CD16/IL-15/CD33 Tri-Specific Killer Engagers (TriKEs) for High Risk Heme Malignancies

Inclusion Criteria: Eligible Diseases

- Diagnosis of one of the following CD33-expressing myeloid malignancies with no good
standard of care treatment options including:

- High Risk Myelodysplastic Syndromes (MDS) progressive on two or more prior regimens
and requiring treatment that meets at least one of the following:

- Revised International Prognostic Scoring System (R-IPSS) Category (refer to
Appendix III): INT-2 or High Risk

- R-IPSS High or Very High Risks

- WHO Classification: RAEB-1 or RAEB-2

- Poor and very-poor risk cytogenetic abnormality as defined by the R-IPSS
cytogenetic classifications

- WHO Based Prognostic Scoring System (WPSS): High or Very High Risk

- Therapy related MDS and not a candidate for induction chemotherapy. Would be eligible
if treated with induction chemotherapy and had an inadequate treatment response.

- Refractory or Relapsed Acute Myelogenous Leukemia (AML) meeting at least one of the
following:

- Refractory AML defined as failure to achieve remission after at least 3 induction
attempts

- Relapsed AML

- Not a candidate for stem cell transplant (HSCT), at least one re-induction
attempt required

- Prior HSCT relapse beyond 12 months without active GVHD requiring

- Advanced systemic mastocytosis (defined as mast cell leukemia, aggressive systemic
mastocytosis, and systemic mastocytosis associated with hematologic neoplasm) may
enroll without any prior treatment, given there is no standard established therapy.

Inclusion Criteria: Age, Performance Status, Organ Function, Contraception Use

- At least 18 years, but not older than 75 years of age

- Karnofsky score ≥ 70% (Appendix II)

- Adequate organ function within 14 days (30 days for cardiac and pulmonary) of study
enrollment defined as:

- Renal: an estimated glomerular filtration rate ≥ 60 mL/min/1.73 m2 using
Modification of Diet in Renal Disease equation

- Hepatic: AST, ALT, and alkaline phosphatase ≤ 3 x upper limit of normal and total
bilirubin ≤ 1.5 х upper limit of normal range (ULN)

- Pulmonary function: DLCOcor on PFTs ≥80% expected

- Cardiac: Absence of decompensated congestive heart failure, or uncontrolled
arrhythmia; left ventricular ejection fraction ≥ 45% by echocardiogram, MUGA or
cardiac MRI.

- Absolute lymphocyte count (ALC) ≥ 200 cells/mm³ and absolute circulating CD56+/CD3- NK
cell count >25 cells/μl within the 14 days prior to start of therapy

- Sexually active females of childbearing potential and males with partners of
child-bearing potential must agree to use adequate birth control during study
treatment

- Participant provides voluntary written consent signed before performance of any
study-related procedure not part of normal medical care

Exclusion Criteria

- Bacterial, fungal or viral infection that has not cleared with appropriate treatment

- Known HIV positivity

- Active Hepatitis B or Hepatitis C (virus detectable by PCR) - chronic asymptomatic
viral hepatitis is allowed

- Pregnant or breast feeding. The effect of 161533 TriKE on the fetus is unknown.
Females of childbearing potential must have a blood test or urine study within 7 days
prior to enrollment to rule out pregnancy - must be repeated if not within 7 days of
treatment initiation

- History of central nervous system malignancy or symptoms of active CNS disease

- A family history of long QT syndrome or with a QTc interval > 480 msec at screening

- Currently taking medications known to prolong QT/QTc interval as the potential risk of
QT/QTc prolongation is unknown in humans (refer to Appendix VI for a list of
prohibited medications for eligibility)

- A candidate for potentially curative therapy, including hematopoietic cell transplant

- Unwilling to remain in the greater Twin Cities metropolitan area through at least Day
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