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Rituximab: 375 mg/m(2) intravenous (IV), day 1 for patients with cluster of differentiation 20 (CD20)-positive disease.

Cyclosporine: IV over 2 hours or orally every 12 hours on days -1 to 100, followed by a taper if graft versus host disease (GVHD) does not develop.

Allogenic stem cell transplant (ASCT)

Fludarabine:30 mg/m(2) per day IV infusion over 30 minutes, daily. On days -6, -5, -4, and -3.

Cyclophosphamide:1200 mg/m(2) per day IV infusion over 2 hours on Days 6, -5, -4, -3 Mesna: 1200 mg/m(2) per day IV infusion, Daily on days 6, -5,-4, and -3

Conditioning Chemotherapy

Tacrolimus: starting day -3 before transplant, given initially at 0.02 mg/kg/day CIV. Continue IV and then switch to an equivalent oral dose (when patient taking po) titrated for a goal level of 5 to 10 ng/ml; Sirolimus: given as an initial loading dose of 12 mg p.o. on day -3 pre-transplant, 4 mg starting day -2 pre-transplant and titrated for levels 3-12 ng/ml; Methotrexate 5 mg/m2 IV on days +1, +3, +6, and +11 post-transplant. Tacrolimus and sirolimus will be tapered at day +63, day +119 and day +180 post-transplant as tolerated.

Fludarabine:25 mg/m(2) per day IV over 30 minutes, Daily on days 1-5 Cytarabine: 2,000 mg/m(2) IV over 4 hours,on Days 1, 2, 3, 4, 5 Filgrastim: 5 mcg/kg per day subcutaneous (SC) beginning 24 hours PRIOR to initiation of chemotherapy

FLAG

Fludarabine:25 mg/m(2) per day IV infusion over 30 minutes, daily on days 1-4 Etoposide :50 mg/m(2) per day continuous IV infusion over 24 hours on days 1-4 Doxorubicin:10 mg/m(2)/day CIV, days 1-4 Vincristine:0.4 mg/m(2) per day continuous IV infusion over 24 hours daily on days 1-4 Cyclophosphamide:750 mg/m(2) IV infusion over 30 minutes on day 5

EPOCH-F

Alemtuzumab:20 mg/day IV over 8 h on days 8 to 4 pre-transplant.

Steven Z Pavletic, M.D.

Background:

Major problems with stem cell transplantation (SCT) for cancer treatment are a lack of suitable donors for patients without a human leukocyte-antigen (HLA) tissue-matched sibling and graft-versus-host disease (GVHD), a serious side effects of immune-suppressing chemotherapy that is given to bring the cancer under control before SCT. In GVHD, the patients immune system attacks the transplanted donor cells.

This study will try to improve the results of SCT from unrelated HLA-matched donors using targeted immune-depleting chemotherapy to bring the cancer under control before transplantation and to lower the chance of graft rejection, followed by reduced-intensity transplant chemotherapy to make the procedure less toxic.

Objectives:

To evaluate the safety and effectiveness of targeted immune-depleting chemotherapy followed by reduced-intensity transplant chemotherapy in patients with advanced cancers of the blood and immune system.

To evaluate the safety and effectiveness of two different drug combinations to prevent GVHD. Both regimens have been successful in preventing GVHD, but they work by different mechanisms and affect the rebuilding of the immune system after the transplant.

Eligibility:

People 18 to 74 years of age with advanced or high-risk cancers of the blood and immune system who do not have a suitable HLA-matched sibling.

Design:

All patients receive chemotherapy before transplant to treat the cancer and suppress immune function.

All patients receive a conditioning regimen of cyclophosphamide for 4 days and fludarabine for 4 days before SCT to prepare for the transplant.

Patients are randomly assigned to one of two combination drug treatments to prevent GHVD as follows:

* Group 1: Tacrolimus starting 3 days before SCT and continuing for 6 months, plus methotrexate on days 1, 3, 6, and 11 post-SCT, plus sirolimus starting 3 days before the SCT and continues for 6 months following SCT.
* Group 2: Alemtuzumab for 4 days starting 8 days before SCT, plus cyclosporine starting 1 day before SCT and continuing for 6 months.

Patients receive the donors stem cells and immune cells 2 days after completing the conditioning regimen.

