Chemotherapy, Total Body Irradiation, and Post-Transplant Cyclophosphamide in Reducing Rates of Graft Versus Host Disease in Patients with Hematologic Malignancies Undergoing Donor Stem Cell Transplant
This phase Ib / II trial studies how well chemotherapy, total body irradiation, and post-transplant cyclophosphamide work in reducing rates of graft versus host disease in patients with hematologic malignancies undergoing a donor stem cell transplant. Drugs used in the chemotherapy, such as fludarabine phosphate and melphalan hydrochloride, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving chemotherapy and total-body irradiation before a donor stem cell transplant helps stop the growth of cells in the bone marrow, including normal blood-forming cells (stem cells) and cancer cells. When the healthy stem cells from a donor are infused into the patient, they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells (called graft versus host disease). Giving cyclophosphamide after the transplant may stop this from happening.
- The patient must have a diagnosis of one of the following (one must be yes): * Acute myeloid leukemia (AML) * Acute lymphoblastic leukemia (ALL) * Chronic lymphocytic leukemia (CLL) * Chronic myelogenous leukemia (CML) (chronic phase intolerant or unresponsive to tyrosine kinase inhibitors, history of accelerated phase, or history of blast crisis) * Myelodysplastic syndrome (MDS) * Non-Hodgkin lymphoma (NHL) * Hodgkin lymphoma (HL) (received and failed frontline therapy or failed autologous transplantation or inability to collect enough peripheral blood stem cells [PBSC] for autologous hematopoietic cell transplant [auto-HCT]) * Multiple myeloma (MM) * Severe aplastic anemia
- Histocompatible donor identified: * Related donor 5/6 or better (A, B, DRB1) * Unrelated donor 7/8 or better (A, B, C and DRB1)
- The following are eligible for study inclusion: * AML may be in morphologic complete remission (CR) or complete remission with incomplete hematologic recovery (CRi) (MRD positive is allowed) * ALL may be in morphologic CR or CRi (MRD positive is allowed) * CLL may be in morphologic CR or CRi (MRD positive is allowed) * CML must be in chronic phase (MRD positive is allowed) * MDS- patients with MDS only require =< 5% myeloblasts on bone marrow evaluation; there is no requirement for platelet or neutrophil recovery * NHL must be in CR * HL must be in CR * MM may be in very good partial response (VGPR) * Severe aplastic anemia (SAA) do not have disease response requirements; however, if the patient has a mismatched donor, the patient must have had prior therapy with antithymocyte globulin (ATG)
- Have a Karnofsky performance status score of >= 50%
- Diffusing capacity of the lung for carbon monoxide (DLCO) >= 40% predicted, corrected for hemoglobin and/or alveolar ventilation
- Left ventricular ejection fraction >= 40%
- Bilirubin =< 3 x upper limit of normal
- Liver alkaline phosphatase =< 3 x upper limit of normal
- Serum glutamic-oxaloacetic transaminase (SGOT) or serum glutamate pyruvate transaminase (SGPT) =< 3 x upper limit of normal
- Calculated creatinine clearance >= 40 cc/min by the modified Cockcroft-Gault formula
- Patient must be cleared pre-transplant by Radiation Oncology to be able to receive 400 cGy
- Participants of child-bearing potential must agree to use adequate contraceptive methods (e.g., hormonal or barrier method of birth control; abstinence) prior to study entry; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately
- Patients who have failed a prior autologous or allogeneic transplant are eligible; however, at least 6 months must have elapsed between the start of this reduced intensity conditioning regimen and the last transplant if patient had a prior autologous or allogeneic bone marrow transplant (BMT)
- At least 2 weeks since prior chemotherapy, radiation treatment and/or surgery; small molecules and targeted agents are allowed up to 24 hours prior to start of conditioning regimen at physician discretion
- Participant or legal representative must understand the investigational nature of this study and sign an Independent Ethics Committee/Institutional Review Board approved written informed consent form prior to receiving any study related procedure
- MDS with moderate to severe myelofibrosis within 60 days prior to transplant
- Presence of human leukocyte antigen (HLA) antibodies to the donor within 60 days prior to transplant
- Uncontrolled central nervous system (CNS) disease (for hematologic malignancies)
- Patients who in the opinion of the treating physician are unlikely to comply with the restrictions of allogeneic stem cell transplantation based on formal psychosocial screening; (i.e., serious, uncontrolled psychiatric illness/social situations that would limit compliance with study requirements)
- Uncontrolled diabetes mellitus, cardiovascular disease, active serious infection or other condition which, in the opinion of treating physician, would make this protocol unreasonably hazardous for the patient
- Known human immunodeficiency virus (HIV) positive
- Pregnant or nursing female participants
- Unwilling or unable to follow protocol requirements
- Any condition which in the Investigator’s opinion deems the participant an unsuitable candidate to receive study intervention
Locations & Contacts
Contact: Christine M. Ho
Trial Objectives and Outline
I. To determine the cumulative incidence of extensive chronic graft versus host disease (GVHD) at 1 year after transplantation utilizing the novel conditioning/GVHD prophylactic regimen for patients undergoing allogeneic hematopoietic cell transplantation, in patients who do not progress before day 100.
I. To evaluate clinical response, engraftment rate, progression-free survival (PFS) at one year and, overall survival (OS).
II. To determine the cumulative incidence of relapse.
III. To evaluate the day 100 transplant-related mortality rate.
IV. To determine the cumulative incidence of grade III-IV acute GVHD.
OUTLINE: This is a dose-escalation study of melphalan hydrochloride.
CONDITIONING REGIMEN: Patients receive fludarabine phosphate intravenously (IV) over 30 minutes on days -5 to -2 and melphalan hydrochloride IV over 30 minutes on day -2. Patients undergo total body irradiation (TBI) on day -1.
STEM CELL INFUSION: Patients undergo allogeneic hematopoietic stem cell transplant on day 0.
GVHD PROPHYLAXIS REGIMEN: Patients receive cyclophosphamide IV over 2 hours on days 3-4, mycophenolate mofetil IV over 2 hours on days 5-35, and sirolimus orally (PO) on days 5-180 with a taper beginning on day 100 for up to 6 months post-transplant.
After completion of study treatment, patients are followed up for 12 months and then annually thereafter for 4 years.
Trial Phase & Type
Roswell Park Cancer Institute
Christine M. Ho
Secondary IDs NCI-2017-01069
Clinicaltrials.gov ID NCT03192397