Total Marrow and Lymphoid Irradiation and Chemotherapy Before Donor Transplant in Treating Patients With Myelodysplastic Syndrome or Acute Leukemia

Study Overview
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Brief Summary
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This phase I trial studies the side effects and best dose of total bone marrow and lymphoid irradiation when given together with chemotherapy before donor stem cell transplant in treating patients with myelodysplastic syndrome or acute leukemia. Total marrow and lymphoid irradiation is a type of radiation therapy that targets bone marrow and blood, where the cancer is, instead of applying radiation to the whole body. Stem cell transplants use high doses of chemotherapy and radiation therapy, such as total marrow and lymphoid irradiation, to kill cancer cells, but these treatments kill normal cells as well. After chemotherapy, healthy cells from a donor are given to the patient to help the patient grow new blood cells.

Detailed Description
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PRIMARY OBJECTIVES: I. To establish safety and determine the maximum tolerated dose of total marrow and lymphoid irradiation when given in combination with fludarabine (fludarabine phosphate) and pre-post-transplant cyclophosphamide, as conditioning for haploidentical hematopoietic cell transplantation (HCT) in patients with high-risk acute lymphocytic or myelogenous leukemia or intermediate/high-risk myelodysplastic syndrome. II. To evaluate the safety of the regimen at each dose level by assessing adverse events: type, frequency, severity, attribution, time course, duration. III. To evaluate the safety of the regimen at each dose level by assessing complications: including acute/chronic graft-versus-host disease (GvHD), infection and delayed engraftment. SECONDARY OBJECTIVES: I. To estimate overall survival (OS), progression-free survival (PFS), cumulative incidence (CI) of relapse/progression, and non-relapse mortality (NRM) at +100 Days, 1 year and 2 years. II. To characterize minimal residual disease from bone marrow aspirates on Days +30, +100, +180 post-transplant and describe in relation to total marrow and lymphoid irradiation (TMLI) dose level and patient disease status. III. To describe the kinetics of immune cell recovery in the first year post-transplantation. OUTLINE: This is a dose-escalation study of TMLI. CONDITIONING: Patients undergo TMLI twice daily (BID) on days -7 to -4 or -3 (depending on the dose level). Patients also receive fludarabine phosphate intravenously (IV) on days -7 to -3 and cyclophosphamide IV on days -7, -6, 3, and 4. TRANSPLANT: Patients undergo bone marrow or peripheral blood stem cell transplant on day 0. GHVD PROPHYLAXIS: Patients receive tacrolimus* IV once daily (QD) or orally (PO) BID on days 5-180. Patients also receive mycophenolate mofetil PO thrice daily (TID) or IV on days 5-35. Treatment with tacrolimus and mycophenolate mofetil may continue in the presence of active GVHD. *NOTE: Patients intolerant of tacrolimus may receive cyclosporine. After completion of study treatment, patients are followed up twice weekly for 100 days, twice monthly until 6 months, monthly until the patient is off immunosuppressive therapy without evidence of GVHD, and then at least yearly for a total of 5 years.

Official Title
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Phase I Study of Escalating Doses of Total Marrow and Lymphoid Irradiation (TMLI) During Conditioning for HLA-Haploidentical Hematopoietic Cell Transplantation With Post-Transplant Cyclophosphamide in Patients With Myelodysplasia or Acute Leukemia

Conditions
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Adult Acute Lymphoblastic Leukemia in Complete Remission, Acute Myeloid Leukemia in Remission, Previously Treated Myelodysplastic Syndrome, Recurrent Adult Acute Lymphoblastic Leukemia, Recurrent Adult Acute Myeloid Leukemia, Recurrent Childhood Acute Lymphoblastic Leukemia, Recurrent Childhood Acute Myeloid Leukemia, Childhood Acute Lymphoblastic Leukemia in Complete Remission

