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Trial record 1 of 1 for:    MDG1021
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HA-1H TCR T Cell for Relapsed/Persistent Hematologic Malignancies After Allogeneic Stem Cell Transplantation

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ClinicalTrials.gov Identifier: NCT04464889
Recruitment Status : Recruiting
First Posted : July 9, 2020
Last Update Posted : July 9, 2020
Sponsor:
Information provided by (Responsible Party):
Medigene AG

Brief Summary:
This is a non-randomised, open-label phase I study of an investigational medicinal product (IMP) consisting of a HLA-A*02:01 restricted HA-1H T cell receptor transduced T cell (MDG1021) immunotherapy for relapsed or persistent hematologic malignancies after allogeneic hematopoietic stem cell transplantation. The aim of the study is to determine the recommended phase II dose of MDG1021.

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia Acute Lymphoid Leukemia Myelodysplastic Syndromes Myeloproliferative Disorders Chronic Myeloid Leukemia Myelofibrosis Multiple Myeloma Malignant Lymphoma Drug: MDG1021 dose 1 Drug: MDG1021 dose 2 Drug: MDG1021 dose 3 Drug: MDG1021 optimal dose Phase 1

Detailed Description:

This phase I is designed to assess the safety and feasibility of a HLA-A*02:01 restricted, HA-1H T cell receptor (TCR) transduced patient-derived T cell (MDG1021) immunotherapy, with secondary endpoints including preliminary efficacy, in patients with relapsed or persistent hematologic malignancies after allogeneic hematopoietic stem cell transplantation. In the dose-escalation part of the study, at least 9 patients will be treated with MDG1021 at 3 different doses to assess the safety and the maximum tolerated dose using a standard 3+3 cohort design. Thereafter, the selected optimal MDG1021 dose will be assessed for safety and preliminary efficacy in 20 additional patients during the dose-expansion part of the study. Manufacturing feasibility will be determined. MDG1021 will be administered by single intravenous infusion.

HA-1H is exclusively expressed on cells of the hematopoietic system. If the patient's blood-cells, and thus lymphoma or leukemic cells, carry the immunogenic version of the HA-1H antigen on their surface and the donor stem cells do not, MDG1021 immunotherapy could eradicate the patient's cancer cells and allow the donor stem cells to repopulate the patient's blood forming system.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 29 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description:

The aim of the study is to determine the recommended phase II dose (RP2D) of MDG1021 that will be determined on the basis of safety and ability to manufacture a cohort specific MDG1021 dose. The dose-escalation part of the study is designed to assess the safety and the MTD of MDG1021, using a standard 3+3 cohort design, with up to 3 additional subjects to be enrolled in case of dose limiting toxicity (DLT).

Upon completion of the dose-escalation part of the study, 20 eligible patients will be treated in the expansion part of the study with MDG1021 at the RP2D to further evaluate safety, feasibility and preliminary efficacy.

Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Dose-Escalation, Open Label Phase I Study to Assess the Safety, Feasibility and Preliminary Efficacy of HA-1H TCR Modified T Cells, MDG1021, in Patients With Relapsed or Persistent Hematologic Malignancies After Allogeneic HSCT With or Without Unmanipulated DLI
Actual Study Start Date : July 2, 2020
Estimated Primary Completion Date : July 2023
Estimated Study Completion Date : January 2024


Arm Intervention/treatment
Experimental: MDG1021
Dose-escalation part of the study to investigate 3 MDG1021 doses. Dose-expansion part of the study to investigate the selected optimal MDG1021 dose.
Drug: MDG1021 dose 1
3 patients to receive dose1: target dose of 0.3x10^6 HA-1H TCR transduced T cells/kg BW ±20% in 100 mL

Drug: MDG1021 dose 2
3 patients to receive dose 2: target dose of 1x10^6 HA-1H TCR transduced T cells/kg BW ±20% in 100 mL

Drug: MDG1021 dose 3
3 patients to receive dose 3: target dose of 3x10^6 HA-1H TCR transduced T cells/kg BW +20% in 100 mL

Drug: MDG1021 optimal dose
20 patients to receive the selected optimal dose




Primary Outcome Measures :
  1. Safety and tolerability of HA-1H TCR transduced T cells: incidence and severity of adverse events [ Time Frame: up to 28 days after T cell infusion ]
    To assess the incidence and severity of adverse events during the dose escalation part of the study according to the NCI CTCAE v5.0

  2. Maximum tolerated dose (MTD) of HA-1H TCR transduced T cells [ Time Frame: up to 28 days after T cell infusion ]
    To asses the maximum tolerated dose (MTD) of MDG1021 as determined by dose-limiting toxicities (DLTs)

