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

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Acute Myeloid Leukemia; Hodgkin Lymphoma; Burkitt Lymphoma; Mantle Cell Lymphoma; Lymphoplasmacytic Lymphoma; Acute Lymphocytic Leukemia; Chronic Myelogenous Leukemia; Myelodysplasia; Relapsed T-Cell Lymphoma; Relapsed Large Cell Lymphoma; Biphenotypic/Undifferentiated Leukemia
• Intervention / Treatment: 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: MGTA 456 Infusion; Drug: Busulfan (BU); Drug: Melphalan

• Study Type: Interventional
• Enrollment (Actual): 22
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • Masonic Cancer Center at University of Minnesota

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 55 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: FLU, CY, TBI + MGTA-456 infusion

Drug: Fludarabine (FLU); 25 mg/m2 IV over 1 hour (<10 kg: 0.83 mg/kg IV over 1 hour); Drug: Cyclophosphamide (CY); 60 mg/kg IV over 2 hours; Drug: Total Body Irradiation (TBI); 165 cGy twice daily; Drug: Tacrolimus (Tac); 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.; Drug: Mycophenolate Mofetil (MMF); 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.; Drug: Granulocyte Colony-Stimulating Factor (G-CSF); 5 ug/kg/d until the absolute neutrophil count (ANC) is >2500/uL for 2 consecutive days; Drug: MGTA 456 Infusion; 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.; Drug: Busulfan (BU); BU IV once daily with dose based on Pharmacokinetics (PK) calculator over 3 hours; Drug: Melphalan; 50 mg/m2/day (1.7 mg/kg/day if < 10 kg) IV over 30 min

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Neutrophil Recover	Percentage of participants with 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

Collaborators and Investigators

• Sponsor: Masonic Cancer Center, University of Minnesota

Study record dates

Study Major Dates

• Study Start (Actual): January 2, 2019
• Primary Completion (Actual): June 23, 2020
• Study Completion (Estimated): June 28, 2024

Study Registration Dates

• First Submitted: September 14, 2018
• First Submitted That Met QC Criteria: September 14, 2018
• First Posted (Actual): September 17, 2018

Study Record Updates

• Last Update Posted (Actual): April 10, 2024
• Last Update Submitted That Met QC Criteria: March 15, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: AML; ALL; MCL; CML
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Virus Diseases; Infections; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Disease Attributes; Bone Marrow Diseases; Hematologic Diseases; Hemorrhagic Disorders; Myeloproliferative Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; DNA Virus Infections; Tumor Virus Infections; Neoplasms, Plasma Cell; Leukemia, Lymphoid; Epstein-Barr Virus Infections; Herpesviridae Infections; Lymphoma, B-Cell; Chronic Disease; Lymphoma; Leukemia; Leukemia, Myeloid; Burkitt Lymphoma; Lymphoma, Mantle-Cell; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Waldenstrom Macroglobulinemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Anti-Bacterial Agents; Adjuvants, Immunologic; Antibiotics, Antineoplastic; Antitubercular Agents; Antibiotics, Antitubercular; Calcineurin Inhibitors; Cyclophosphamide; Lenograstim; Melphalan; Fludarabine; Tacrolimus; Mycophenolic Acid; Busulfan
• Other Study ID Numbers: 2018LS051; MT2018-06 (Other Identifier: University of Minnesota Masonic Cancer Center)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No