Campath (Alemtuzumab) Dose Escalation, Low-Dose TBI and Fludarabine Followed by HLA Class II Mismatched Donor Stem Cell Transplantation for Patients With Hematologic Malignancies: A Multicenter Trial
Overview
- Phase
- Phase 2
- Intervention
- alemtuzumab
- Conditions
- Acute Undifferentiated Leukemia
- Sponsor
- Fred Hutchinson Cancer Center
- Enrollment
- 12
- Locations
- 2
- Primary Endpoint
- Incidence of Grade III-IV Acute GVHD
- Status
- Completed
- Last Updated
- 8 years ago
Overview
Brief Summary
This phase II trial is studying the side effects and best dose of alemtuzumab when given together with fludarabine phosphate and total-body irradiation followed by cyclosporine and mycophenolate mofetil in treating patients who are undergoing a donor stem cell transplant for hematologic cancer. Giving low doses of chemotherapy, such as fludarabine phosphate, a monoclonal antibody, such as alemtuzumab, and radiation therapy before a donor stem cell transplant helps stop the growth of cancer cells. Giving chemotherapy or radiation therapy before or after transplant also stops the patient's immune system from rejecting the donor's bone marrow stem cells. The donated stem cells may replace the patient's immune cells 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 and mycophenolate mofetil after the transplant may stop this from happening.
Detailed Description
PRIMARY OBJECTIVES: I. To determine which dose of Campath (alemtuzumab) allows related and unrelated human leukocyte antigen (HLA) class-II mismatched hematopoietic cell transplantation (HCT) with an incidence of grade III-IV acute graft-versus-host disease (GVHD) less than 40%. SECONDARY OBJECTIVES: I. Incidence of graft rejection. II. Number of days of steroids \>= 1mg/kg required before day 100 in each patient. III. Incidence of non-relapse mortality. IV. Risk/incidence of infections. V. Immune reconstitution. VI. Risk for disease progression and relapse. OUTLINE: This is a dose-escalation study of alemtuzumab. NONMYELOABLATIVE CONDITIONING REGIMEN: Patients receive alemtuzumab intravenously (IV) over 6 hours once daily on days -6, -5, and -4 OR days -5 and -4 and fludarabine phosphate IV over 30 minutes on days -4, -3, and -2. Patients also undergo low-dose total-body irradiation (TBI) on day 0. ALLOGENEIC PERIPHERAL BLOOD STEM CELL TRANSPLANTATION (PBSCT): After completion of TBI, patients undergo allogeneic PBSCT on day 0. IMMUNOSUPPRESSION: Patients receive cyclosporine orally (PO) or IV every 12 hours on days -3 to 180 followed by a taper until day 365 in the absence of GVHD. Beginning 4-6 hours after completion of allogeneic PBSCT, patients receive mycophenolate mofetil PO every 8 hours on days 0 to 100 followed by a taper until day 156 in the absence of GVHD. After completion of study treatment, patients are followed up periodically for 12 months, at 18 months, and then annually for 5 years.
Investigators
Brenda Sandmaier
Principal Investigator
Fred Hutchinson Cancer Center
Eligibility Criteria
Inclusion Criteria
- •The patient must be not eligible for conventional transplants and must have disease expected to be stable for at least 100 days without chemotherapy
- •Patients with hematologic malignancies treatable with HCT will be included:
- •Aggressive non-Hodgkin lymphomas (NHLs) and other histologies such as diffuse large B-cell NHL: not eligible for autologous HCT, not eligible for conventional myeloablative HCT, or after failed autologous HCT;
- •Low grade NHL: with \< 6 month duration of complete response (CR) between courses of conventional therapy;
- •Mantle cell NHL: may be treated in first CR;
- •Chronic lymphocytic leukemia (CLL): must have failed 2 lines of conventional therapy and must be refractory to fludarabine; this includes patients who fail to have a complete or partial response after therapy with a regimen containing fludarabine (or another nucleoside analog\] or experience disease relapse within 12 months after completing therapy with a regimen containing fludarabine \[or another nucleoside analog);
- •Hodgkin's disease (HD): must have received and failed frontline therapy and have failed or were not eligible for autologous transplant;
- •Multiple myeloma (MM): must have received prior chemotherapy or failed autografting; following a planned autologous transplant \[tandem\] is allowed;
- •Acute myeloid leukemia (AML): must have \< 5% marrow blasts at the time of transplant;
- •Acute lymphocytic leukemia (ALL): must have \< 5% marrow blasts at the time of transplant;
Exclusion Criteria
- •Positive crossmatch between donor and recipients
- •Patient's life expectancy is severely limited by diseases other than malignancy
- •Patient has central nervous system (CNS) involvement with disease refractory to intrathecal chemotherapy
- •Presence of circulating leukemic blasts (in the peripheral blood) detected by standard pathology for patients with AML, ALL or CML
- •Patient is a fertile man or woman unwilling to use contraceptives during and for up to 12 months post treatment
- •Patient is a female who is pregnant or breastfeeding
- •Patient is human immunodeficiency virus (HIV) positive
- •Patients with active non-hematologic malignancies (except non-melanoma skin cancers)
- •Patients with a history of non-hematologic malignancies (except non-melanoma skin cancers) currently in a complete remission, who are less than 5 years from the time of complete remission, and have a \> 20% risk of disease recurrence
- •Patient has a fungal infection with radiological progression after receipt of amphotericin B or active triazole for greater than 1 month
Arms & Interventions
Treatment (chemotherapy, TBI, transplant)
NONMYELOABLATIVE CONDITIONING REGIMEN: Patients receive alemtuzumab IV over 6 hours once daily on days -6, -5, and -4 OR days -5 and -4 and fludarabine phosphate IV over 30 minutes on days -4, -3, and -2. Patients also undergo low-dose TBI on day 0. ALLOGENEIC PBSCT: After completion of TBI, patients undergo allogeneic PBSCT on day 0. IMMUNOSUPPRESSION: Patients receive cyclosporine PO or IV every 12 hours on days -3 to 180 followed by a taper until day 365 in the absence of GVHD. Beginning 4-6 hours after completion of allogeneic PBSCT, patients receive mycophenolate mofetil PO every 8 hours on days 0 to 100 followed by a taper until day 156 in the absence of GVHD.
