Daratumumab and Donor Lymphocyte Infusion in Treating Participants With Relapsed Acute Myeloid Leukemia After Stem Cell Transplant

PRIMARY OBJECTIVES:

I. To evaluate safety and tolerability 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 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.

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 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 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 (ii)
antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis
(ADCP) 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.

Participants receive daratumumab intravenously once a week for 8 weeks and donor lymphocyte
infusion in weeks 3 or 4 in the absence of disease progression or unacceptable toxicity.
Participants found to be in complete response (CR) at the end of 8 weeks may receive
daratumumab IV once every 2 weeks for 8 weeks, and then once monthly for 6 months in the
absence of disease progression or unacceptable toxicity.

After completion of study treatment, participants are followed up for 1 year.

Inclusion Criteria:

- AML or MDS relapse following allo-HSCT (morphological relapse, or MRD positive by flow
cytometry, cytogenetics, molecular mutations)

- 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

Exclusion Criteria:

- Active graft-versus-host disease (GvHD) grades II-IV; prior acute GVHD could have
occurred but resolved at time of initiation of daratumumab

- Extensive chronic GvHD requiring ongoing immunosuppression with calcineurin inhibitors

- Active central nervous system (CNS) disease

- History of grade IV anaphylactic reaction to monoclonal antibody therapy

- Active autoimmune disease prior to transplant