Patients are followed at the clinic regularly for the first 6 months after SCT, and then less often for at least 5 years. Some visits may include bone marrow aspirates and biopsies, blood draws, and other tests to monitor disease status.

A skin biopsy, oral mucosa biopsy, and saliva collection are done to study chronic GVHD.

...

Background:

* The major limitations to the broader applicability of allogeneic hematopoietic stem cell transplantation (HSCT) for the treatment of malignancies are lack of suitable donors and therapy-related toxicities which include delayed and incomplete immune reconstitution and graft-versus-host disease (GVHD). Based on the theory that the rapid establishment of donor chimerism was essential for an optimal graft-versus-tumor effect, we have employed a strategy of targeted immune depleting chemotherapy prior to reduced-intensity allogeneic HSCT. It is our intent to investigate this approach in the setting of human leukocyte-antigen (HLA)-matched unrelated donors in a pilot manner.
* A clearly superior GVHD prophylaxis regimen has not been established in the unrelated donor transplant setting. The best results that have been reported are with the combination of alemtuzumab plus cyclosporine \[AC\] and the combination of tacrolimus, methotrexate, and sirolimus \[TMS\]. These two regimens work by mechanisms which are biologically distinct and potentially have markedly different effects upon immune reconstitution that have not been well studied. In addition, neither of these regimens has been assessed for their effects on chronic GVHD using the National Institutes of Health (NIH) Consensus Conference Criteria. It is our intent to study the effects that these two regimens have on immune reconstitution and chronic GVHD in the setting sequential targeted immune-depleting chemotherapy and reduced-intensity allogeneic HSCT from HLA-matched unrelated donors.

Objectives:

* Primary objectives:

  1. to assess the effects of two biologically distinct GVHD prophylaxis regimens, TMS and AC, on immune reconstitution in patients receiving targeted-immune depletion and reduced-intensity allogeneic HSCT from HLA-matched unrelated donors. As part of a comprehensive assessment of immune reconstitution, the primary immunologic endpoint will be the determination of cluster of differentiation 4 (CD4)+ T cell receptor V BETA repertoire by complementarity determining region 3 (CDR3) spectratyping at 3 months post-transplant.
  2. to assess overall safety of these two regimens in this setting, as determined by engraftment, acute GVHD, early and late treatment-related mortality, and overall survival.
  3. to determine and monitor incidence, organ severity and overall severity of chronic GVHD prospectively using the newly developed NIH Consensus Conference diagnosis and staging criteria and preliminarily validate those tools for use in clinical practice and trials.
* Secondary objectives include further assessment of immune reconstitution, study of engraftment kinetics, and assessment of those patients who receive higher doses of anthracyclines for long and short term toxicities

Eligibility:

* Adults (18-74 years) with advanced or high risk hematologic malignancies including acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), myelodysplastic syndrome (MDS), chronic lymphocytic leukemia (CLL), non-hodgkin lymphoma (NHL), hodgkin lymphoma (HL), chronic myelogenous leukemia (CML), multiple myeloma, and myeloproliferative disorder (MPD) who lack a suitable HLA matched sibling.
* An unrelated donor matched at a minimum of 7 of 8 alleles (HLA-A,-B,-C, and DRB1) by high resolution typing, identified through the National Marrow Donor Program.
* Life expectancy of at least 3 months, Eastern Cooperative Oncology Group (ECOG) less than or equal to 2 and relatively normal major organ functions.

Design:

* Patients will receive disease-specific induction chemotherapy (etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin (EPOCH-fludarabine (F)/rituximab (R) or fludarabine, cytarabine, and granulocyte colony-stimulating factor (FLAG)) prior to transplant for disease control and immune depletion. If disease is controlled (greater than partial response (PR)) and immune depletion objectives have been met, patients may forgo induction chemotherapy and move forward to the transplant conditioning regimen.
* All patients will receive an identical conditioning regimen consisting of cyclophosphamide 1200 mg/m(2)/day intravenous (IV) for 4 days and fludarabine 30 mg/m(2)/day for 4 days.
* Patients will be stratified according to degree of HLA-match and randomized at the time of enrollment to one of two GHVD prophylaxis regimens:

  * Group 1: Tacrolimus starting 3 days before stem cell transplant (SCT), and continuing for 6 months, plus methotrexate on days 1, 3, 6, and 11 post-SCT, plus sirolimus starting 3 days before the SCT and continues for 6 months following SCT.
  * Group 2: Alemtuzumab for 4 days starting 8 days before SCT, plus cyclosporine starting 1 day before SCT and continuing for 6 months.
* A maximum of 105 patients will be enrolled and randomly assigned to the two arms in order to yield 44 patients per arm (88 total patients) who are able to be evaluated for development of severe chronic GVHD.

