Cyclophosphamide and Bendamustine after Donor Bone Marrow Transplant in Preventing GVHD in Patients with Leukemia or Lymphoma
This phase I/Ib trial is to find out the best dose, possible benefits and/or side effects of bendamustine when given together with cyclophosphamide after donor bone marrow transplant and to see how well they work in preventing graft versus host disease (GVHD) in patients with leukemia or lymphoma. Sometimes the transplanted cells from a donor can attack the body's normal cells (called graft-versus-host disease). Giving bendamustine and cyclophosphamide after the transplant may stop this from happening.
Inclusion Criteria
- Be willing and able to provide written consent/assent for the trial
- Require a bone marrow transplant
- Diagnosed with one of the following high-risk malignancies, which require hematopoietic cell transplant (HCT) but do not have a readily available human leukocyte antigen (HLA)-matched (8/8) related or unrelated donor * High risk acute lymphoblastic leukemia (ALL) in first complete remission (CR1) or greater * High risk acute myelogenous leukemia (AML) in CR1 or greater * High risk undifferentiated acute leukemia * High risk myelodysplastic syndrome (MDS) * Chronic myelogenous leukemia (CML) failing or intolerant to tyrosine kinase inhibitors (TKIs) * Lymphoma, (Hodgkin and non-Hodgkin lymphoma [NHL] including marginal zone, follicular lymphoma, chemotherapy-sensitive large-cell, mantle cell lymphoma, gray zone, and Burkitt’s lymphoma in remission)
- At least one haploidentical (5/10 antigen mismatched) related donor is available for bone marrow harvest * Molecular based HLA typing for the HLA-A, -B, -Cw, -DRB1 and -DQB1 loci to the resolution is needed to establish haploidentity * A minimum match of 5/10 is required * No availability of an 8/8 HLA-matched related or unrelated donor or clinical urgency for transplant (e.g., needed within 4-8 weeks) at which time an acceptable unrelated donor will not be available
- DONOR: HLA-haploidentical first-degree relatives of the patient, including biological parents, siblings, or children, or half-siblings
- DONOR: Weight > 25 kg
- DONOR: Age > 8 and < 55 years
- DONOR: Ability of donors < 18 years of age to undergo bone marrow harvest
- DONOR: Cardiac, renal, pulmonary, and hepatic function within normal limits
- DONOR: Complete blood count (CBC) with differential and platelet count within normal limits, and CMP within normal limits as deemed acceptable by the principal investigator and provider evaluating donor
- IMMUNE RECONSTITUTION STUDY ONLY: Decline to participate in the main trial, or main trial closed to accrual due to safety review
- IMMUNE RECONSTITUTION STUDY ONLY: Received haploidentical BMT with the current standard of two days of PT-CY (and no PT-BEN)
- IMMUNE RECONSTITUTION STUDY ONLY: Be willing and able to provide written consent/assent for the immune reconstitution portion of the trial only
- IMMUNE RECONSTITUTION STUDY ONLY: Between 4 and 30 years old
- IMMUNE RECONSTITUTION STUDY ONLY: Diagnosed with one of the following high-risk malignancies, which require HCT but do not have an available HLA-matched (8/8) related or unrelated donor * High risk acute lymphoblastic leukemia (ALL) in CR1 or greater * High risk acute myelogenous leukemia (AML) in CR1 or greater * High risk myelodysplastic syndrome (MDS) * Chronic myelogenous leukemia (CML) failing or intolerant to TKIs * Lymphoma, (Hodgkin and NHL including marginal zone, follicular lymphoma, chemotherapy-sensitive large-cell, mantle cell lymphoma, gray zone, and Burkitt's lymphoma in remission
- IMMUNE RECONSTITUTION STUDY ONLY: At least one haploidentical (5/10 antigen mismatched) related donor is available for bone marrow harvest * Molecular based HLA typing for the HLA-A, -B, -Cw, -DRB1 and -DQB1 loci to the resolution is needed to establish haploidentity * A minimum match of 5/10 is required * No availability of an 8/8 HLA-matched related or unrelated donor or clinical urgency for transplant (e.g., needed within 4-8 weeks) at which time an acceptable unrelated donor will not be available