  3. Recommended phase 2 dose (RP2D) of HA-1H TCR transduced T cells [ Time Frame: up to 28 days after T cell infusion ]
    To asses the recommended phase II dose (RP2D) of MDG1021

  4. Safety and tolerability of HA-1H TCR transduced T cells at recommended phase II dose: incidence and severity of adverse events [ Time Frame: up to 28 days after T cell infusion ]
    To assess the incidence and severity of adverse events of MDG1021 at the RP2D during the expansion part of the study according to the NCI CTCAE v5.0


Secondary Outcome Measures :
  1. Safety and tolerability (both parts of the study): incidence and severity of adverse events [ Time Frame: Up to 12 months after T cell infusion ]
    To assess the incidence and severity of AEs ≥ grade 3 (NCI CTCAE v5.0)

  2. Overall response rate [ Time Frame: Up to 12 months after T cell infusion ]
    To assess the overall response rate defined as the proportion of patients with a best overall response of complete response (CR), partial response (PR), and/or their disease specific subcategories

  3. Overall survival [ Time Frame: Up to 12 months afterT cell infusion ]
    To assess the overall survival (OS) defined as the time from the date of signing the informed consent until the documented date of death.

  4. Progression free survival [ Time Frame: Up to 12 months afterT cell infusion ]
    To assess the progression-free survival (PFS) defined as the time from the date of signing the date of signed informed consent until progressive disease/relapse or death, whichever occurs first.

  5. Duration of response [ Time Frame: Up to 12 months afterT cell infusion ]
    To assess the duration of response (DoR) defined as time from the date of the first documented response to the first documented progression of disease or death due to underlying cancer.

  6. Quality of life (EQ-5D-5L) [ Time Frame: Up to 12 months afterT cell infusion ]
    The quality of life will be assessed by using the EQ-5D-5L questionnaire, consisting of 5 questions. Higher scores correspond to higher quality of life.

  7. Quality of life (VAS) [ Time Frame: Up to 12 months afterT cell infusion ]
    The quality of life will be assessed by a visual analog scale (EuroQoL), having a range of 0 ot 100, with higher scores corresponding to better quality of life.


Other Outcome Measures:
  1. Feasibility of manufacturing HA-1H TCR transducer T cells: proportion of patients for whom leukapheresis was feasible [ Time Frame: Up to Day 0 after T cell infusion ]
    Feasibility is determined by the proportion of patients for whom leukapheresis was feasible, for whom manufacturing MDG1021 was feasible, and whom received MDG1021 by intravenous infusion

  2. Persistence and expansion of HA-1H transduced T cells in peripheral blood [ Time Frame: Up to 12 months afterT cell infusion ]
    To evaluate the persistence (flow cytometry with tetramers evaluating the % HA-1H transduced T cells among all T cells) and expansion of HA-1H transduced T cells (as % HA-1H transduced T cells among all T cells over time) in peripheral blood

  3. Function of HA-1H TCR transduced T cells detectable in peripheral blood [ Time Frame: Up to 12 months afterT cell infusion ]
    To evaluate the function of HA-1H TCR transduced T cells detectable in peripheral blood by ELISA, measuring Interferon gamma production

  4. Phenotype of HA-1H TCR transduced T cells detectable in peripheral blood [ Time Frame: Up to 12 months afterT cell infusion ]
    To evaluate the phenotype of HA-1H TCR transduced T cells detectable in peripheral blood by flow cytometry of T cell subtypes expressed in % of all T cells

  5. Disappearance of recipient hematopoiesis (chimerism analysis) in the blood [ Time Frame: Up to 12 months after T cell infusion ]
    To evaluate disappearance of recipient hematopoiesis (chimerism analysis) in the blood

  6. Disappearance of recipient hematopoiesis (chimerism analysis) in the bone marrow [ Time Frame: Up to 3 months after T cell infusion ]
    To evaluate disappearance of recipient hematopoiesis (chimerism analysis) in the bone marrow

  7. Other explorative endpoints [ Time Frame: Up to 12 months after T infusion ]
    To investigate biomarkers and molecular signatures, potentially related to safety, anti-tumor activity, the mode-of-action of MDG1021 and the pathophysiology of disease



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Relapsed or persistent disease is defined according to disease specific guidelines (AML, CML, MM, ALL, MDS, MPN, MF and malignant B- or T-cell lymphoma) and includes MRD positivity.
  2. Patients positive for HLA-A*02:01 according to genotyping results
  3. Patients positive for HA-1H
  4. Patients who received the allo-HSCT at least 100 days preceding the leukapheresis
  5. Patients (i.e. recipient) transplanted with a sibling or unrelated HSCT donor

