Study of Palifermin (Kepivance) in Persons Undergoing Unrelated Donor Allogeneic Hematopoietic Cell Transplantation
- Conditions
- Hodgkin's LymphomaNon-Hodgkin's LymphomaMyelodysplastic SyndromeMultiple MyelomaAcute Leukemia
- Interventions
- Drug: Conditioning chemotherapyDrug: TMSDrug: FLAGDrug: EPOCH-FProcedure: Hematopoietic stem cell transplant
- Registration Number
- NCT02356159
- Lead Sponsor
- National Cancer Institute (NCI)
- Brief Summary
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.
- Detailed Description
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
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 34
Verification of donor eligibility (clearance must be received from the NMDP)
-
Donors are evaluated by NMDP affiliated donor centers per NMDP Standards .
- Donors who are medically suitable, but ineligible by FDA guidelines may still donate PBSC with documentation of urgent medical need by the PI.
- Patients who receive stem cell products from ineligible donors will be informed of any increase in risk of transfusion-related diseases prior to initiation of conditioning chemotherapy.
-
Donors who are ineligible or unwilling to donate bone marrow will not be eligible to donate to study recipients. However, in the event that the patient has already begun conditioning chemotherapy and a donor PBSC collection is terminated early for donor-related medical concerns, a bone marrow graft may be infused. Should this occur, the recipient will continue to be managed on this protocol for all transplant-related care and complications. Patient will stay on study but clinical outcomes will not be eligible for the statistics and end point calculations.
-
Inadequate stem cell collection from the selected donor is defined as less than or equal to 2 x 106 CD34+ cells/kg. In most cases, donor cell collections are infused fresh. If a fresh collection is found to have an inadequate cell count, the cells will still be infused, but the recipient will be removed from the study, and managed clinically for all transplantrelated care and complications on this protocol. If the patient fails to engraft, the donor may be requested for a second collection or an emergency bone marrow harvest at the discretion of the PI and NMDP Medical Director. In the event of an inadequate collection obtained prior to patient conditioning, the donor may be asked to donate a second time, or another eligible donor may be requested.
-
Renal and hepatic function continues to meet eligibility criteria, reassessed as follows:
- 24 hour creatinine clearance or calculated (using the Cockcroft-Gault formula) creatinine clearance > 60 mL/min/1.73 m2 (induction phase only)
- (((140-age)*mass(kg))/(72*serum creatinine (mg/dL))) x 1.73 m2/patients BSA
- If the patient is female, multiply the above by 0.85
- In patients with suspected liver disease, bilirubin must be less than or equal to 2.5 mg/dL, AST and ALT must be less than or equal to 2.5 times institutional ULN
-
The malignancy must be restaged prior to research phase and must not have progressed during induction chemotherapy (stable disease or better). Persons with acute leukemia, MDS/RAEB-I or II or CML with previous accelerated or blast phase must have <5% blasts in the bone marrow. Persons with chronic phase CML may have up to 10% blasts in the bone marrow.
EXCLUSION CRITERIA (applies to all phases of this protocol) :
- Active infection that is not responding to antimicrobial therapy.
- Active CNS involvement by malignancy (patients with known positive CSF cytology or parenchymal lesions visible by CT or MRI).
- Previous other malignancies unless they have undergone curative intent therapy for that malignancy and (1) have had no evidence of that disease for 5 years, and/or (2) be deemed at low risk for recurrence (less than or equal to 20% at 5 years).
- HIV positive patients are ineligible as allogeneic stem cell transplant is not yet a proven approach in this patient population, and patients are at increased risk of lethal infections when treated with marrow suppressive therapy.
- Pregnant women are excluded from this study because palifermin has been shown to be embryotoxic and fetotoxic in animal studies. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with palifermin, breastfeeding should be discontinued for the duration of active study therapy. These potential risks may also apply to other agents used in this study.
- History of psychiatric disorder or any other condition which may compromise compliance with transplant protocol or expose patient to unnecessary risk as determined by principal investigator or lead associate investigator.
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description 1/Phase 1: Dose escalation arm Conditioning chemotherapy Induction chemotherapy, then palifermin at escalating doses, then conditioning chemotherapy, then allogeneic stem cell transplant, then immunosuppression 1/Phase 1: Dose escalation arm TMS Induction chemotherapy, then palifermin at escalating doses, then conditioning chemotherapy, then allogeneic stem cell transplant, then immunosuppression 1/Phase 1: Dose escalation arm FLAG Induction chemotherapy, then palifermin at escalating doses, then conditioning chemotherapy, then allogeneic stem cell transplant, then immunosuppression 1/Phase 1: Dose escalation arm EPOCH-F Induction chemotherapy, then palifermin at escalating doses, then conditioning chemotherapy, then allogeneic stem cell transplant, then immunosuppression 1/Phase 1: Dose escalation arm Hematopoietic stem cell transplant Induction chemotherapy, then palifermin at escalating doses, then conditioning chemotherapy, then allogeneic stem cell transplant, then immunosuppression 2/ Phase II arm Conditioning chemotherapy Induction chemotherapy, then palifermin at the MTDdetermined in Phase 1, then conditioning chemotherapy, then allogeneic stem cell transplant, then immunosuppression 2/ Phase II arm TMS Induction chemotherapy, then palifermin at the MTDdetermined in Phase 1, then conditioning chemotherapy, then allogeneic stem cell transplant, then immunosuppression 2/ Phase II arm FLAG Induction chemotherapy, then palifermin at the MTDdetermined in Phase 1, then conditioning chemotherapy, then allogeneic stem cell transplant, then immunosuppression 2/ Phase II arm EPOCH-F Induction chemotherapy, then palifermin at the MTDdetermined in Phase 1, then conditioning chemotherapy, then allogeneic stem cell transplant, then immunosuppression 2/ Phase II arm Hematopoietic stem cell transplant Induction chemotherapy, then palifermin at the MTDdetermined in Phase 1, then conditioning chemotherapy, then allogeneic stem cell transplant, then immunosuppression 1/Phase 1: Dose escalation arm Rituximab Induction chemotherapy, then palifermin at escalating doses, then conditioning chemotherapy, then allogeneic stem cell transplant, then immunosuppression 2/ Phase II arm Rituximab Induction chemotherapy, then palifermin at the MTDdetermined in Phase 1, then conditioning chemotherapy, then allogeneic stem cell transplant, then immunosuppression 1/Phase 1: Dose escalation arm Palifermin Induction chemotherapy, then palifermin at escalating doses, then conditioning chemotherapy, then allogeneic stem cell transplant, then immunosuppression 2/ Phase II arm Palifermin Induction chemotherapy, then palifermin at the MTDdetermined in Phase 1, then conditioning chemotherapy, then allogeneic stem cell transplant, then immunosuppression
- Primary Outcome Measures
Name Time Method For Phase II portion: to determine the incidence of severe chronic GVHD 60 months Frequency of GVHD occurrence.
For Phase I:To assess the safety and tolerability 1 year Safety assessment.
- Secondary Outcome Measures
Name Time Method
Trial Locations
- Locations (2)
National Marrow Donor Program
🇺🇸Minneapolis, Minnesota, United States
National Institutes of Health Clinical Center
🇺🇸Bethesda, Maryland, United States