Chemotherapy and Unrelated Donor Stem Cell Transplantation for Patients With Cancers of the Blood and Immune System

Phase II Trial of Targeted Immune-Depleting Chemotherapy and Reduced-Intensity Allogeneic Hematopoietic Stem Cell Transplantation Using 8/8 and 7/8 HLA-matched Unrelated Donors and Utilizing Two Graft-versus-Host Disease Prophylaxis Regimens for the Treatment of Leukemias, Lymphomas, and Pre-malignant Blood Disorders

Acute GVHD is assessed by the 1994 Consensus Conference on Acute GVHD Grading criteria. See Przepiorka D, Weisdorf D, Martin P, et al. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant. 1995; 15:825-8., for grading criteria.

Chronic GVHD is assessed by the 2005 Chronic GVHD Consensus Project. First the individual organ scoring is done, and then based on that the Global score is determined (mild-moderate-severe). See Citation: Filipovich AH, Weisdorf D, Pavletic S, et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant. 2005; 11:945-56., for grading criteria.

The percentage of C-C motif chemokine receptor 7 (CCR7)+CD45RA+ naïve T cells within the CD4 T cell populations was determined by flow cytometry.

The percentage of CCR7+CD45RA+ naïve T cells within the CD4 and CD8 T cell populations was determined by flow cytometry.

Ribonucleic acid (RNA) was extracted from sorted CD4 and cluster of differentiation 8 (CD8) T cells and analyzed for Vbeta repertoire by nested polymerase chain reaction (PCR) analysis using Vbeta family specific primers and a labeled constant region primer (spectratyping). The receptor repertoire diversity was calculated from spectratyping data by creating a normal standard for repertoire diversity from healthy normal controls and assessing the divergence of individual patient's T cell receptor repertoire from these standard normal donor values. In this Vbeta repertoire divergence index, lower numbers are consistent with a more normal highly diverse repertoire, and high numbers represent a highly skewed, oligoclonal repertoire. The assay is described in Memon SA et al, J Immunol Methods, 2012, 375: 84-92. The repertoire diversity of the CD4 and CD8 T cells of the donor infusion is shown for comparison.

Acute GVHD is assessed by the 1994 Consensus Conference on acute GVHD Grading criteria. See Przepiorka D, Weisdorf D, Martin P, et al. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant. 1995; 15:825-8., for grading criteria.

Here are the number of participants with adverse events. For a detailed list of adverse events, see the adverse event module.

Days to engraftment is defined as neutrophil recovery: designated by the first of 3 consecutive days with an absolute neutrophil count (ANC) above 500/mm(3).

Platelet recovery: designated by the first of 7 days where the platelet count remains above 20,000/mm(3) without transfusion support

Lymphocyte recovery: designated by the first of 3 consecutive days with absolute lymphocyte count (ALC) above 500/mm(3).

Time between the first day of transplant to the day of death.

Any death occurring within 28 days after transplantation in a patient in continuous remission.

Any death occurring 28 days or more after transplantation in a patient in continuous remission.

During depletion of lymphocytes during transplant conditioning, levels of homeostatic cytokines increase in the blood. These then decline with the expansion of new donor-derived cells. The rapidity of decline may predict acute graft versus host disease (AGVHD). Decline in cytokine IL-7 will be assessed by the enzyme-linked immunosorbent assay (ELISA).

Cluster of differentiation 3 (CD3) - cluster of differentiation 56 (CD56) + Natural Killer (NK) cells within the lymphocyte population were determined by flow cytometry. The absolute numbers of cells/µl were calculated from the absolute lymphocyte count.

Cluster of Differentiation 3 (CD3)+CD4+ and CD3+Cluster of Differentiation 8 (CD8)+ T cells within the lymphocyte population were determined by flow cytometry. The absolute numbers of cells/µl were calculated from the absolute lymphocyte count.

