Daratumumab and Donor Lymphocyte Infusion in Treating Patients with Relapsed Acute Myeloid Leukemia after Stem Cell Transplant
This phase I/II trial studies the side effects and best dose of donor lymphocyte infusions when given together with daratumumab and to see how well they work in treating patients with acute myeloid leukemia that has come back (relapsed) after a stem cell transplant. A donor lymphocyte infusion is a type of therapy in which lymphocytes (white blood cells) from the blood of a donor are given to a participant who has already received a stem cell transplant from the same donor. The donor lymphocytes may kill remaining cancer cells. Monoclonal antibodies, such as daratumumab, may interfere with the ability of cancer cells to grow and spread. Giving daratumumab and donor white blood cells may work better in treating patients with acute myeloid leukemia.
Inclusion Criteria
- AML or MDS relapse following allo-HSCT (morphological relapse, or MRD positive by flow cytometry, cytogenetics, molecular mutations)
- Patients who received a 10/10 HLA-matched allogeneic HCT either from sibling donors or unrelated donors or at least a 5/10 haploidentical transplant
- Patients with relapsed/refractory (R/R) AML must not be candidates for available therapies known to be effective for treatment of their AML
- For patients in dose level 1 (daratumumab only), relapsed refractory AML patients who have previously not received an allogeneic HCT are eligible
- Engraftment must have occurred as defined by platelet (PLT) count > 20,000/uL and absolute neutrophil count (ANC) >= 0.5
- Eastern Cooperative Oncology Group (ECOG) performance status < 3
- Creatinine clearance > 40 ml/min (calculated or measured)
- Aspartate aminotransferase (AST) < 3 x upper limit of normal (ULN), alanine aminotransferase (ALT) < 3 x ULN
- Total bilirubin < 1.5 x ULN
- Off calcineurin inhibitors for at least 2 weeks
- Prednisone dose =< 20 mg/day
- Patients with proliferative disease can be cytoreduced with cytotoxic chemotherapy at investigator’s discretion, but there should be at least a 14 day window between start of cytoreductive therapy and start of daratumumab
- Blast count ˂ 20 K/day (hydrea use is allowed)
- Patient willing to agree to study-related research marrows
- Female patients of childbearing potential who are sexually active must be willing to use an effective barrier method of birth control to avoid pregnancy during the study and for a minimum of 3 months after stopping study treatment
- Male patients with partners of childbearing potential who are sexually active must be willing to use an effective barrier method of birth control to avoid pregnancy during the study and for a minimum of 3 months after stopping study treatment
Exclusion Criteria
- No demonstrable evidence of donor chimerism (˂ 55 donor CD3 or CD33 chimerism)
- Patients with a molecular mutation without chromosomal abnormalities or declining chimerisms (MRD status must be verified by surface marker and mutational analyses)
- Active graft-versus-host disease (GvHD) grades I-IV; prior acute GVHD could have occurred but resolved at time of initiation of daratumumab
- Extensive chronic GvHD requiring ongoing immunosuppression with calcineurin inhibitors or more than 20 mg of prednisone
- Patients with FLT3+ AML or blast crisis chronic myelogenous leukemia (CML) who have not yet received post-transplant tyrosine kinase inhibitor (TKI) therapy
- Active central nervous system (CNS) disease or testicular disease
- Subject is: * Seropositive for human immunodeficiency virus (HIV) * Seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]). Subjects with resolved infection (ie, subjects who are HBsAg negative but positive for antibodies to hepatitis B core antigen [anti-HBc] and/or antibodies to hepatitis B surface antigen [anti-HBs]) must be screened using real-time polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) deoxyribonucleic acid (DNA) levels. Those who are PCR positive will be excluded. EXCEPTION: Subjects with serologic findings suggestive of HBV vaccination (anti-HBs positivity as the only serologic marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV DNA by PCR.
