Study of Palifermin (Kepivance) in Persons Undergoing Unrelated Donor Allogeneic Hematopoietic Cell Transplantation
- Conditions
- Myelodysplastic SyndromesHodgkin's LymphomaNon-Hodgkin's LymphomaAcute LeukemiaMultiple Myeloma
- Interventions
- Drug: Conditioning chemotherapyDrug: TMSDrug: FLAGDrug: EPOCH-FProcedure: Hematopoietic stem cell transplantOther: IV SalineDiagnostic Test: ECGDiagnostic Test: ECHODiagnostic Test: MUGADiagnostic Test: DEXADiagnostic Test: CT chestDiagnostic Test: PETDiagnostic Test: MRIProcedure: BM aspirateProcedure: BM biopsyProcedure: Lumbar puncture
- 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 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.
- 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 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
Recruitment & Eligibility
- Status
- COMPLETED
- 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 Food and Drug Administration (FDA) guidelines may still donate peripheral blood stem cells (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 10^6 cluster of differentiation 34 (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 transplant related 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.
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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 m^2 (induction phase only)
- (((140-age)*mass(kg))/(72*serum creatinine (mg/dL))) x 1.73 m^2/patients body surface area (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 upper limit of normal (ULN)
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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, myelodysplastic syndrome (MDS)/refractory anemia with excess blasts (RAEB)-I or II or chronic myeloid leukemia (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 central nervous system (CNS) involvement by malignancy (patients with known positive cerebrospinal fluid (CSF) cytology or parenchymal lesions visible by computed tomography (CT) or magnetic resonance imaging (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).
- Human immunodeficiency virus (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 - Palifermin FLAG Induction chemotherapy, then palifermin at escalating doses, then conditioning chemotherapy, then allogeneic stem cell transplant, then immunosuppression. 1/Phase 1: Dose Escalation Arm - Palifermin 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 - Palifermin Hematopoietic stem cell transplant Induction chemotherapy, then palifermin at escalating doses, then conditioning chemotherapy, then allogeneic stem cell transplant, then immunosuppression. 1/Phase 1: Dose Escalation Arm - Palifermin Palifermin Induction chemotherapy, then palifermin at escalating doses, then conditioning chemotherapy, then allogeneic stem cell transplant, then immunosuppression. 1/Phase 1: Dose Escalation Arm - Palifermin Acetaminophen Induction chemotherapy, then palifermin at escalating doses, then conditioning chemotherapy, then allogeneic stem cell transplant, then immunosuppression. 1/Phase 1: Dose Escalation Arm - Palifermin Diphenhydramine Induction chemotherapy, then palifermin at escalating doses, then conditioning chemotherapy, then allogeneic stem cell transplant, then immunosuppression. 1/Phase 1: Dose Escalation Arm - Palifermin Prednisone Induction chemotherapy, then palifermin at escalating doses, then conditioning chemotherapy, then allogeneic stem cell transplant, then immunosuppression. 1/Phase 1: Dose Escalation Arm - Palifermin ECG Induction chemotherapy, then palifermin at escalating doses, then conditioning chemotherapy, then allogeneic stem cell transplant, then immunosuppression. 1/Phase 1: Dose Escalation Arm - Palifermin ECHO Induction chemotherapy, then palifermin at escalating doses, then conditioning chemotherapy, then allogeneic stem cell transplant, then immunosuppression. 1/Phase 1: Dose Escalation Arm - Palifermin Epinephrine Induction chemotherapy, then palifermin at escalating doses, then conditioning chemotherapy, then allogeneic stem cell transplant, then immunosuppression. 1/Phase 1: Dose Escalation Arm - Palifermin IV Saline Induction chemotherapy, then palifermin at escalating doses, then conditioning chemotherapy, then allogeneic stem cell transplant, then immunosuppression. 