Exclusion Criteria
- Refractory acute leukemia or progressive disease
- Untreated or progressive central nervous system leukemia
- Refractory to chemotherapy lymphoma
- Co-morbidities precluding patient's ability to tolerate BMT
- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) > 5 x upper limit of normal (ULN)
- Bilirubin > 2 x ULN
- Creatinine greater than > 2 x ULN for age or creatinine clearance/glomerular filtration rate (GFR) < 40 ml/min/1.73 m^2
- Diffusion capacity of the lung for carbon monoxide (DLCO) < 40% of normal or oxygen saturation (O2 Sat) < 92%
- Left ventricular ejection fraction < 35%
- Active infection at time of hospital admission of haploidentical (Haplo) BMT
- Documented fungal infection or highly suspected and receiving treatment for presumed fungal infection within 3 months of BMT
- Human immunodeficiency virus (HIV) positive
- Karnofsky score (adults) < 60% or Lansky score < 50% (pediatrics)
- Positive serum or urine pregnancy test for girls post menarche or women of childbearing age
- Severe psychiatric illness or mental deficiency making compliance to treatment unlikely and/or informed consent impossible
- Any reason, at the investigator’s discretion, that the participation of the patient in this protocol would not be in patient’s best interest, or where the patient would be unable to adhere to the study requirements
- DONOR: Positive anti-donor HLA antibody
- DONOR: Pregnant or lactating
- DONOR: Active infection
- DONOR: Positivity for HIV, hepatitis B (hepatitis B virus [HBV]), hepatitis C (hepatitis C virus [HCV]), human T-cell lymphotropic virus (HTLV-I/II)
- DONOR: Presence of a hemoglobinopathy
- DONOR: Severe psychiatric illness or mental deficiency making compliance with donation unlikely and/or informed consent impossible
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT02996773.
PRIMARY OBJECTIVES:
I. Determine the safety of haploidentical bone marrow transplant (BMT) using a preparative regimen of busulfan, fludarabine and melphalan, or total body irradiation and fludarabine followed by post-transplant cyclophosphamide (PT-CY) and/or post-transplant bendamustine (PT-BEN).
II. Demonstrate that the post-transplant regimen is well tolerated and will not result in unacceptable rates of high-grade acute or chronic graft versus (vs) host disease (GvHD), graft failure, infections, non-relapse mortality or relapse compared to concurrently treated control patients and published data with PT-CY.
III. Examine the effects of PT-BEN on immune reconstitution and function following human haploidentical BMT.
OUTLINE: This is a phase I, dose-escalation study of bendamustine followed by a phase Ib study.
CONDITIONING REGIMEN: Patients either receive busulfan intravenously (IV) every 6 hours (Q6H) on days -8 to -6 for 12 doses, fludarabine IV over 2 hours on days -5 to -2, and melphalan IV over 30 minutes on day -2 or total body irradiation (TBI) twice daily (BID) on days -8 to -6 and receive fludarabine IV over 2 hours on days -5 to -2.
TRANSPLANT: Patients undergo bone marrow transplant on day 0.
POST-TRANSPLANT TREATMENT: Beginning 68-72 hours after bone marrow transplant, patients receive cyclophosphamide IV over 2 hours on days 3-4. Patients may also receive bendamustine IV over 10 minutes on days 3-4. Patients then receive tacrolimus IV over 4 hours every 12 hours on days 5-20, mycophenolate mofetil IV every 8 hours or orally (PO) on days 5-28, and filgrastim IV on day 5 until the absolute neutrophil count exceeds 1.5 x 10^9/L for 3 consecutive days.
After completion of study treatment, patients are followed up for 3 years.
Trial PhasePhase I
Trial Typetreatment
Lead OrganizationBanner University Medical Center - Tucson
Principal InvestigatorEmmanuel Katsanis
- Primary ID1609876907
- Secondary IDsNCI-2016-01933, Haplo
- ClinicalTrials.gov IDNCT02996773