Cluster of differentiation 3 (CD3)+cluster of differentiation 4 (CD4)+ and CD3+CD8+ T cells within the lymphocyte population were determined by flow cytometry. The absolute numbers of cells/µl were calculated from the absolute lymphocyte count.

National Cancer Institute (NCI)

Principal Investigator

One participant was enrolled and given induction chemotherapy but was never randomized to Arm TMS or AC. Subject had one AE (infection with normal ANC or Grade 1 or 2 neutrophils: Pharynx). Subject was taken off study for disease progression and died.

TMS Arm

Rituximab: Rituximab: 375 mg/m2 IV, day 1 for patients with CD20-positive disease

Allogenic stem cell transplant (ASCT): Allogenic stem cell transplant

Conditioning Chemotherapy: Fludarabine:30 mg/m2 per day IV infusion over 30 minutes, daily On days -6, -5, -4, and -3 Cyclophosphamide:1200 mg/m2 per day IV infusion over 2 hours on Days 6, -5, -4, -3 Mesna: 1200 mg/m2 per day IV infusion, Daily on days 6, -5,-4, and -3

TMS: Tacrolimus: 0.02 mg/kg , start day 3. Continue IV or PO. Taper will begin at day +63 if no acute GVHD then at day +119 and discontinue at day +180 as tolerated Methotrexate: 5 mg/m2 IV over 15 minutes on days 1, 3, 6, and 11. Sirolimus: 12 mg PO on days -3 to 63, followed by a taper if GVHD does not develop.

FLAG: Fludarabine:25 mg/m2 per day IV over 30 minutes, Daily on days 1-5 Cytarabine: 2,000 mg/m2 IV over 4 hours,on Days 1, 2, 3, 4, 5 Filgrastim: 5 mcg/kg per day SC beginning 24 hours PRIOR to initiation of chemotherapy

A - Tacrolimus, Methotrexate, Sirolimus (TMS) Arm

AC Arm

Rituximab: Rituximab: 375 mg/m2 IV, day 1 for patients with CD20-positive disease

Cyclosporine: Cyclosporine: IV over 2 hours or orally every 12 hours on days -1 to 100, followed by a taper if GVHD does not develop.

Allogenic stem cell transplant (ASCT): Allogenic stem cell transplant

Conditioning Chemotherapy: Fludarabine:30 mg/m2 per day IV infusion over 30 minutes, daily On days -6, -5, -4, and -3 Cyclophosphamide:1200 mg/m2 per day IV infusion over 2 hours on Days 6, -5, -4, -3 Mesna: 1200 mg/m2 per day IV infusion, Daily on days 6, -5,-4, and -3

FLAG: Fludarabine:25 mg/m2 per day IV over 30 minutes, Daily on days 1-5 Cytarabine: 2,000 mg/m2 IV over 4 hours,on Days 1, 2, 3, 4, 5 Filgrastim: 5 mcg/kg per day SC beginning 24 hours PRIOR to initiation of chemotherapy EPOCH-F: Fludarabine:25 mg/m2 per day IV infusion over 30 minutes, daily on days 1-4 Etoposide :50 mg/m2 per day continuous IV infusion over 24 hours on days 1-4 Doxorubicin:10 mg/m2/d

B - Cyclosporine (AC) Arm

Rituximab:375 mg/m2 IV, day 1 for patients with CD20-positive disease. Allogenic stem cell transplant (ASCT):Conditioning Chemotherapy:Fludarabine:30 mg/m2 per day IV infusion over 30 minutes, daily On days -6, -5, -4, and -3. Cyclophosphamide:1200 mg/m2 per day IV infusion over 2 hours on Days 6, -5, -4, -3.Mesna: 1200 mg/m2 per day IV infusion, Daily on days 6, -5,-4, and -3.Tacrolimus: 0.02 mg/kg, start day 3. Continue IV or PO. Taper will begin at day +63 if no acute GVHD then at day +119 and discontinue at day +180 as tolerated. Methotrexate: 5mg/m2 IV over 15 minutes on days 1, 3, 6, and 11. Sirolimus: 12 mg PO on days -3 to 63, followed by a taper if GVHD does not develop. Sirolimus: 12 mg PO on days -3 to 63, followed by a taper if GVHD does not develop.FLAG: Fludarabine:25 mg/m2 per day IV over 30 minutes, Daily on days 1-5. Cytarabine: 2,000 mg/m2 IV over 4 hours, on Days 1, 2, 3, 4, 5. Filgrastim: 5 mcg/kg per day SC beginning 24 hours PRIOR to initiation of chemotherapy