1/Phase 1: Dose Escalation Arm - Palifermin MUGA Induction chemotherapy, then palifermin at escalating doses, then conditioning chemotherapy, then allogeneic stem cell transplant, then immunosuppression. 1/Phase 1: Dose Escalation Arm - Palifermin BM aspirate Induction chemotherapy, then palifermin at escalating doses, then conditioning chemotherapy, then allogeneic stem cell transplant, then immunosuppression. 1/Phase 1: Dose Escalation Arm - Palifermin BM biopsy Induction chemotherapy, then palifermin at escalating doses, then conditioning chemotherapy, then allogeneic stem cell transplant, then immunosuppression. 1/Phase 1: Dose Escalation Arm - Palifermin DEXA Induction chemotherapy, then palifermin at escalating doses, then conditioning chemotherapy, then allogeneic stem cell transplant, then immunosuppression. 1/Phase 1: Dose Escalation Arm - Palifermin CT chest Induction chemotherapy, then palifermin at escalating doses, then conditioning chemotherapy, then allogeneic stem cell transplant, then immunosuppression. 1/Phase 1: Dose Escalation Arm - Palifermin PET Induction chemotherapy, then palifermin at escalating doses, then conditioning chemotherapy, then allogeneic stem cell transplant, then immunosuppression. 1/Phase 1: Dose Escalation Arm - Palifermin MRI Induction chemotherapy, then palifermin at escalating doses, then conditioning chemotherapy, then allogeneic stem cell transplant, then immunosuppression. 1/Phase 1: Dose Escalation Arm - Palifermin Lumbar puncture Induction chemotherapy, then palifermin at escalating doses, then conditioning chemotherapy, then allogeneic stem cell transplant, then immunosuppression. 2/Phase II Arm - Palifermin at the Recommended Phase 2 Dose Rituximab Induction chemotherapy, then palifermin at the recommended phase 2 dose determined in Phase 1, then conditioning chemotherapy, then allogeneic stem cell transplant, then immunosuppression. 2/Phase II Arm - Palifermin at the Recommended Phase 2 Dose Conditioning chemotherapy Induction chemotherapy, then palifermin at the recommended phase 2 dose determined in Phase 1, then conditioning chemotherapy, then allogeneic stem cell transplant, then immunosuppression. 2/Phase II Arm - Palifermin at the Recommended Phase 2 Dose TMS Induction chemotherapy, then palifermin at the recommended phase 2 dose determined in Phase 1, then conditioning chemotherapy, then allogeneic stem cell transplant, then immunosuppression. 2/Phase II Arm - Palifermin at the Recommended Phase 2 Dose FLAG Induction chemotherapy, then palifermin at the recommended phase 2 dose determined in Phase 1, then conditioning chemotherapy, then allogeneic stem cell transplant, then immunosuppression. 2/Phase II Arm - Palifermin at the Recommended Phase 2 Dose PET Induction chemotherapy, then palifermin at the recommended phase 2 dose determined in Phase 1, then conditioning chemotherapy, then allogeneic stem cell transplant, then immunosuppression. 2/Phase II Arm - Palifermin at the Recommended Phase 2 Dose MRI Induction chemotherapy, then palifermin at the recommended phase 2 dose determined in Phase 1, then conditioning chemotherapy, then allogeneic stem cell transplant, then immunosuppression. 2/Phase II Arm - Palifermin at the Recommended Phase 2 Dose BM aspirate Induction chemotherapy, then palifermin at the recommended phase 2 dose determined in Phase 1, then conditioning chemotherapy, then allogeneic stem cell transplant, then immunosuppression. 2/Phase II Arm - Palifermin at the Recommended Phase 2 Dose BM biopsy Induction chemotherapy, then palifermin at the recommended phase 2 dose determined in Phase 1, then conditioning chemotherapy, then allogeneic stem cell transplant, then immunosuppression. 2/Phase II Arm - Palifermin at the Recommended Phase 2 Dose Lumbar puncture Induction chemotherapy, then palifermin at the recommended phase 2 dose determined in Phase 1, then conditioning chemotherapy, then allogeneic stem cell transplant, then immunosuppression. 1/Phase 1: Dose Escalation Arm - Palifermin Rituximab Induction chemotherapy, then palifermin at escalating doses, then conditioning chemotherapy, then allogeneic stem cell transplant, then immunosuppression. 1/Phase 1: Dose Escalation Arm - Palifermin 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 - Palifermin TMS Induction chemotherapy, then palifermin at escalating doses, then conditioning chemotherapy, then allogeneic stem cell transplant, then immunosuppression. 