Intervention / Treatment
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* Procedure: Bone Marrow Transplantation
* Drug: Cyclophosphamide
* Drug: Fludarabine Phosphate
* Other: Laboratory Biomarker Analysis
* Drug: Mycophenolate Mofetil
* Procedure: Peripheral Blood Stem Cell Transplantation
* Drug: Tacrolimus
* Radiation: Total Marrow Irradiation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Eligible patients will have a histopathologically confirmed diagnosis of hematologic malignancy in one of the following categories: Acute myelogenous leukemia In first complete remission (CR1) with poor risk cytogenetics according to National Comprehensive Cancer Network (NCCN) guidelines for acute myeloid leukemia (AML): monosomal karyotype, -5, 5q-,-7,7q-, inv (3), t(3;3), t(6;9), t(9;22) and complex karyotypes (>= 3 unrelated abnormalities [abn]) and normal cytogenetics with fms-related tyrosine kinase 3 (FLT3)-internal tandem duplications (ITD) mutation In pediatrics, all of the above and 11q23-non t(9;11) In second complete remission (CR2) or third complete remission (CR3) With chemosensitive primary refractory disease Acute lymphocytic leukemia In CR1 with poor risk cytogenetics: For adults according to NCCN guidelines for acute lymphoblastic leukemia (ALL): hypoploidy (< 44 chromosomes); t(v;11q23): mixed lineage leukemia (MLL) rearranged; t(9;22) (q34;q11.2); complex cytogenetics (5 or more chromosomal abnormalities); high white blood cell (WBC) at diagnosis (>= 30,000 for B lineage or >= 50,000 for T lineage) For pediatrics t(9;22), intrachromosomal amplification of chromosome 21 (iAMP21)loss of 13q, and abnormal 17p In CR2 or CR3 With chemosensitive primary refractory disease Myelodysplastic syndrome in high-intermediate (int-2) and high risk categories Karnofsky or Lansky performance status >= 80 A pretreatment measured creatinine clearance (absolute value) of >= 50 ml/minute Serum bilirubin =< 2.0 mg/dl Serum glutamic oxaloacetic transaminase (SGOT) and serum glutamate pyruvate transaminase (SGPT) =< 2.5 times the institutional upper limits of normal Ejection fraction measured by echocardiogram or multigated acquisition scan (MUGA) >= 50% Diffusing capacity of the lung for carbon monoxide (DLCO) and forced expiratory volume in one second (FEV1) > 60% predicted Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control or abstinence) prior to study entry and for six months following duration of study participation; should a woman become pregnant or suspect that she is pregnant while participating on the trial, she should inform her treating physician immediately The recipient must have a related donor genotypically human leukocyte antigen (HLA)-A, B,C and DRB1 loci haploidentical to the recipient No HLA matched sibling or matched unrelated donor is available Patients should be off all previous intensive therapy, chemotherapy or radiotherapy for 3 weeks prior to commencing therapy on this study * (NOTE: Low dose chemotherapy or maintenance chemotherapy given within 7 days of planned study enrollment is permitted; these include: hydroxyurea, 6-meraptopurine, oral methotrexate, vincristine, oral etoposide, and tyrosine kinase inhibitors [TKIs]; FLT-3 inhibitors such as sorafenib, crenolanib, quizartinib, midostaurin can also be given up to 3 days before conditioning regimen) Adequate organ function All subjects must have the ability to understand and the willingness to sign a written informed consent Prior radiation therapy that would exclude the use of TMLI DONOR ELIGIBILITY CRITERIA: DONOR: Age =< 60 years of age DONOR: For younger donors, no more than 20 mL bone marrow may be harvested per kg of donor body weight DONOR: Medical history and physical examination confirm good health status as defined by institutional standards DONOR: Seronegative for human immunodeficiency virus (HIV) antigen (Ag), HIV 1+2 antibody (Ab), human T-lymphotropic virus (HTLV) I/II Ab, hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb) (immunoglobulin [Ig]M and IgG), hepatitis C virus (HCV) Ab, rapid plasma reagin (RPR) for syphilis within 30 days of apheresis collection DONOR: Genotypically haploidentical as determined by HLA typing, preferably a non-maternal HLA haploidentical relative; eligible donors include biological parents, siblings or half siblings, or children DONOR: Female donors of child-bearing potential must have a negative serum or urine beta-human chorionic gonadotropin (HCG) test within three weeks of mobilization DONOR: The donor must have been informed of the investigational nature of this study and have signed a consent form in accordance with federal guidelines and the guidelines of the participating institution DONOR: Selection of a haploidentical donor will require absence of pre-existing donor-directed anti-HLA antibodies in the recipient Exclusion Criteria: Patients should not have any uncontrolled illness including ongoing or active bacterial, viral or fungal infection Patients may not be receiving any other investigational agents, or concurrent biological, intensive chemotherapy, or radiation therapy for the previous three weeks from conditioning * (NOTE: Low dose chemotherapy or maintenance chemotherapy given within 7 days of planned study enrollment is permitted; these include: hydroxyurea, 6-meraptopurine, oral methotrexate, vincristine, oral etoposide, and tyrosine kinase inhibitors [TKIs]; FLT-3 inhibitors such as sorafenib, crenolanib, quizartinib, midostaurin can also be given up to 3 days before conditioning regimen) History of allergic reactions attributed to compounds of similar chemical or biologic composition to any in the pre- or post-transplant regimen Pregnant women are excluded from this study Patients with other active malignancies are ineligible for this study, other than non-melanoma skin cancers The recipient has a medical problem or neurologic/psychiatric dysfunction which would impair his/her ability to be compliant with the medical regimen and to tolerate transplantation or would prolong hematologic recovery which in the opinion of the principal investigator would place the recipient at unacceptable risk Patients may not have had a prior autologous or allogeneic transplant HLA-matched or partially matched (7/8 or 8/8) related or unrelated donor is available to donate Patients may not have received more than 3 prior regimens, where the regimen intent was to induce remission Patients treatment history may not include anti-CD33 monoclonal antibody therapy (e.g., SGN-CD33 or Mylotarg) Subjects, who in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study DONOR EXCLUSION CRITERIA: DONOR: Evidence of active infection DONOR: Medical or physical reason which makes the donor unlikely to tolerate or cooperate with growth factor therapy and leukapheresis DONOR: Factors which place the donor at increased risk for complications from leukapheresis or granulocyte-colony stimulating factor (G-CSF) therapy DONOR: HIV positive

