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

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.

Study Overview

• Status: Withdrawn
• Conditions: Acute Myeloid Leukemia; Myelodysplastic Syndromes; Myeloproliferative Disorders; Multiple Myeloma; Myelofibrosis; Chronic Myeloid Leukemia; Acute Lymphoid Leukemia; Malignant Lymphoma
• Intervention / Treatment: Drug: MDG1021 dose 1; Drug: MDG1021 dose 2; Drug: MDG1021 dose 3; Drug: MDG1021 optimal dose

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.

• Study Type: Interventional
• Phase: Phase 1

Contacts and Locations

Study Locations

• Netherlands
  • Zuid Holland
    • Leiden, Zuid Holland, Netherlands, 2333 ZA Leiden
      • Leiden University Medical Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

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: 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety and tolerability of HA-1H TCR transduced T cells: incidence and severity of adverse events	To assess the incidence and severity of adverse events during the dose escalation part of the study according to the NCI CTCAE v5.0	up to 28 days after T cell infusion
Maximum tolerated dose (MTD) of HA-1H TCR transduced T cells	To asses the maximum tolerated dose (MTD) of MDG1021 as determined by dose-limiting toxicities (DLTs)	up to 28 days after T cell infusion
Recommended phase 2 dose (RP2D) of HA-1H TCR transduced T cells	To asses the recommended phase II dose (RP2D) of MDG1021	up to 28 days after T cell infusion
Safety and tolerability of HA-1H TCR transduced T cells at recommended phase II dose: incidence and severity of adverse events	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	up to 28 days after T cell infusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety and tolerability (both parts of the study): incidence and severity of adverse events	To assess the incidence and severity of AEs ≥ grade 3 (NCI CTCAE v5.0)	Up to 12 months after T cell infusion
Overall response rate	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	Up to 12 months after T cell infusion
Overall survival	To assess the overall survival (OS) defined as the time from the date of signing the informed consent until the documented date of death.	Up to 12 months afterT cell infusion
Progression free survival	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.	Up to 12 months afterT cell infusion
Duration of response	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.	Up to 12 months afterT cell infusion
Quality of life (EQ-5D-5L)	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.	Up to 12 months afterT cell infusion
Quality of life (VAS)	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.	Up to 12 months afterT cell infusion

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Feasibility of manufacturing HA-1H TCR transducer T cells: proportion of patients for whom leukapheresis was feasible	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	Up to Day 0 after T cell infusion
Persistence and expansion of HA-1H transduced T cells in peripheral blood	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	Up to 12 months afterT cell infusion
Function of HA-1H TCR transduced T cells detectable in peripheral blood	To evaluate the function of HA-1H TCR transduced T cells detectable in peripheral blood by ELISA, measuring Interferon gamma production	Up to 12 months afterT cell infusion
Phenotype of HA-1H TCR transduced T cells detectable in peripheral blood	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	Up to 12 months afterT cell infusion
Disappearance of recipient hematopoiesis (chimerism analysis) in the blood	To evaluate disappearance of recipient hematopoiesis (chimerism analysis) in the blood	Up to 12 months after T cell infusion
Disappearance of recipient hematopoiesis (chimerism analysis) in the bone marrow	To evaluate disappearance of recipient hematopoiesis (chimerism analysis) in the bone marrow	Up to 3 months after T cell infusion
Other explorative endpoints	To investigate biomarkers and molecular signatures, potentially related to safety, anti-tumor activity, the mode-of-action of MDG1021 and the pathophysiology of disease	Up to 12 months after T infusion

Collaborators and Investigators

• Sponsor: Medigene AG
• Investigators: Principal Investigator: Peter van Balen, MD, Leiden University Medical Centre; Study Director: Rene Goedkoop, MD, Medigene AG

Study record dates

Study Major Dates

• Study Start (Actual): July 2, 2020
• Primary Completion (Anticipated): July 1, 2023
• Study Completion (Anticipated): July 1, 2025

Study Registration Dates

• First Submitted: July 1, 2020
• First Submitted That Met QC Criteria: July 6, 2020
• First Posted (Actual): July 9, 2020

Study Record Updates

• Last Update Posted (Actual): October 8, 2021
• Last Update Submitted That Met QC Criteria: September 30, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Keywords: Allogeneic hematopoietic stem cell transplantation; Relapsed hematologic malignancy; Persistent hematologic malignancy
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Neoplasms by Site; Bone Marrow Diseases; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Neoplasms, Plasma Cell; Neoplasms; Lymphoma; Myelodysplastic Syndromes; Hematologic Neoplasms; Multiple Myeloma; Leukemia; Leukemia, Myeloid; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Myeloproliferative Disorders
• Other Study ID Numbers: CD-TCR-003

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No