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Dose-escalation part of the study to investigate 3 MDG1021 doses. Dose-expansion part of the study to investigate the selected optimal MDG1021 dose.

3 patients to receive dose1: target dose of 0.3x10\^6 HA-1H TCR transduced T cells/kg BW ±20% in 100 mL

MDG1021 dose 1

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

MDG1021 dose 2

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

MDG1021 dose 3

20 patients to receive the selected optimal dose

MDG1021 optimal dose

Peter van Balen, MD

Rene Goedkoop, MD

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.

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.

HA-1H TCR T Cell for Relapsed/Persistent Hematologic Malignancies After Allogeneic Stem Cell Transplantation

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

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

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

To evaluate the function of HA-1H TCR transduced T cells detectable in peripheral blood by ELISA, measuring Interferon gamma production

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

To evaluate disappearance of recipient hematopoiesis (chimerism analysis) in the blood

To evaluate disappearance of recipient hematopoiesis (chimerism analysis) in the bone marrow

To investigate biomarkers and molecular signatures, potentially related to safety, anti-tumor activity, the mode-of-action of MDG1021 and the pathophysiology of disease

To assess the incidence and severity of adverse events during the dose escalation part of the study according to the NCI CTCAE v5.0

To asses the maximum tolerated dose (MTD) of MDG1021 as determined by dose-limiting toxicities (DLTs)

To asses the recommended phase II dose (RP2D) of MDG1021

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

To assess the incidence and severity of AEs ≥ grade 3 (NCI CTCAE v5.0)

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

To assess the overall survival (OS) defined as the time from the date of signing the informed consent until the documented date of death.

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.

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.

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.

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.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
HA-1H TCR T Cell for Relapsed/Persistent Hematologic Malignancies After Allogeneic Stem Cell Transplantation	NCT04464889	Acute Myeloid L... Acute Lymphoid ... Myelodysplastic... Myeloproliferat... Chronic Myeloid... Myelofibrosis Multiple Myelom... Malignant Lymph...	MDG1021 dose 1 MDG1021 dose 2 MDG1021 dose 3 MDG1021 optimal...	18 Years -	Medigene AG
HA-1H TCR T Cell for Relapsed/Persistent Hematologic Malignancies After Allogeneic Stem Cell Transplantation	NCT04464889	Acute Myeloid L... Acute Lymphoid ... Myelodysplastic... Myeloproliferat... Chronic Myeloid... Myelofibrosis Multiple Myelom... Malignant Lymph...	MDG1021 dose 1 MDG1021 dose 2 MDG1021 dose 3 MDG1021 optimal...	18 Years -	Medigene AG
HA-1H TCR T Cell for Relapsed/Persistent Hematologic Malignancies After Allogeneic Stem Cell Transplantation	NCT04464889	Acute Myeloid L... Acute Lymphoid ... Myelodysplastic... Myeloproliferat... Chronic Myeloid... Myelofibrosis Multiple Myelom... Malignant Lymph...	MDG1021 dose 1 MDG1021 dose 2 MDG1021 dose 3 MDG1021 optimal...	18 Years -	Medigene AG

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