Trial Evaluating MGTA-456 in Patients With High-Risk Malignancy

Study Overview
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Brief Summary
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This is an single arm, open label, interventional phase II trial evaluating the efficacy of umbilical cord blood (UCB) hematopoietic stem and progenitor cells (HSPC) expanded in culture with stimulatory cytokines (SCF, Flt-3L, IL-6 and thromopoietin) on lympho-hematopoietic recovery. Patients will receive a uniform myeloablative conditioning and post-transplant immunoprophylaxis.

Official Title
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Single-Arm, Open Label, Interventional Phase II Clinical Trial Evaluating MGTA-456 in Patients With High-Risk Malignancy

Conditions
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Acute Myeloid Leukemia, Acute Lymphocytic Leukemia, Biphenotypic/Undifferentiated Leukemia, Chronic Myelogenous Leukemia, Myelodysplasia, Relapsed Large Cell Lymphoma, Mantle Cell Lymphoma, Hodgkin Lymphoma, Burkitt Lymphoma, Relapsed T-Cell Lymphoma, Lymphoplasmacytic Lymphoma

Intervention / Treatment
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* Drug: Fludarabine (FLU)
* Drug: Cyclophosphamide (CY)
* Drug: Total Body Irradiation (TBI)
* Drug: Tacrolimus (Tac)
* Drug: Mycophenolate Mofetil (MMF)
* Drug: Granulocyte Colony-Stimulating Factor (G-CSF)
* Drug: Busulfan (BU)
* Drug: Melphalan
* Drug: MGTA 456 Infusion


Participation Criteria
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Eligibility Criteria
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Age, Unit Cell Dose and HLA Match Criteria Subjects must be ≤55 years of age Subjects must weigh >11 kg Subjects must have a partially HLA matched UCB unit with a pre-cryopreserved TNC dose >1.0 x 107 per kilogram recipient weight. HLA matching is initially based on a minimum of 5 of 8 HLA alleles at high resolution A, B, C, DRB1 typing; searches will be performed according to the current Magenta Cord Blood Search Algorithm. Eligible Diseases: Acute myelogenous leukemia (AML) in morphological complete remission with: Minimal residual disease (MRD) by flow cytometry, or Intermediate to high risk leukemia in first (CR1) based on institutional criteria, eg. not favorable risk AML which is defined as having one of the following: t(8,21) without cKIT mutation inv(16) or t(16;16) without cKIT mutation Normal karyotype with mutated NPM1 but FLT3-ITD wild type Normal karyotype with double mutated CEBPA Acute promyelocytic leukemia (APL) in first molecular remission at the end of consolidation Any second or subsequent CR, or Secondary AML with prior malignancy that has been in remission for at least 12 months. Acute lymphocytic leukemia (ALL) at the following stages: High risk first morphological, cytogenetic and molecular CR with: MRD by flow cytometry, or Diagnosis of Philadelphia chromosome (Ph)+ ALL, or MLL rearrangement at diagnosis with slow early response at Day 14, or Hypodiploidy (< 44 chromosomes or DNA index < 0.81) at diagnosis, or End of induction M3 bone marrow, or End of induction M2 with M2-3 at Day 42. High risk second CR based on institutional criteria (eg, for children, bone marrow relapse <36 months from induction or T-lineage bone marrow relapse or very early isolated central nervous system (CNS) relapse <6 months from diagnosis, or slow re-induction (stage M2-3 at day 28 after induction) regardless of length remission. All patients with MRD by flow cytometry. Any third or subsequent CR. Secondary ALL Biphenotypic/undifferentiated leukemia in morphological, cytogenetic and molecular CR . Chronic Myelogenous Leukemia (CML) in high risk first chronic phase (failure of two tyrosine kinase inhibitors (TKI) or TKI intolerance), accelerated phase or second chronic phase. Myelodysplasia (MDS) IPSS Int-2 or High risk (i.e. RAEB, RAEBt <5% blasts) or other high risk features, including multiple cytopenias, high risk cytogenetics or lack of response to standard therapy.. Relapsed large-cell lymphoma, mantle-cell lymphoma and Hodgkin lymphoma that is chemotherapy sensitive and ineligible for an autologous transplant. Burkitt's lymphoma in CR2 or subsequent CR. Relapsed T-cell lymphoma that is chemotherapy sensitive in CR/PR that is ineligible for an autologous transplant. Organ Specific Inclusion Criteria Karnofsky score ≥70 (16 years and older), Lansky play score >50 (children 2-16 years, or 'adequate' score for children <2 years, as detailed in Appendix II. Adequate organ function defined as: Renal: Serum creatinine within normal range for age, or if serum creatinine outside normal range for age, then creatinine clearance >40 ml/min or GFR ≥70 mL/min/1.73 m2.normal for age Hepatic: Bilirubin <3x upper limit of normal (ULN) and AST, ALT and alkaline phosphatase <5x ULN. Pulmonary function: DLCO, FEV1, FEC (diffusion capacity) >5030% of predicted (corrected for hemoglobin); if unable to perform pulmonary function tests, then O2 saturation >95% on room air. Cardiac: No uncontrolled arrhythmia and left ventricular ejection fraction at rest must be >3545%. Available 'back-up' HSPC graft (e.g, second UCB unit, haploidentical related donor). Females of child bearing potential and sexually active males must agree to use adequate birth control during study treatment. Voluntary written consent signed (adult or parental) before performance of any study-related procedure not part of normal medical care. Exclusion Criteria Patients with a HLA matched sibling donor or a HLA matched unrelated donor who is available for marrow or peripheral blood stem cell collection at the desired time of transplant. Pregnant or breast feeding. The agents used in this study may be teratogenic to a fetus and there is no information on the excretion of agents into breast milk. Females of childbearing potential must have a blood test or urine study within 14 days prior to study enrollment to rule out pregnancy. Evidence of human immunodeficiency virus (HIV) infection or known HIV positive serology. Active bacterial, viral or fungal infection (currently taking medication and persistence of clinical signs and symptoms) with a minimum of 4 weeks of anti-fungal treatment Prior autologous or allogeneic transplant. Other active malignancy. Subjects >2 3 years of age unable to receive TBI 1320 cGy due to extensive prior therapy including >12 months alkylator therapy or >6 months alkylator therapy with extensive radiation, or prior Y-90 ibritumomab (Zevalin) or I-131 tostumomab (Bexxar), as part of their salvage therapy.