Intervention: alemtuzumab
Treatment (chemotherapy, TBI, transplant)
NONMYELOABLATIVE CONDITIONING REGIMEN: Patients receive alemtuzumab IV over 6 hours once daily on days -6, -5, and -4 OR days -5 and -4 and fludarabine phosphate IV over 30 minutes on days -4, -3, and -2. Patients also undergo low-dose TBI on day 0. ALLOGENEIC PBSCT: After completion of TBI, patients undergo allogeneic PBSCT on day 0. IMMUNOSUPPRESSION: Patients receive cyclosporine PO or IV every 12 hours on days -3 to 180 followed by a taper until day 365 in the absence of GVHD. Beginning 4-6 hours after completion of allogeneic PBSCT, patients receive mycophenolate mofetil PO every 8 hours on days 0 to 100 followed by a taper until day 156 in the absence of GVHD.
Intervention: total-body irradiation
Treatment (chemotherapy, TBI, transplant)
NONMYELOABLATIVE CONDITIONING REGIMEN: Patients receive alemtuzumab IV over 6 hours once daily on days -6, -5, and -4 OR days -5 and -4 and fludarabine phosphate IV over 30 minutes on days -4, -3, and -2. Patients also undergo low-dose TBI on day 0. ALLOGENEIC PBSCT: After completion of TBI, patients undergo allogeneic PBSCT on day 0. IMMUNOSUPPRESSION: Patients receive cyclosporine PO or IV every 12 hours on days -3 to 180 followed by a taper until day 365 in the absence of GVHD. Beginning 4-6 hours after completion of allogeneic PBSCT, patients receive mycophenolate mofetil PO every 8 hours on days 0 to 100 followed by a taper until day 156 in the absence of GVHD.
Intervention: fludarabine phosphate
Treatment (chemotherapy, TBI, transplant)
NONMYELOABLATIVE CONDITIONING REGIMEN: Patients receive alemtuzumab IV over 6 hours once daily on days -6, -5, and -4 OR days -5 and -4 and fludarabine phosphate IV over 30 minutes on days -4, -3, and -2. Patients also undergo low-dose TBI on day 0. ALLOGENEIC PBSCT: After completion of TBI, patients undergo allogeneic PBSCT on day 0. IMMUNOSUPPRESSION: Patients receive cyclosporine PO or IV every 12 hours on days -3 to 180 followed by a taper until day 365 in the absence of GVHD. Beginning 4-6 hours after completion of allogeneic PBSCT, patients receive mycophenolate mofetil PO every 8 hours on days 0 to 100 followed by a taper until day 156 in the absence of GVHD.
Intervention: cyclosporine
Treatment (chemotherapy, TBI, transplant)
NONMYELOABLATIVE CONDITIONING REGIMEN: Patients receive alemtuzumab IV over 6 hours once daily on days -6, -5, and -4 OR days -5 and -4 and fludarabine phosphate IV over 30 minutes on days -4, -3, and -2. Patients also undergo low-dose TBI on day 0. ALLOGENEIC PBSCT: After completion of TBI, patients undergo allogeneic PBSCT on day 0. IMMUNOSUPPRESSION: Patients receive cyclosporine PO or IV every 12 hours on days -3 to 180 followed by a taper until day 365 in the absence of GVHD. Beginning 4-6 hours after completion of allogeneic PBSCT, patients receive mycophenolate mofetil PO every 8 hours on days 0 to 100 followed by a taper until day 156 in the absence of GVHD.