2/Phase II Arm - Palifermin at the Recommended Phase 2 Dose EPOCH-F Induction chemotherapy, then palifermin at the recommended phase 2 dose determined in Phase 1, then conditioning chemotherapy, then allogeneic stem cell transplant, then immunosuppression. 2/Phase II Arm - Palifermin at the Recommended Phase 2 Dose Hematopoietic stem cell transplant Induction chemotherapy, then palifermin at the recommended phase 2 dose determined in Phase 1, then conditioning chemotherapy, then allogeneic stem cell transplant, then immunosuppression. 2/Phase II Arm - Palifermin at the Recommended Phase 2 Dose Palifermin Induction chemotherapy, then palifermin at the recommended phase 2 dose determined in Phase 1, then conditioning chemotherapy, then allogeneic stem cell transplant, then immunosuppression. 2/Phase II Arm - Palifermin at the Recommended Phase 2 Dose Acetaminophen Induction chemotherapy, then palifermin at the recommended phase 2 dose determined in Phase 1, then conditioning chemotherapy, then allogeneic stem cell transplant, then immunosuppression. 2/Phase II Arm - Palifermin at the Recommended Phase 2 Dose Diphenhydramine Induction chemotherapy, then palifermin at the recommended phase 2 dose determined in Phase 1, then conditioning chemotherapy, then allogeneic stem cell transplant, then immunosuppression. 2/Phase II Arm - Palifermin at the Recommended Phase 2 Dose Prednisone Induction chemotherapy, then palifermin at the recommended phase 2 dose determined in Phase 1, then conditioning chemotherapy, then allogeneic stem cell transplant, then immunosuppression. 2/Phase II Arm - Palifermin at the Recommended Phase 2 Dose Epinephrine Induction chemotherapy, then palifermin at the recommended phase 2 dose determined in Phase 1, then conditioning chemotherapy, then allogeneic stem cell transplant, then immunosuppression. 2/Phase II Arm - Palifermin at the Recommended Phase 2 Dose IV Saline Induction chemotherapy, then palifermin at the recommended phase 2 dose determined in Phase 1, then conditioning chemotherapy, then allogeneic stem cell transplant, then immunosuppression. 2/Phase II Arm - Palifermin at the Recommended Phase 2 Dose ECG Induction chemotherapy, then palifermin at the recommended phase 2 dose determined in Phase 1, then conditioning chemotherapy, then allogeneic stem cell transplant, then immunosuppression. 2/Phase II Arm - Palifermin at the Recommended Phase 2 Dose ECHO Induction chemotherapy, then palifermin at the recommended phase 2 dose determined in Phase 1, then conditioning chemotherapy, then allogeneic stem cell transplant, then immunosuppression. 2/Phase II Arm - Palifermin at the Recommended Phase 2 Dose MUGA Induction chemotherapy, then palifermin at the recommended phase 2 dose determined in Phase 1, then conditioning chemotherapy, then allogeneic stem cell transplant, then immunosuppression. 2/Phase II Arm - Palifermin at the Recommended Phase 2 Dose DEXA Induction chemotherapy, then palifermin at the recommended phase 2 dose determined in Phase 1, then conditioning chemotherapy, then allogeneic stem cell transplant, then immunosuppression. 2/Phase II Arm - Palifermin at the Recommended Phase 2 Dose CT chest Induction chemotherapy, then palifermin at the recommended phase 2 dose determined in Phase 1, then conditioning chemotherapy, then allogeneic stem cell transplant, then immunosuppression.
- Primary Outcome Measures
Name Time Method Phase II: Estimated Percent of Participants Who Experienced Severe Chronic Graft Versus Host Disease (GVHD) 60 months 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.
Phase I: Maximum Tolerated Dose (MTD) of Palifermin Approximately 30-day post-transplant 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.
Phase 1: Number of Participants With a Dose-limiting Toxicity (DLT) ≤day 30 post-transplant 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.
- Secondary Outcome Measures
Name Time Method
Trial Locations
- Locations (2)
National Institutes of Health Clinical Center
🇺🇸Bethesda, Maryland, United States
National Marrow Donor Program
🇺🇸Minneapolis, Minnesota, United States
National Institutes of Health Clinical Center🇺🇸Bethesda, Maryland, United States