Tacrolimus, Methotrexate, Sirolimus (TMS) Arm

Rituximab375 mg/m2 IV, day 1 for pts with CD20-positive disease. Cyclosporine IV over 2 hrs or orally every 12 hrs on days -1-100, followed by a taper if GVHD does not develop. Allogenic stem cell transplant. Conditioning Chemotherapy Fludarabine:30 mg/m2 per day IV infusion over 30 min., daily on days -6, -5, -4, and -3. Cyclophosphamide1200 mg/m2 per day IV infusion over 2 hrs on Days 6, -5, -4, -3. Mesna1200 mg/m2 per day IV infusion, Daily on days 6, -5,-4, and -3. FLAG: Fludarabine25 mg/m2 per day IV over 30 min., Daily on days 1-5. Cytarabine 2,000 mg/m2 IV over 4 hrs, on Days 1, 2, 3, 4, 5. Filgrastim 5 mcg/kg per day SC beginning 24 hrs PRIOR to start of chemotherapy. EPOCH-F: Fludarabine25 mg/m2 per day IV infusion over 30 min., daily on days 1-4. Etoposide 50 mg/m2 per day continuous IV infusion over 24 hrs on days 1-4. Doxorubicin10 mg/m2/d. Grp 2 Alemtuzumab for 4 days starting 8 days before SCT + cyclosporine starting 1 day before SCT and continuing for 6 months.

Cyclosporine (AC) Arm

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Non Hodgkin's Lymphoma (NHL)

Hodgkin's Lymphoma (HL)

Chroni Lymphocytic Leukemia (CLL)

AML/MDS

Chronic Myeloid Leukemia (CML)

CTCL/PTCL

Acute Lymphoblastic Leukemia (ALL)

Multiple Myeloma (MM)

Other

Acute Myeloid Leukemia (AML)/Myelodysplastic Syndrome (MDS); Cutaneous T Cell Lymphoma (CTCL)/Peripheral T Cell Lymphoma (PTCL)

Histology

There were 89 participants in the study. 3 patients enrolled and their cancers progressed prior to randomization so they were taken off study. 3 of these participants went back into remission with additional chemo and were re-enrolled on the protocol and randomized. They are counted twice in the enrolment (e.g. 92) but only once in the Started row.

Dr. Steven Z. Pavletic

2 of 44 patients who completed the AC arm were transplanted after our cutoff for data analysis and are not included.

Percentage of Participants With Grade II-IV Acute Graft Versus Host Disease (GVHD)

Moderate or Severe cGVHD

Severe cGVHD

Percentage of Participants With Chronic Graft Versus Host Disease (cGVHD)

6 mo (TMS=28; AC= 28)

12 mo (TMS=25; AC= 21)

24 mo (TMS=18; AC= 13)

A few measurements were missed, one patient was not evaluable for technical reasons and removed from the analysis, but most of the decline was due to patients that had gone off study.

Recovery of Naïve Cluster of Differentiation 4 (CD4) T Cells

Recovery of Naïve Cluster of Differentiation 8 (CD8) T Cells

1 month

3 months

6 mo (TMS=7; AC= 9)

12 mo (TMS=7; AC=9)

Donor CD4 cells (TMS=8; AC=8)

Rituximab: 375 mg/m2 intravenous (IV), day 1 for patients (pts) with cluster of differentiation 20-positive disease. Allogenic stem cell transplant (txplt). Fludarabine:30 mg/m2 per day IV over 30 min. daily. On days -6, -5, -4, and -3. Cyclophosphamide:1200 mg/m2 per day IV over 2 hrs on Days 6, -5, -4, -3. Mesna:1200 mg/m2 per day IV, Daily on days 6, -5,-4, and -3.Tacrolimus: day -3 before txplt, 0.02 mg/kg/day CIV, then switch to an equivalent oral dose (when pts taking po) titrated for a goal level of 5-10 ng/ml; Sirolimus: loading dose of 12 mg p.o. on day -3 pre-txplt, 4 mg day -2 pre-txplt and titrated for levels 3-12 ng/ml; Methotrexate 5 mg/m2 IV on days +1, +3, +6, and +11 post txplt). Tacrolimus and sirolimus will be tapered at day +63, day +119 and day +180 post-txplt as tolerated. Fludarabine:25 mg/m2 per day IV over 30 minutes, Daily on days 1-5.Cytarabine: 2,000 mg/m2 IV over 4 hrs, on Days 1, 2, 3, 4, 5. Filgrastim: 5 mcg/kg per day SC beginning 24 hrs before chemo.

