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 donors' 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 donor, but with a HLA-matched unrelated donor. Description of Research Study: * 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. * Have more tests to make sure they can have the transplant, including medical history, physical exam, blood tests, disease specific restaging. * Get palifermin by intravenous (IV) and conditioning chemotherapy to prepare for hematopoietic stem cell transplantation (HSCT). They will get other drugs; some they will take at least 6 months. * Participants will get the HSCT. * After transplant, participants will: * Be hospitalized at least 3-4 weeks. * Monitored at least weekly for the first 100 days. * Stay near District of Columbia (D.C). for approximately 100 days post-transplant. * After 100 days post-transplant - visit National Institutes of Health (NIH) 5 times the first 2 years, then yearly until 5 years post-transplant. * Additional tests/procedures may be performed to monitor safety, response to transplant, side effects.
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 Fibroblast growth factor (FGF) receptor 2b, which is expressed in the epidermis, oral mucosa, gastrointestinal (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 Food and Drug Administration (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 acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), myelodysplastic syndrome (MDS), chronic lymphocytic leukemia (CLL), non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL), chronic myeloid leukemia (CML), multiple myeloma, and myeloproliferative neoplasm (MPN) who lack a suitable human leukocyte antigens (HLA)-matched sibling donor. * An unrelated donor matched at a minimum of 8 alleles (HLA-A,-B,-C, and major histocompatibility complex, class II, DR beta 1 (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 etoposide phosphate, prednisone, vincristine sulfate, cyclophosphamide, and doxorubicin hydrochloride with fludarabine and rituximab (EPOCH-F/R or fludararbine, ara-c, granulocyte colony-stimulating factor (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 intravenous (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 Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
34
Rituximab: 375 mg/m\^2 intravenous (IV) day 1 for patients with cluster of differentiation 20 (CD20)-positive disease.
Fludarabine:30 mg/m\^2 per day intravenous (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 Furosemide: 20 mg IV flat dose on days -6, -5, -4, -3; Furosemide: 20 mg IV flat dose on days -6, -5, -4, -3.
Tacrolimus: 0.02 mg/kg, start day 3. Continue intravenous (IV) or by mouth (PO). Taper will begin at day +60 if no acute graft-versus-host disease (GVHD) then at day +100 and discontinue at day +180 as tolerated. Methotrexate: 5 mg/m\^2 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/m\^2 per day intravenous (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.
Fludarabine: 25 mg/m\^2 per day intravenous (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 continuous intravenous (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. Prednisone: 60 mg/m\^2 per day by mouth (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.
Before each infusion of rituximab as indicated.
Before each infusion of rituximab as indicated.
For engraftment syndrome.
Emergency medication as indicated.
Before each infusion of rituximab as indicated.
As indicated.
As indicated.
As indicated.
As indicated.
As indicated.
As indicated.
As indicated.
As indicated.
As indicated.
As indicated.
National Institutes of Health Clinical Center
Bethesda, Maryland, United States
National Marrow Donor Program
Minneapolis, Minnesota, United States
Phase II: Estimated Percent of Participants Who Experienced Severe Chronic Graft Versus Host Disease (GVHD)
The estimated percent of participants who experienced severe chronic graft versus host disease (GVHD) was assessed by the 1994 Consensus Conference Working Criteria. Severe GVHD is defined using the Global Staging per 2014 National Institutes of Health (NIH) Consensus Criteria for chronic GVHD.
Time frame: 60 months
Phase I: Maximum Tolerated Dose (MTD) of Palifermin
MTD is defined as the dose level at which no more than 1 (of ≤ 6) participants who experience dose-limiting toxicity (DLT), and the dose below that at which at least 2 (of ≤ 6) participants have a DLT as a result of the drug. A DLT is non-relapse mortality before day 30 post transplantation regardless of attribution to palifermin. and non-hematologic grade 4 (life-threatening) adverse events within 14 days after treatment with palifermin possibly related to drug.
Time frame: Approximately 30-day post-transplant
Phase 1: Number of Participants With a Dose-limiting Toxicity (DLT)
A DLT is non-relapse mortality before day 30 post transplantation regardless of attribution to palifermin. Persons who expire from malignancy related causes are not considered DLTs; and non-hematologic Common Terminology Criteria for Adverse Events (CTCAE) ≥ grade 4 adverse events (AEs), occurring within 14 days after administration of palifermin that are determined by the investigator to be at least possibly related to the study drug. An isolated laboratory value is not considered an AE unless it meets the guidelines. Note: Participants will not be removed from study therapy due to palifermin toxicity as only 1 dose is administered. DLT criteria are established only to determine dose levels for subsequent participants.
Time frame: ≤day 30 post-transplant
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