- Seropositive for hepatitis C (except in the setting of a sustained virologic response [SVR], defined as aviremia at least 12 weeks after completion of antiviral therapy)
- Patients must not have chronic obstructive pulmonary disease with a forced expiratory volume in 1 second (FEV1) < 50% of predicted normal. FEV1 is required for patients suspected of having chronic obstructive pulmonary disease and are not eligible if FEV1 is < 50% of predicted normal
- Patients must not have moderate or severe persistent asthma within the past 2 years and must not have currently uncontrolled asthma of any classification
- Active autoimmune disease prior to transplant
- Female patients of childbearing potential who are sexually active and unwilling to use an effective barrier method of birth control to avoid pregnancy during the study and for a minimum of 3 months after study treatment
- Male patients with partners of childbearing potential who are sexually active and unwilling to use an effective barrier method of birth control to avoid pregnancy during the study and for a minimum of 3 months after study treatment
- Concurrent use of any other investigational drugs
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT03537599.
PRIMARY OBJECTIVES:
I. To determine the maximum tolerated dose (MTD) of daratumumab and escalating doses of donor lymphocyte infusions (DLI) in post-hematopoietic cell transplantation (HCT) patients with relapsed acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) transformed to AML (phase I).
II. To evaluate overall response rate to daratumumab and DLI by week 8 in patients with post-HCT relapsed AML and MDS (phase II).
SECONDARY OBJECTIVES:
I. To assess overall response rates in minimal residual disease (MRD) positive patients and in patients with overt morphological relapse.
II. To assess MRD conversion rates from MRD positive to MRD negative.
III. To determine the post-relapse 6-month overall response (OS) rates of patients with relapsed AML and MDS following allogeneic hematopoietic stem cell transplantation (allo-HSCT) who are treated with daratumumab.
IV. To determine the rates of graft-versus-host disease (GVHD) (both grades II-IV and III-IV) and autoimmune side effects of daratumumab within 3 months of completion of study.
V. To determine the post-relapse 6-month progression-free survival (PFS) rates of patients with relapsed AML and MDS following allo-HSCT who are treated with daratumumab.
EXPLORATORY OBJECTIVES:
I. To compare CD38 expression levels in myeloid blasts and interferon gamma (IFN-y) levels in plasma, by flow cytometry and polymerase chain reaction (PCR) at the time of relapse before starting daratumumab and at progression or relapse after daratumumab.
II. To compare peripheral blood T cell number and subsets (CD3, CD4, CD8, (CD38 expression on regulatory T cells [T-regs], CD4 and CD8), T regs, B-regulatory cells, natural killer (NK) cell numbers and bone marrow T cell subsets, by flow cytometry, at the time of relapse before starting daratumumab, at the time of partial/complete response to daratumumab, and at the time of progression or relapse after daratumumab.
III. To evaluate whether daratumumab has (i) direct anti-leukemia effects by measuring the expression of the M1 markers CD80 and CD86 by flow cytometry and PCR (ii) antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) by using chromium based ADCC assays, and a phagocytosis assay using antibody-opsonized sheep red blood cells as targets and (iii) immune modulation of autologous immune system (NK cells, T cells, T-regs, B-regulatory cells [B-regs], and myeloid-derived suppressor cells [MDSCS]) in AML.
IV. To evaluate the effect of daratumumab on exosome content and clearance along with other soluble factors in AML.
V. To evaluate serum interferon (IFN) levels pre-daratumumab, during and post-daratumumab.
VI. To evaluate whether fratricide occurs in patients treated with daratumumab.
OUTLINE: This is a phase I, dose escalation study of donor lymphocyte infusions followed by a phase II study.
Patients receive daratumumab intravenously (IV) once a week for 8 weeks and donor lymphocyte infusion within 72 hours of daratumumab dose during weeks 3 or 4 in the absence of disease progression or unacceptable toxicity. Patients found to be in complete response (CR) at the end of 8 weeks may receive daratumumab IV once every 2 weeks for 16 weeks, and then once monthly for 6 months in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up for at least 12 months.
Trial PhasePhase I/II
Trial Typetreatment
Lead OrganizationOhio State University Comprehensive Cancer Center
Principal InvestigatorSumithira Vasu
- Primary IDOSU-17102
- Secondary IDsNCI-2018-00616, 2018C0058
- ClinicalTrials.gov IDNCT03537599