IPA Targeted Adoptive Immunotherapy vs Adult Haplo-identical Cell Infusion During Induction of High Risk Leukemia

This is a phase 2 trial to evaluate the safety of adoptive immunotherapy with Non-Inherited
Maternal Antigen (NIMA) compatible, Inherited Paternal Antigen (IPA) targeted CBU or with
haplo-identical stem cells after conventional induction therapy for very high risk Acute
Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS).

The study has 2 cohorts - patients in cohort 1 will receive CBU cells as adoptive
immunotherapy. Patients in cohort 2 will receive haplo-identical cells. Both cohorts will be
evaluated separately and no formal statistical comparison between cohorts will be performed.

There will be approximately 20 patients in each cohort, and a 95% confidence interval for the
proportion of patients experiencing grade III-IV GVHD complications or unexplained prolonged
myelosuppression complications in each cohort can be constructed to be within +/- 13.1% of
the observed complication proportions. This calculation assumes an expected prevalence of
each of these complication proportions of no greater than 10%.

After 10 patients are enrolled in each group, the incidence of the above-defined
life-threatening complications will be assessed. If more than one patient out of 10 enrolled
patients (i.e., greater than 10%) in a cohort experiences either of these complications, the
cohort will be stopped for safety.

All potential recipients will have complete HLA typing and determination of HLA antibodies.
An appropriate umbilical cord blood unit (CBU) will be identified or in the absence of an
appropriate CBU, a haplo-identical donor will be identified.

Treatment will be as per the treating physician's choice..

The umbilical cord graft or haplo-graft will be administered between 24 - 72 hours after the
completion of the chemotherapy regimen.

The Graft Selection Algorithm is as follows:

1. CBU Unit 5/6 Matched - 1 NIMA match with patient

2. CBU Unit 5/6 Matched - Shared IPA target(s) with patient

3. Haplo-identical relative

4. CBU Unit 4/6 Matched - 1-2 NIMA matches with patient

5. CBU Unit 4/6 Matched - Shared IPA target(s) with patient

Within 42 days of transplant, the recipient's pre-treatment evaluation includes: medical
history and physical examinations, Eastern Cooperative Group Oncology Group (ECOG) score,
complete blood count (CBC), HLA antibodies, and cytomegalovirus (CMV) antibody testing.

Patients will continue with the therapy specified in this protocol until one of the following
occurs:

- Achievement of protocol endpoint complete remission (CR) or CR with incomplete platelet
recovery (CRp) after induction and cellular therapy;

- Failure to achieve CR or CRp; or,

- Extraordinary Medical Circumstances: If, at any time the constraints of this protocol
are detrimental to the patient's health and/or the patient no longer wishes to continue
protocol therapy, remove the patient from protocol treatment. In this event.

After removal from protocol therapy, patients will continue to be followed for survival and
disease status. Samples for correlative studies will continue to be collected every two
months until one year after cell infusion.

Inclusion Criteria:

1. Patients must be 18 years of age or older

2. Patients with a confirmed diagnosis of AML or MDS, according to World Health
Organization (WHO) classification (excluding acute promyelocytic leukaemia) with
recurrent or refractory disease as defined below.

1. For AML:

1. Primary induction failure (PIF) after ≥ 2 cycles of chemotherapy.

2. First relapse.

3. Relapse refractory to salvage chemotherapy

4. Second or subsequent relapse.

2. For MDS, either refractory anemia with excess blasts (RAEB) I or RAEB II who
failed at least one chemotherapy regimen including either cytarabine or a
hypomethylating agent.

3. Patients must have Karnofsky Performance score of ≥70

4. Women of child-bearing potential must have a negative serum or urine pregnancy test
within 2 weeks prior to treatment start

5. Patients must be capable of understanding and complying with protocol requirements,
and must be able and willing to sign a written informed consent form

Exclusion Criteria:

1. Persistent clinically significant toxicities from previous chemotherapy

2. Known positive status for human immunodeficiency virus (HIV)

3. Pregnant and nursing patients

4. Uncontrolled intercurrent illness including, but not limited to, uncontrolled
infection, or psychiatric illness/social situations that would limit compliance with
study requirements

5. Impairment of hepatic or renal function to such an extent that the patient, in the
opinion of the investigator, will be exposed to an excessive risk if entered into this
clinical study

6. Active heart disease including myocardial infarction within previous 3 months,
symptomatic coronary artery disease, arrhythmias not controlled by medication, or
uncontrolled congestive heart failure. Any New York Heart Association (NYHA) grade 3
or 4.

7. Any medical condition which in the opinion of the investigator places the patient at
an unacceptably high risk for toxicities