Ages Eligible for Study
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Maximum Age: 55 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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: FLU, CY, TBI + MGTA-456 infusion<br> | Drug: Fludarabine (FLU)<br>* 25 mg/m2 IV over 1 hour (<10 kg: 0.83 mg/kg IV over 1 hour)<br>Drug: Cyclophosphamide (CY)<br>* 60 mg/kg IV over 2 hours<br>Drug: Total Body Irradiation (TBI)<br>* 165 cGy twice daily<br>Drug: Tacrolimus (Tac)<br>* Tacrolimus will start day -3 and will be administered as a continuous IV infusion at a starting dose of 0.03 mg/kg/day. Goal trough levels will be 10-15 ng/mL for the first 14 days post-transplant and then decreased to a goal of 5-10 ng/ml thereafter.<br>Drug: Mycophenolate Mofetil (MMF)<br>* MMF 3 gram/day IV/PO for adult patients divided in 2 or 3 doses. Pediatric patients will receive MMF at the dose of 15 mg/kg/dose (max 1 gram per dose) every 8 hours beginning day -3.<br>Drug: Granulocyte Colony-Stimulating Factor (G-CSF)<br>* 5 ug/kg/d until the absolute neutrophil count (ANC) is >2500/uL for 2 consecutive days<br>Drug: MGTA 456 Infusion<br>* The target cell dose is >10 x 106 CD34/kg with a maximum TNC 2.7 x 108/kg for children (<18 years) and 8.1 × 108 cells/kg [expanded product only] for adults based on the highest cell dose windows evaluated in prior studies.<br>|
| Experimental: BU/ FLU/ MEL + MGTA-456 infusion Suspended: No<br> | Drug: Fludarabine (FLU)<br>* 25 mg/m2 IV over 1 hour (<10 kg: 0.83 mg/kg IV over 1 hour)<br>Drug: Tacrolimus (Tac)<br>* Tacrolimus will start day -3 and will be administered as a continuous IV infusion at a starting dose of 0.03 mg/kg/day. Goal trough levels will be 10-15 ng/mL for the first 14 days post-transplant and then decreased to a goal of 5-10 ng/ml thereafter.<br>Drug: Mycophenolate Mofetil (MMF)<br>* MMF 3 gram/day IV/PO for adult patients divided in 2 or 3 doses. Pediatric patients will receive MMF at the dose of 15 mg/kg/dose (max 1 gram per dose) every 8 hours beginning day -3.<br>Drug: Granulocyte Colony-Stimulating Factor (G-CSF)<br>* 5 ug/kg/d until the absolute neutrophil count (ANC) is >2500/uL for 2 consecutive days<br>Drug: Busulfan (BU)<br>* BU IV once daily with dose based on Pharmacokinetics (PK) calculator over 3 hours<br>Drug: Melphalan<br>* 50 mg/m2/day (1.7 mg/kg/day if < 10 kg) IV over 30 min<br>Drug: MGTA 456 Infusion<br>* The target cell dose is >10 x 106 CD34/kg with a maximum TNC 2.7 x 108/kg for children (<18 years) and 8.1 × 108 cells/kg [expanded product only] for adults based on the highest cell dose windows evaluated in prior studies.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Neutrophil Recovery | Incidence of neutrophil recovery by day 14 after transplantation in recipients of MGTA-456. | Day 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hospitalization Rates | Number of days alive without hospitalization between days 0 and 100 after transplantation | Day 0 and Day 100 | 
| Secondary Graft Failure | Incidence of secondary graft failure | 2 Years | 
| Platelet Recovery | Incidence of platelet recovery at day 42 | Day 42 | 
| Treatment Related Mortality (TRM) | Incidence of TRM at 6 months | 6 Months | 
| Grades II-IV Acute GVHD | Incidence of grades II-IV acute GVHD at day 100 | Day 100 | 
| Grades III-IV Acute GVHD | Incidence of grades III-IV acute GVHD at day 100 | Day 100 | 
| Chronic GVHD | Incidence of chronic GVHD at 1 year | 1 Year | 
| Relapse | Incidence of relapse at 2 years | 2 Years | 
| Non-catheter Associated Bacterial Infections | Incidence of non-catheter associated bacterial infections by day 100 | Day 100 | 
| Overall Survival (OS) | Incidence of overall survival (OS) at 2 years | 2 Years | 
| Event-Free Survival (EFS) | Incidence of event-free survival (EFS) at 2 years | 2 Years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CML, MCL, AML, ALL