    1. donor being HLA-A*02:01 positive and HA-1H negative, or
    2. a donor with a single mismatch at HLA-A*02:01, being HA-1H positive or negative
  6. Patients from whom at least 10x10^6 donor CD8+ T cells can be harvested by leukapheresis
  7. Age ≥ 18 years, of either sex
  8. ECOG performance status 0-2.
  9. Life expectancy of at least 3 months
  10. Patients must be able to understand and be willing to give signed informed consent

Exclusion Criteria:

  1. Evidence of acute or chronic graft versus host disease (GVHD) ≥ grade II
  2. Serologic evidence of acute or chronic hepatitis B virus infection (i.e. positive for HBsAg or IgM anti-HBc). Positive HIV and HCV serology or active bacterial infection
  3. Medical or psychological conditions that would make the patient unsuitable candidate for cell therapy at the discretion of the investigator. Special risks to be considered:

    1. Creatinine > 2.5 times the upper limit of normal (ULN) serum level
    2. Total bilirubin, ALAT, ASAT > 3.0 x ULN serum level
    3. Cardiac left ventricular ejection fraction < 35% at rest
    4. Severe restrictive or obstructive lung disease
  4. Clinically significant and ongoing immune suppression including, but not limited to immunosuppressive agents (e.g. cyclosporine or corticosteroids (at an equivalent dose of ≥ 10 mg prednisone per day)). Inhaled steroid and physiological replacement for adrenal insufficiency is allowed
  5. Patients with a history of primary immunodeficiency
  6. Patients with a currently active second malignancy other than nonmelanoma skin cancers or subjects with history of prior malignancy and previously treated with a curative intent therapy less than 1 year ago
  7. Patients both with urinary outflow obstructions and on dialysis or patients for whom cyclophosphamide is contraindicated for other reasons
  8. Known or suspected hypersensitivity or intolerance to IMP, cyclophosphamide, fludarabine and/or tocilizumab or to any of the excipients
  9. Participation in any clinical study < 60 days prior to first IMP administration in case of antibodies and < 14 days for all other IMPs
  10. Vulnerable patients and/or patients unwilling or unable to comply with procedures required in this clinical study protocol
  11. Pregnant or lactating women
  12. Women of child-bearing potential not using highly effective method(s) of birth control (i.e., with low failure rate < 1% per year) throughout the study and/or unwilling to be tested for pregnancy. A negative serum β-hCG test is required at baseline
  13. Fertile men not agreeing to use effective contraceptive methods during the clinical study

    Exclusion criteria at time of IMP administration:

  14. Uncontrolled central nervous system (CNS) disease
  15. Uncontrolled, life threatening infections or uncontrolled disseminated intravascular coagulation; however, if these problems resolve, the start of treatment can be initiated on a delayed schedule
  16. Evidence of acute or chronic graft versus host disease (GVHD) ≥ grade II
  17. Unable to generate HA-1H TCR transduced T cells for transfusion (out of specification). However, if a lower than planned number of cells is available, the patient will have the option to receive the OOS HA-1H TCR transduced T cells product (cell dose must be at least the lowest dose level of D1 and will be analyzed in the safety and full analysis set populations.
  18. If not enough starting material is collected during leukapheresis, the patient will be excluded from study participation and receive best available standard therapy.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04464889


Contacts
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Contact: Peter van Balen, MD +31 71 5262267 p.van_Balen@lumc.nl

Locations
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Netherlands
Leiden University Medical Centre Recruiting
Leiden, Zuid Holland, Netherlands, 2333 ZA Leiden
Contact: Peter van Balen, MD    +31 71 5262267    p.van_balen@lumc.nl   
Sponsors and Collaborators
Medigene AG
Investigators
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Principal Investigator: Peter van Balen, MD Leiden University Medical Centre
Study Director: Rene Goedkoop, MD Medigene AG
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Responsible Party: Medigene AG
ClinicalTrials.gov Identifier: NCT04464889    
Other Study ID Numbers: CD-TCR-003
First Posted: July 9, 2020    Key Record Dates
Last Update Posted: July 9, 2020
Last Verified: July 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Medigene AG:
Allogeneic hematopoietic stem cell transplantation
Relapsed hematologic malignancy
Persistent hematologic malignancy
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Multiple Myeloma
Hematologic Neoplasms
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Leukemia, Lymphoid
Lymphoma
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Myelodysplastic Syndromes
Myeloproliferative Disorders
Neoplasms
Neoplasms by Histologic Type
Neoplasms, Plasma Cell
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Bone Marrow Diseases
Neoplasms by Site
Lymphatic Diseases