The original intention was to perform these assays on the first 10 pts within each arm. One pt died within the first mo., others died within the 1st yr. Not all donors gave consent for research analyses to be done on their cells, hence cells from those donors were not available.

Changes in Cluster of Differentiation 4 (CD4) T Cell Receptor Vbeta Repertoire

12 mo (TMS=7; AC= 9)

Donor CD8 cells (TMS=8; AC= 8)

Changes in CD8 T Cell Receptor Vbeta Repertoire

Percentage of Participants With Grade III-IV Acute Graft Versus Host Disease (GVHD)

Toxicities

B - Cyclosporine (AC Arm)

One myeloma patient had graft failure in the AC Arm. 2 of 44 patients who completed the AC arm were transplanted after our cutoff for data analysis and are not included.

Days to Engraftment of Neutrophils

Days to Engraftment of Platelets

Days to Engraftment of Lymphocytes

Overall Survival

B - Cyclosporine (C) Arm

Early Treatment Related Mortality

Percentage of Participants With Late Treatment Related Mortality

Following the focus on chronic graft-versus host disease (GVHD) as a primary outcome measure in 2011, this measure was not assessed.

Decline in Homeostatic Cytokine Interleukin 7 (IL-7) Post-Transplant

2 weeks

6 months

12 months

24 months

TMS Arm Rituximab: 375 mg/m2 IV, day 1 for patients with cluster of differentiation 20 (CD20)-positive disease Allogenic stem cell transplant (ASCT):Allogenic stem cell transplant Conditioning Chemotherapy:Fludarabine:30 mg/m2 per day IV infusion over 30 minutes, daily. On days -6, -5, -4, and -3 Cyclophosphamide:1200 mg/m2 per day IV infusion over 2 hours on Days 6, -5, -4, -3 Mesna:1200 mg/m2 per day IV infusion, Daily on days 6, -5,-4, and -3 TMS: Tacrolimus: 0.02 mg/kg, start day 3. Continue IV or PO. Taper will begin at day +63 if no acute GVHD then at day +119 and discontinue at day +180 as tolerated Methotrexate: 5 mg/m2 IV over 15 minutes on days 1, 3, 6, and 11 Sirolimus: 12 mg PO on days -3 to 63, followed by a taper if GVHD does not develop.

FLAG: Fludarabine:25 mg/m2 per day IV over 30 minutes, Daily on days 1-5 Cytarabine: 2,000 mg/m2 IV over 4 hours, on Days 1, 2, 3, 4, 5 Filgrastim: 5 mcg/kg per day SC beginning 24 hours PRIOR to initiation of chemotherapy

2 of 44 patients who completed the AC arm were transplanted after our cutoff for data analysis and are not included. A total of 5 completed participants did not contribute data due to missing samples, and participants who died and were not able to supply samples for the time points indicated.

Immune Reconstitution of Normal Killer (NK) Cells

Immune Reconstitution of Cluster of Differentiation 4 (CD4) T Cell Populations

Immune Reconstitution of Cluster of Differentiation 8 (CD8) T Cell Populations

Overall Study

Anti-Inflammatory Agents

Natriuretic Agents

Prednisone

Furosemide

Induction chemotherapy, then palifermin at escalating doses, then conditioning chemotherapy, then allogeneic stem cell transplant, then immunosuppression

Induction chemotherapy, then palifermin at the MTDdetermined in Phase 1, then conditioning chemotherapy, then allogeneic stem cell transplant, then immunosuppression

Rituximab: 375 mg/m2 IV, day 1 for patients with CD20-positive disease

Fludarabine:30 mg/m2 per day IV infusion over 30 minutes, daily On days -6, -5, -4, and -3; Cyclophosphamide:1200 mg/m2 per day IV infusion over 2 hours on Days 6, -5, -4, -3 Mesna: 1200 mg/m2 per day IV infusion, Daily on days 6, -5,-4, and -3 Furosemide: 20 mg IV flat dose on days -6, -5, -4, -3; Furosemide: 20 mg IV flat dose on days -6, -5, -4, -3

Conditioning chemotherapy

Tacrolimus: 0.02 mg/kg, start day 3. Continue IV or PO. Taper will begin at day +60 if no acute GVHD then at day +100 and discontinue at day +180 as tolerated. Methotrexate: 5 mg/m2 IV over 15 minutes on days 1, 3, 6, and 11. Sirolimus: 12 mg PO on days -3 to 60, followed by a taper if GVHD does not develop.

Fludarabine: 25 mg/m2 per day IV over 30 minutes, Daily on days 1-5 Cytarabine: 2,000 mg/m2 IV over 4 hours, on Days 1, 2, 3, 4, 5 Filgrastim: 5 mcg/kg per day SC beginning 24 hours PRIOR to initiation of chemotherapy

Fludarabine: 25 mg/m2 per day IV infusion over 30 minutes, daily on days 1-4. Etoposide: 50 mg/m2 per day continuous IV infusion over 24 hours on days 1-4. Doxorubicin: 10 mg/m2/day CIV, days 1-4. Vincristine: 0.4 mg/m2 per day continuous IV infusion over 24 hours daily on days 1-4 Cyclophosphamide: 750 mg/m2 IV infusion over 30 minutes on day 5 Prednisone: 60 mg/m2 per day PO daily on days 1-5. Filgrastim: 5 mcg/kg per day SC or IV.

Hematopoietic stem cell transplant

Escalating doses of palifermin given during transplant phase

Palifermin

Ashley E Carpenter

John Miller, M.D.

Background:

- In allogeneic stem cell transplantation (SCT), stem cells are taken from a donor and given to a recipient. Sometimes the recipient s immune system destroys the donor s cells. Or donor immune cells attack the recipient s tissues, called graft-versus-host disease (GVHD). This is less likely when the recipient and donor have similar human leukocyte antigens (HLA). Researchers want to see if the drug palifermin improves the results of allogeneic SCT from HLA-matched unrelated donors.

Objective:

- To see if high doses of palifermin before chemotherapy are safe, prevent chronic GVHD, and improve immune function after transplant.

Eligibility:

- Adults 18 years of age or older with blood or bone marrow cancer with no HLA-matched sibling, but with a possible HLA-matched donor.

Design:

* Participants will be screened with medical history, physical exam, and blood and urine tests. They will have scans and heart and lung exams.
* Before transplant, participants will:
* Have many tests and exams. These include blood tests throughout the study and bone marrow biopsy.
* Get a central line catheter if they do not have one.
* Have 1-3 rounds of chemotherapy.
* Take more tests to make sure they can have the transplant, including medical history, physical exam, and CT scan.
* Get palifermin by IV and more chemotherapy. They will get other drugs, some they will take for 6 months.
* Participants will get the SCT.
* After transplant, participants will:
* Be hospitalized at least 3-4 weeks.
* Have tests for GVHD at 60 days and 6 months. These include mouth and skin photos and biopsies.
* Stay near D.C. for 3 months.
* Visit NIH 5 times the first 2 years, then yearly. They may have scans and biopsies.

Background:

* Graft versus host disease (GVHD) and impaired immune reconstitution are major transplant complications and barriers to improving outcomes after allogeneic hematopoietic stem cell transplantation (alloHSCT) for hematologic malignancies. GVHD is initiated when donor T-cells become alloreactive against recipient major or minor histocompatibility antigens. This process may be exacerbated during the transplantation process by exposure of tissue antigens to donor T-lymphocytes after chemotherapy-induced injury.
* Palifermin, a recombinant keratinocyte growth factor-1 (KGF-1), imitates the actions of intrinsic KGF and binds to the FGF receptor 2b, which is expressed in the epidermis, oral mucosa, GI mucosa and urothelium, thereby increasing the regenerative capacity of these tissues. Palifermin has been shown to reduce the duration and severity of oral mucositis after intensive chemo-radiotherapy and autologous HSCT for hematologic cancers and is FDA approved. In pre-clinical studies, palifermin has been shown to have an effect on control of acute or chronic GVHD and immune reconstitution after alloHSCT. However, subsequent clinical studies in alloHSCT indicate that the dose and schedule of palifermin as currently

used in humans does not optimize its activity in terms of prevention of GVHD or thymus recovery following alloHSCT.

- We hypothesize that higher doses of palifermin in the immediate pre alloHSCT conditioning setting will lead to enhanced thymopoiesis, decreased chronic GVHD, and improved immune reconstitution. A dose escalation study is necessary to determine safe dosing levels in persons undergoing alloHSCT.

Objectives:

* The primary objective of the phase I portion is to assess the safety and tolerability of the administration of the recombinant keratinocyte growth factor (KGF) palifermin in alloHSCT using unrelated donor peripheral blood stem cells.
* The primary objective of the phase II portion is to determine the incidence of severe chronic GVHD after the addition of palifermin to TMS (tacrolimus, methotrexate and sirolimus) based GVHD prophylaxis delivered in the identical fashion to the NCI 07-C-0195 study.

Eligibility:

* Adults (greater than or equal to 18 years) with advanced or high risk hematologic malignancies (including AML, ALL, MDS, CLL, NHL, HL, CML, multiple myeloma, and MPN)who lack a suitable HLA-matched sibling donor.
* An unrelated donor matched at a minimum of 8 alleles (HLA-A,-B,-C, and DRB1) by high-resolution typing, identified through the National Marrow Donor Program.
* Karnofsky greater than or equal to 60 and acceptable organ functions.

Design:

* Patients will receive disease-specific induction chemotherapy (EPOCH-F/R or FLAG) prior to transplant as needed for disease control and immune depletion.
* All patients will receive an identical conditioning regimen consisting of cyclophosphamide 1200 mg/m\^2/day IV for 4 days and fludarabine 30 mg/m\^2/day for 4 days (transplant days -6 to -3).
* All patients will receive a peripheral blood stem cell product from an unrelated donor matched at HLA-A, -B, -C, -DRB1 (8/8) by high-resolution typing.
* Palifermin will be administered in a phase 1, open label design with the following proposed schedule:

  * Dose level 1: 180 mcg/kg on day -7
  * Dose level 2: 360 mcg/kg on day -7
  * Dose level 3: 540 mcg/kg on day -7
  * Dose level 4: 720 mcg/kg on day -7
* The phase I portion will be conducted in a standard 3+3 design; the maximum possible number of patients accrued to this portion will be 24.
* The maximum tolerated dose (MTD) from the phase I portion of the study will be used to conduct a phase II study. Total accrual on the phase II study will be 27 patients, including 3-6 patients treated at the MTD in the phase I portion of the study

Study of Palifermin (Kepivance) in Persons Undergoing Unrelated Donor Allogeneic Hematopoietic Cell Transplantation

A Phase I/II Open Label, Dose Escalation Study of Palifermin (Kepivance) in Persons Undergoing Unrelated Donor Allogeneic Hematopoietic Cell Transplantation

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Chemotherapy and Unrelated Donor Stem Cell Transplantation for Patients With Cancers of the Blood and Immune System	NCT00520130	Myelodysplastic... Hodgkin's Lymph... Non-Hodgkin's D... Acute Leukemia Multiple Myelom...	Rituximab Cyclosporine Allogenic stem ... Conditioning Ch... TMS FLAG EPOCH-F Alemtuzumab	18 Years - 74 Years	National Institutes of Health Clinical Center (CC)
Chemotherapy and Unrelated Donor Stem Cell Transplantation for Patients With Cancers of the Blood and Immune System	NCT00520130	Myelodysplastic... Hodgkin's Lymph... Non-Hodgkin's D... Acute Leukemia Multiple Myelom...	Rituximab Cyclosporine Allogenic stem ... Conditioning Ch... TMS FLAG EPOCH-F Alemtuzumab	18 Years - 74 Years	National Institutes of Health Clinical Center (CC)
Study of Palifermin (Kepivance) in Persons Undergoing Unrelated Donor Allogeneic Hematopoietic Cell Transplantation	NCT02356159	Myelodysplastic... Hodgkin's Lymph... Non-Hodgkin's L... Acute Leukemia Multiple Myelom...	Rituximab Conditioning ch... TMS FLAG EPOCH-F Hematopoietic s... Palifermin	18 Years -	National Institutes of Health Clinical Center (CC)

Spots Global Cancer Trial Database for flag

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Spots Global Cancer Trial Database for flag

Every month we try and update this database with for flag cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for flag cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.