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

• ClinicalTrials.gov Identifier: NCT03674411
• Recruitment Status: Active, not recruiting
• First Posted: September 17, 2018
• Last Update Posted: August 16, 2021
• Sponsor: Masonic Cancer Center, University of Minnesota
• Information provided by (Responsible Party): Masonic Cancer Center, University of Minnesota

Study Description

Brief 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.

Condition or disease	Intervention/treatment	Phase
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	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	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 22 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Single-Arm, Open Label, Interventional Phase II Clinical Trial Evaluating MGTA-456 in Patients With High-Risk Malignancy
• Actual Study Start Date: January 2, 2019
• Estimated Primary Completion Date: July 2023
• Estimated Study Completion Date: August 2023

Arms and Interventions

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.
Experimental: BU/ FLU/ MEL + MGTA-456 infusion Suspended: No	Drug: Fludarabine (FLU); 25 mg/m2 IV over 1 hour (<10 kg: 0.83 mg/kg IV over 1 hour); 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: 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; 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.

Outcome Measures

Primary Outcome Measures :

1. Neutrophil Recovery [ Time Frame: Day 14 ]
   Incidence of neutrophil recovery by day 14 after transplantation in recipients of MGTA-456.

Secondary Outcome Measures :

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

Eligibility Criteria

• Ages Eligible for Study: up to 55 Years (Child, Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

United States, Minnesota

Masonic Cancer Center at University of Minnesota

Minneapolis, Minnesota, United States, 55455

Sponsors and Collaborators

Masonic Cancer Center, University of Minnesota

More Information

• Responsible Party: Masonic Cancer Center, University of Minnesota
• ClinicalTrials.gov Identifier: NCT03674411
• Other Study ID Numbers: 2018LS051; MT2018-06 ( Other Identifier: University of Minnesota Masonic Cancer Center )
• First Posted: September 17, 2018
• Last Update Posted: August 16, 2021
• Last Verified: August 2021

• 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

Keywords provided by Masonic Cancer Center, University of Minnesota:

AML; ALL; CML; MCL

Additional relevant MeSH terms:

Burkitt Lymphoma; Lymphoma; Leukemia; Leukemia, Myeloid; Lymphoma, Mantle-Cell; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Waldenstrom Macroglobulinemia; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Leukemia, Lymphoid; Lymphoma, Non-Hodgkin; Myeloproliferative Disorders; Bone Marrow Diseases; Hematologic Diseases; Epstein-Barr Virus Infections; Herpesviridae Infections; DNA Virus Infections; Virus Diseases; Infections; Tumor Virus Infections; Lymphoma, B-Cell; Neoplasms, Plasma Cell; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases