Medigene transfered all rights to a new Sponsor

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.

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.

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.