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

Study Overview
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Brief Summary
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The purpose of this study is to determine the overall safety of adoptive immunotherapy when given after chemotherapy for AML/MDS. Adoptive immunotherapy means using an infusion of cells from a donor to help fight cancer. The donor cells will be either from the umbilical cord blood (UCB) of a newborn baby or they will be cells collected from a relative (haplo-identical cells). The 2 cohorts that were discussed - adoptive immunotherapy with either UCB or haplo-identical stem cells - will be analyzed separately. Preliminary data from other centers has suggested that adoptive immunotherapy with cells from a relative is an effective approach that may improve remission rates and survival in AML and MDS, because they exert anti-cancer effects of their own (so called graft vs leukemia effects) and possibly because they hasten recovery of cell counts from chemotherapy. The Investigators are interested in confirming these data, but also in testing umbilical cord blood cells for the same purpose. Preliminary data indicate that umbilical cord blood cells may have more powerful graft vs leukemia effects and cause fewer side-effects.

Detailed Description
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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: CBU Unit 5/6 Matched - 1 NIMA match with patient CBU Unit 5/6 Matched - Shared IPA target(s) with patient Haplo-identical relative CBU Unit 4/6 Matched - 1-2 NIMA matches with patient 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.

Official Title
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Parallel Phase II Trial of IPA Targeted Adoptive Immunotherapy vs Adult Haplo-identical Cell Infusion During Induction of High Risk Leukemia

Conditions
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Acute Myeloid Leukemia, Myelodysplastic Syndrome

Intervention / Treatment
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* Biological: haplo-identical cells (donor)
* Biological: umbilical cord blood unit (CBU)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must be 18 years of age or older 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. For AML: Primary induction failure (PIF) after ≥ 2 cycles of chemotherapy. First relapse. Relapse refractory to salvage chemotherapy Second or subsequent relapse. 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. Patients must have Karnofsky Performance score of ≥70 Women of child-bearing potential must have a negative serum or urine pregnancy test within 2 weeks prior to treatment start 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: Persistent clinically significant toxicities from previous chemotherapy Known positive status for human immunodeficiency virus (HIV) Pregnant and nursing patients Uncontrolled intercurrent illness including, but not limited to, uncontrolled infection, or psychiatric illness/social situations that would limit compliance with study requirements 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 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. Any medical condition which in the opinion of the investigator places the patient at an unacceptably high risk for toxicities

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Intervention<br>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 cells (donor) will be identified. Within 72 hours after completion of the chemotherapy regimen, and no sooner than 24 hours after administration of the last dose of chemotherapy, umbilical cord graft or haplo-graft will be administered. | Biological: haplo-identical cells (donor)<br>* Treatment: Haplo-identical healthy related donor. i.e. Parent, child, sibling, possibly third degree or further removed relative (cousin, aunt, nephew etc). They will be collected using standard methods and approximately 3 x10^6 CD34 cells/kg will be infused within 72 hours after completion of the treatment.<br>Biological: umbilical cord blood unit (CBU)<br>* Treatment: The CBU unit must supply a minimum of 0.5 x107/kg and a maximum of 2.5x107/kg nucleated cell dose pre-cryopreservation. The unit must match at a minimum of 4 of 6 at HLA-A, -B antigens, -DRB1 alleles with the recipient. Mismatches (0-2) can be at any loci -. Although molecular level typing will be available for the patient and the CBU unit, a match is defined at intermediate resolution for HLA-A and -B and at high resolution for -DRB1. The CBU donor will also have undergone HLA typing of the mother, thus allowing determination of the CBU-IPA and NIMA. CBU grafts used in this study will be investigational units that meet all criteria for clinical use. Better matching units will be preferred over less matching units as long as the CBU dose exceeds 0.5 x107 nucleated blood cells/kg<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of cellular immunotherapy | 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 AML or MDS. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Graft Versus Host Disease (GVHD) <10% | To assess the incidence and severity of Graft Versus Host Disease (GVHD), after conventional induction therapy followed by adoptive immunotherapy with NIMA compatible, IPA targeted CBU. | 6 months | 
| Detection of graft chimerism after infusion | To study kinetics of graft chimerism (including umbilical cord blood-microchimerism) after each of these treatments | 6 months | 
| Detection of HLA-antibodies after after infusion <10% | To study development of HLA-antibodies after each of these treatments | 6 months | 
| The response rate of leukemia | To assess response rates and duration of response after each of these treatments | 6 months |