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 60 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: Treatment (TMLI, chemotherapy, transplant, GVHD prophylaxis)<br>CONDITIONING: Patients undergo TMLI BID on days -7 to -4 or -3 (depending on the dose level). Patients also receive fludarabine phosphate IV on days -7 to -3 and cyclophosphamide IV on days -7, -6, 3, and 4. TRANSPLANT: Patients undergo bone marrow or peripheral blood stem cell transplant on day 0. GHVD PROPHYLAXIS: Patients receive tacrolimus* IV QD or PO BID on days 5-180. Patients also receive mycophenolate mofetil PO TID or IV on days 5-35. Treatment with tacrolimus and mycophenolate mofetil may continue in the presence of active GVHD. *NOTE: Patients intolerant of tacrolimus may receive cyclosporine. | Procedure: Bone Marrow Transplantation<br>* Undergo bone marrow transplant<br>* Other names: Marrow Transplantation;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Drug: Fludarabine Phosphate<br>* Given IV<br>* Other names: SH T 586;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Mycophenolate Mofetil<br>* Given PO or IV<br>* Other names: MMF;Procedure: Peripheral Blood Stem Cell Transplantation<br>* Undergo peripheral blood stem cell transplant<br>* Other names: Peripheral Stem Cell Transplantation;Drug: Tacrolimus<br>* Given IV and PO<br>* Other names: Protopic;Radiation: Total Marrow Irradiation<br>* Undergo TMLI<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of dose-limiting toxicity (DLT) scored on both the Bearman Scale and National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 | Toxicity information recorded will include the type, severity, and the probable association with the study regimen. Tables will be constructed to summarize the observed incidence by severity and type of toxicity. | Up to 100 days | 
| Maximum tolerated dose of TMLI when given in combination with fludarabine phosphate and cyclophosphamide, defined as the highest dose where 6 patients have been treated and at most one patient experiences DLT | Toxicity information recorded will include the type, severity, and the probable association with the study regimen. Tables will be constructed to summarize the observed incidence by severity and type of toxicity. | Up to day -3 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete remission proportion |  | At day 30 | 
| Immune reconstitution of B, T and NK cells |  | Up to 1 year | 
| Incidence of acute GVHD of grades 2-4 and 3-4 | The cumulative incidence of relapse/progression, non-relapse mortality and acute/chronic GVHD will be calculated as competing risks. | Within the first 100 days post-transplant | 
| Incidence of chronic GVHD | The cumulative incidence of relapse/progression, non-relapse mortality and acute/chronic GVHD will be calculated as competing risks. | After 180 days post-transplant assessed up to 5 years | 
| Incidence of infection | Microbiologically documented infections will be reported by site of disease, date of onset, severity and resolution, if any. | Up to day 100 | 
| Minimal residual disease |  | Up to 180 days post-transplant | 
| Non-relapse mortality (NRM) | The cumulative incidence of relapse/progression, non-relapse mortality and acute/chronic GVHD will be calculated as competing risks. | Up to 5 years | 
| Overall survival | Survival estimates will be calculated using the Kaplan-Meier method. | Time from start of protocol therapy to death, or last follow-up, whichever comes first, assessed up to 5 years | 
| Progression-free survival | Survival estimates will be calculated using the Kaplan-Meier method. | Time from start of protocol therapy to death, relapse/progression, or last follow-up, whichever comes first, assessed up to 5 years | 
| Incidence of grade 3-5 adverse events per CTCAE v4.03 | Toxicity information recorded will include the type, severity, and the probable association with the study regimen. Tables will be constructed to summarize the observed incidence by severity and type of toxicity. | Up to 100 days post-transplant |