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

Sponsor

Medigene AG (Industry)

Overall Status

Withdrawn

CT.gov ID

NCT04464889

Collaborator

(none)

Enrollment

Location

Arm

Anticipated Duration (Months)

Patients Per Site Per Month

Study Details

Study Description

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

0 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.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 :

Jul 2, 2020

Anticipated Primary Completion Date :

Jul 1, 2023

Anticipated Study Completion Date :

Jul 1, 2025

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

Safety and tolerability of HA-1H TCR transduced T cells: incidence and severity of adverse events [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
Maximum tolerated dose (MTD) of HA-1H TCR transduced T cells [up to 28 days after T cell infusion]
To asses the maximum tolerated dose (MTD) of MDG1021 as determined by dose-limiting toxicities (DLTs)
Recommended phase 2 dose (RP2D) of HA-1H TCR transduced T cells [up to 28 days after T cell infusion]
To asses the recommended phase II dose (RP2D) of MDG1021
Safety and tolerability of HA-1H TCR transduced T cells at recommended phase II dose: incidence and severity of adverse events [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

Safety and tolerability (both parts of the study): incidence and severity of adverse events [Up to 12 months after T cell infusion]
To assess the incidence and severity of AEs ≥ grade 3 (NCI CTCAE v5.0)
Overall response rate [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
Overall survival [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.
Progression free survival [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.
Duration of response [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.
Quality of life (EQ-5D-5L) [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.
Quality of life (VAS) [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

Feasibility of manufacturing HA-1H TCR transducer T cells: proportion of patients for whom leukapheresis was feasible [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
Persistence and expansion of HA-1H transduced T cells in peripheral blood [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
Function of HA-1H TCR transduced T cells detectable in peripheral blood [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
Phenotype of HA-1H TCR transduced T cells detectable in peripheral blood [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
Disappearance of recipient hematopoiesis (chimerism analysis) in the blood [Up to 12 months after T cell infusion]
To evaluate disappearance of recipient hematopoiesis (chimerism analysis) in the blood
Disappearance of recipient hematopoiesis (chimerism analysis) in the bone marrow [Up to 3 months after T cell infusion]
To evaluate disappearance of recipient hematopoiesis (chimerism analysis) in the bone marrow
Other explorative endpoints [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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

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.
Patients positive for HLA-A*02:01 according to genotyping results
Patients positive for HA-1H
Patients who received the allo-HSCT at least 100 days preceding the leukapheresis
Patients (i.e. recipient) transplanted with a sibling or unrelated HSCT donor
donor being HLA-A*02:01 positive and HA-1H negative, or
a donor with a single mismatch at HLA-A*02:01, being HA-1H positive or negative
Patients from whom at least 10x10^6 donor CD8+ T cells can be harvested by leukapheresis
Age ≥ 18 years, of either sex
ECOG performance status 0-2.
Life expectancy of at least 3 months
Patients must be able to understand and be willing to give signed informed consent

Exclusion Criteria:

Evidence of acute or chronic graft versus host disease (GVHD) ≥ grade II
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
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:
Creatinine > 2.5 times the upper limit of normal (ULN) serum level
Total bilirubin, ALAT, ASAT > 3.0 x ULN serum level
Cardiac left ventricular ejection fraction < 35% at rest
Severe restrictive or obstructive lung disease
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
Patients with a history of primary immunodeficiency
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
Patients both with urinary outflow obstructions and on dialysis or patients for whom cyclophosphamide is contraindicated for other reasons
Known or suspected hypersensitivity or intolerance to IMP, cyclophosphamide, fludarabine and/or tocilizumab or to any of the excipients
Participation in any clinical study < 60 days prior to first IMP administration in case of antibodies and < 14 days for all other IMPs
Vulnerable patients and/or patients unwilling or unable to comply with procedures required in this clinical study protocol
Pregnant or lactating women
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
Fertile men not agreeing to use effective contraceptive methods during the clinical study

Exclusion criteria at time of IMP administration:

Uncontrolled central nervous system (CNS) disease
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
Evidence of acute or chronic graft versus host disease (GVHD) ≥ grade II
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.
If not enough starting material is collected during leukapheresis, the patient will be excluded from study participation and receive best available standard therapy.