Secondary	Acute Graft-versus-Host Disease Unrelated and Mismatched Related Patients	Grade III-IV Acute Graft-versus-Host Disease	up to 4 months post transplant	No
Secondary	Extensive Chronic Graft-versus-Host Disease Matched Related Patients		up to 2 years post transplant	No
Secondary	Extensive Chronic Graft-versus-Host Disease Unrelated and Mismatched Related Patients		up to 2 years post transplant	No