A Randomized Phase II Trial to Evaluate Progression-Free Survival Rates in Patients Receiving NK Cell-Enriched Donor Cell Infusions When Administered Alone or Administered With the TLR9 Agonist, DUK-CPG-001, From a 4-6/8 HLA-Matched Related or 7-8/8 HLA-Matched Donor Following Reduced Intensity or Non-Ablative Allogeneic Stem Cell Transplantation

This is a randomized, parallel phase II study to evaluate the rates of progression-free survival and unacceptable toxicity in patients receiving NK cell-enriched donor lymphocyte infusions (DLIs) when administered alone or administered with the TLR9 agonist, DUK-CPG-001, from a 7-8/8 HLA-matched related or unrelated donor (Cohort A) or 4-6/8 HLA-matched related donor (Cohort B) following reduced intensity or non-ablative allogeneic stem cell transplantation. Randomization will be stratified for disease types (myeloid versus lymphoid malignancies).

Patient prior to starting therapy Within 21 days prior to initiating therapy, patients will have an updated history and physical examination performed, lab tests, stool collection, and pregnancy test if the patient is a female of childbearing potential. Patients will have blood or marrow stored for analysis of immune function and chimerism. Tests documenting the patient's disease state are required at study entry as well (bone marrow aspirate/biopsy, blood studies, and/or radiographic tests such as CTs, MRI, PET scans as determined by treating physician,and as required for standardized response evaluations).

Donor apheresis and cell processing Donors will return to the center for a fresh collection of NK cells and they will not need growth factor mobilization. One collection will be used for each NK cell infusion. Cells will be transfused immediately after collection and processing or the next day. Cell processing will be performed in our cryopreservation lab according to SOP for collection, labeling and handling. The cells will be NK selected using a CD56 antibody (CliniMACS CD56 Reagent), CliniMACSplus instrument and CliniMACS tubing set provided by Miltenyi Biotec using the company protocol (Miltenyi Biotec Inc, Auburn, California). Pre and post processing cell count, viability, Hematopoietic Progenitor Cell Assay (HPCA) and flow analysis per SOP will be done.

Patient Evaluation Assessment of disease will use standardized criteria and shall include a careful examination of the studies needed to detect the disease (PET, radiographs, immuno phenotype, marrow, molecular studies etc). Restaging may be altered at the discretion of the transplant physician following the patient (who are all subinvestigators in this study) if the patient is felt to be progressing before these time points but the recommended restaging is q3 months for 1 year after the last NK-enriched DLI, q6 months for the next 2 years, then as indicated clinically. Immune reconstitution studies prior to and 1 and 7 days after each NK cell-enriched DLI, and 3, 6, and 12 months after the last NK-enriched DLI. Determination of chimerism (by short tandem repeat analysis in use in our DUKE HLA laboratory with a 2% sensitivity) just prior to each NK cell-enriched DLI, and 3, 6, 12 months after the last NK-enriched DLI.

Toxicity will be formally evaluated post infusion and a week later (more as determined by treatment team) and at a minimum of every other week through 6 weeks post infusion, then q3 months starting at 3 months post-second DLI for the first year. Assessments include history (specific to GI toxicity as well as overall new problems), physical exam, CBC, liver function tests (AST, ALT, bilirubin at a minimum), and Chemistry CS to include creatinine and BUN for toxicity assessment following the NCI common toxicity criteria (version 4) and standard GVHD criteria (appendix I). Further follow up will be required as needed if the patient has a toxicity due the transplant or infusion procedures. Patients with a grade 3 or greater toxicity due to the study will be seen every other week at a minimum until the toxicity is < grade 3, and then will be seen as clinically appropriate.