Trial Evaluating MGTA-456 in Patients With High-Risk Malignancy
Condition: 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
MeSH terms: Burkitt Lymphoma; Lymphoma; Leukemia; Leukemia, Myeloid; Lymphoma, Mantle-Cell; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Waldenstrom Macroglobulinemia
Intervention: Fludarabine (FLU); Cyclophosphamide (CY); Total Body Irradiation (TBI); Tacrolimus (Tac); Mycophenolate Mofetil (MMF); Granulocyte Colony-Stimulating Factor (G-CSF); Busulfan (BU); Melphalan; MGTA 456 Infusion
Intervention description: 25 mg/m2 IV over 1 hour (<10 kg: 0.83 mg/kg IV over 1 hour); 60 mg/kg IV over 2 hours; 165 cGy twice daily; 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.; 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.; 5 ug/kg/d until the absolute neutrophil count (ANC) is >2500/uL for 2 consecutive days; BU IV once daily with dose based on Pharmacokinetics (PK) calculator over 3 hours; 50 mg/m2/day (1.7 mg/kg/day if < 10 kg) IV over 30 min; 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.
Intervention MeSH terms: Mycophenolic Acid; Cyclophosphamide; Melphalan; Busulfan; Fludarabine; Tacrolimus; Lenograstim
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 22.0
Sex: All
Maximum age: 55 Years
Healthy volunteers: No
Keywords: AML; ALL; CML; MCL

Summary:

      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.
    

Eligibility criteria:

        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.