Phase I/II Study of Treg/Tcon Addback to Partially Matched Related Donor Stem Cells With Myeloablative Conditioning and Post-transplant Cyclophosphamide for High Risk Hematologic Malignancies

Study Overview
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Brief Summary
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Open label, dose finding trial to assess the efficacy of Treg/Tcon addback to partially matched related donor stem cells. The maximum tolerated dose will be established using 3 subjects per dose level, with an expansion cohort at the maximum tolerated dose.

Official Title
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Phase I/II Study of Treg/Tcon Addback to Partially Matched Related Donor Stem Cells With Myeloablative Conditioning and Post-transplant Cyclophosphamide for High Risk Hematologic Malignancies

Conditions
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High Risk Hematologic Malignancies

Intervention / Treatment
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* Biological: stem cell transplant
* Procedure: Stem cell transplant


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1. Age 0-70 years 2. Karnofsky or Lansky Performance status >70% 3. High risk hematologic malignancy 4. Acute myeloid leukemia (AML) with one or more of the following criteria: 4a.Poor risk cytogenetics, including -5, 5q-, -7, 7q-, t(9;22); complex cytogenetics (>3 abnormalities); or normal cytogenetics with Flt3 internal tandem duplication (ITD), in first or subsequent complete remission (CR). 4b. Relapsed or primary refractory AML with <10% blasts in the peripheral blood. 4c. Subjects in first complete remission (CR1) who required two cycles of induction to achieve remission may be included at the discretion of the treating physician. 4d. Standard risk or intermediate risk cytogenetics in second or subsequent CR (enrolled at the discretion of the treating physician). 5. Acute lymphoblastic leukemia (ALL) with one of the following criteria: 5a. Second or subsequent CR 5b. Any partial remission (PR) (no circulating blasts) 5c. High-risk ALL in first CR including (Ph+, t(4:11), complex karyotype, hypodiploidy (<44 chromosomes), or positive minimal residual disease (MRD) after induction 6. Myelodysplasia, intermediate -2 (score 1.5-2.0) or high risk (score >2.5) by the International Prognostic Score System. 7. Myeloproliferative Disorders (include chronic myelomonocytic leukemia (CMML), agnogenic myeloid metaplasia (AMM) or Idiopathic Myelofibrosis, and JMML) with excess blasts (>5%) 8. Chronic myeloid leukemia (CML) with one of the following criteria: 8a. Second or subsequent chronic phase 8b. Accelerated phase 8c. blast crisis 9. Non-Hodgkin's lymphoma (NHL) meeting one of the following criteria: 9a. Relapse after autologous stem cell transplantation with evidence of responsive disease. 9b. Subject with chemosensitive relapse who have no option for autologous stem cell transplantation due to blood or marrow involvement or failure to mobilize autologous stem cells or are not considered eligible for autologous transplant by their treating physician. 9c. Hodgkin's Lymphoma: relapse after autologous hematopoietic cell transplantation (HCT), chemo-refractory disease 9d. Multiple myeloma: per National Comprehensive Cancer Network (NCCN) guidelines. Updated annually at: www.nccn.org 10. No suitable human leukocyte antigen (HLA)-identical sibling donor. 11. No identified 8/8 (based upon A, B, C, DR beta 1 (DRB1) loci) allele matched unrelated donor, or unable to wait sufficient time to procure a 8/8 allele matched unrelated donor 12. Available HLA 3-5/6 matched genotypically haploidentical partially matched related donor 13. Female subjects must be surgically sterile, postmenopausal (minimum 1 year without menses), or agree to use approved form of contraception from the time of signing the informed consent form through Day +100. Male subjects must also agree to use an approved form of birth control for either themselves or their partner, as appropriate, from the time of signing the informed consent form through Day +100. 14. Able to provide informed consent and have signed an approved consent form that conforms to federal and institutional guidelines. Exclusion Criteria: Available HLA identical matched sibling donor (unless having failed a prior allogeneic transplant from an HLA identical matched sibling) Recipient HLA antibodies against donor HLA Any of the following organ dysfunctions: Cardiac- left ventricular ejection fraction <40%, symptomatic coronary artery disease, or uncontrolled arrhythmias Pulmonary- forced expiratory volume at one second (FEV1) or diffusion capacity of lung for carbon monoxide (DLco)<40% or need for use of supplemental oxygen Renal- calculated or measured glomerular filtration rate (GFR) <30 ml/min, dialysis requirement, or prior renal transplant Hepatic- bilirubin > 2.0, alanine aminotransferase (ALT) > 2.5 X upper limit of normal (ULN), cirrhosis Subjects with active or uncontrolled bacterial, viral, or fungal infections requiring systemic therapy. Subjects who have tested positive for HIV. Pregnant women, nursing mothers or women of child-bearing potential who are unwilling to use medically accepted methods of contraception.

Ages Eligible for Study
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Maximum Age: 70 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 |
| --- | --- |
| Experimental: All participants<br> | Biological: stem cell transplant<br>* Open label, dose finding trial with two treatment regimens, Busulfan and Total Body Irradiation (TBI) with four dose escalation cohorts, to assess the efficacy of Treg/Tcon addback to partially matched related donor stem cells.<br>Procedure: Stem cell transplant<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of acute GVHD | Rate of acute Graft Versus Host Disease (GVHD) grade III-IV at Day +100 post transplant | 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Engraftment | Day +28 and +100 neutrophil engraftment | 36 months | 
| Survival at Day 100 | Day +100 and one year survival Day +100 and one year transplant related mortality Day +100 and one year relapse rates | 36 months |