Intervention: mycophenolate mofetil
Treatment (chemotherapy, TBI, transplant)
NONMYELOABLATIVE CONDITIONING REGIMEN: Patients receive alemtuzumab IV over 6 hours once daily on days -6, -5, and -4 OR days -5 and -4 and fludarabine phosphate IV over 30 minutes on days -4, -3, and -2. Patients also undergo low-dose TBI on day 0. ALLOGENEIC PBSCT: After completion of TBI, patients undergo allogeneic PBSCT on day 0. IMMUNOSUPPRESSION: Patients receive cyclosporine PO or IV every 12 hours on days -3 to 180 followed by a taper until day 365 in the absence of GVHD. Beginning 4-6 hours after completion of allogeneic PBSCT, patients receive mycophenolate mofetil PO every 8 hours on days 0 to 100 followed by a taper until day 156 in the absence of GVHD.
Intervention: allogeneic hematopoietic stem cell transplantation
Treatment (chemotherapy, TBI, transplant)
NONMYELOABLATIVE CONDITIONING REGIMEN: Patients receive alemtuzumab IV over 6 hours once daily on days -6, -5, and -4 OR days -5 and -4 and fludarabine phosphate IV over 30 minutes on days -4, -3, and -2. Patients also undergo low-dose TBI on day 0. ALLOGENEIC PBSCT: After completion of TBI, patients undergo allogeneic PBSCT on day 0. IMMUNOSUPPRESSION: Patients receive cyclosporine PO or IV every 12 hours on days -3 to 180 followed by a taper until day 365 in the absence of GVHD. Beginning 4-6 hours after completion of allogeneic PBSCT, patients receive mycophenolate mofetil PO every 8 hours on days 0 to 100 followed by a taper until day 156 in the absence of GVHD.
Intervention: peripheral blood stem cell transplantation
Treatment (chemotherapy, TBI, transplant)
NONMYELOABLATIVE CONDITIONING REGIMEN: Patients receive alemtuzumab IV over 6 hours once daily on days -6, -5, and -4 OR days -5 and -4 and fludarabine phosphate IV over 30 minutes on days -4, -3, and -2. Patients also undergo low-dose TBI on day 0. ALLOGENEIC PBSCT: After completion of TBI, patients undergo allogeneic PBSCT on day 0. IMMUNOSUPPRESSION: Patients receive cyclosporine PO or IV every 12 hours on days -3 to 180 followed by a taper until day 365 in the absence of GVHD. Beginning 4-6 hours after completion of allogeneic PBSCT, patients receive mycophenolate mofetil PO every 8 hours on days 0 to 100 followed by a taper until day 156 in the absence of GVHD.
Intervention: graft versus host disease prophylaxis/therapy
Treatment (chemotherapy, TBI, transplant)
NONMYELOABLATIVE CONDITIONING REGIMEN: Patients receive alemtuzumab IV over 6 hours once daily on days -6, -5, and -4 OR days -5 and -4 and fludarabine phosphate IV over 30 minutes on days -4, -3, and -2. Patients also undergo low-dose TBI on day 0. ALLOGENEIC PBSCT: After completion of TBI, patients undergo allogeneic PBSCT on day 0. IMMUNOSUPPRESSION: Patients receive cyclosporine PO or IV every 12 hours on days -3 to 180 followed by a taper until day 365 in the absence of GVHD. Beginning 4-6 hours after completion of allogeneic PBSCT, patients receive mycophenolate mofetil PO every 8 hours on days 0 to 100 followed by a taper until day 156 in the absence of GVHD.
Intervention: laboratory biomarker analysis
Outcomes
Primary Outcomes
Incidence of Grade III-IV Acute GVHD
Time Frame: 100 days after transplant
Severity of Individual Organ Involvement Liver: Stage 2 - bilirubin (3-5.9mg/100ml) Stage 3 - bilirubin (6-14.9mg/100ml) Stage 4 - bilirubin \> 15mg/100ml Gut: Diarrhea is graded stage 1 to stage 4 in severity. Nausea and vomiting and/or anorexia caused by GVHD is assigned as stage 1 in severity. The severity of gut involvement is assigned to the most severe involvement noted. Patients with visible bloody diarrhea are at least stage 2 gut and grade 3 overall Severity of GVHD Grade III - Stage 2 to 4 gastrointestinal involvement and/or Stage 2 to 4 liver involvement with or without a rash Grade IV - Pattern and severity of GVHD similar to grade 3 with extreme constitutional symptoms or death
Secondary Outcomes
- Incidence of Graft Rejection(84 days after transplant)
- Immune Reconstitution(Up to 1 year post-transplant)
- Disease Progression/Relapse(Up to 5 years)
- Incidence of High-dose Corticosteroid Utilization.(100 days after transplant)
- Incidence of Infection(Up to 5 years post-transplant)
- Incidence of Non-relapse Mortality(100 days after transplant)