Clinical trial NCT04464889: HA-1H TCR T Cell for Relapsed/Persistent Hematologic Malignancies After Allogeneic Stem Cell Transplantation
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
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE1
Conditions: Acute Myeloid Leukemia
Acute Lymphoid Leukemia
Myelodysplastic Syndromes
Myeloproliferative Disorders
Chronic Myeloid Leukemia
Myelofibrosis
Multiple Myeloma
Malignant Lymphoma
Keywords: Allogeneic hematopoietic stem cell transplantation
Relapsed hematologic malignancy
Persistent hematologic malignancy
Lead sponsor: Medigene AG
Sponsor class: INDUSTRY
First posted: 2020-07-09
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
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.
Primary purpose: TREATMENT

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.

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.

Eligibility 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.

Primary outcomes:
measure: Safety and tolerability of HA-1H TCR transduced T cells: incidence and severity of adverse events
timeFrame: up to 28 days after T cell infusion
measure: Maximum tolerated dose (MTD) of HA-1H TCR transduced T cells
timeFrame: up to 28 days after T cell infusion
measure: Recommended phase 2 dose (RP2D) of HA-1H TCR transduced T cells
timeFrame: up to 28 days after T cell infusion
measure: Safety and tolerability of HA-1H TCR transduced T cells at recommended phase II dose: incidence and severity of adverse events
timeFrame: up to 28 days after T cell infusion
Secondary outcomes:
measure: Safety and tolerability (both parts of the study): incidence and severity of adverse events
timeFrame: Up to 12 months after T cell infusion
measure: Overall response rate
timeFrame: Up to 12 months after T cell infusion
measure: Overall survival
timeFrame: Up to 12 months afterT cell infusion
measure: Progression free survival
timeFrame: Up to 12 months afterT cell infusion
measure: Duration of response
timeFrame: Up to 12 months afterT cell infusion
measure: Quality of life (EQ-5D-5L)
timeFrame: Up to 12 months afterT cell infusion
measure: Quality of life (VAS)
timeFrame: Up to 12 months afterT cell infusion
Other outcomes:
measure: Feasibility of manufacturing HA-1H TCR transducer T cells: proportion of patients for whom leukapheresis was feasible
timeFrame: Up to Day 0 after T cell infusion
measure: Persistence and expansion of HA-1H transduced T cells in peripheral blood
timeFrame: Up to 12 months afterT cell infusion
measure: Function of HA-1H TCR transduced T cells detectable in peripheral blood
timeFrame: Up to 12 months afterT cell infusion
measure: Phenotype of HA-1H TCR transduced T cells detectable in peripheral blood
timeFrame: Up to 12 months afterT cell infusion
measure: Disappearance of recipient hematopoiesis (chimerism analysis) in the blood
timeFrame: Up to 12 months after T cell infusion
measure: Disappearance of recipient hematopoiesis (chimerism analysis) in the bone marrow
timeFrame: Up to 3 months after T cell infusion
measure: Other explorative endpoints
timeFrame: Up to 12 months after T infusion
Locations:
city: Leiden
country: Netherlands
facility: Leiden University Medical Centre
state: Zuid Holland
Study officials:
affiliation: Leiden University Medical Centre
name: Peter van Balen, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Medigene AG
name: Rene Goedkoop, MD
role: STUDY_DIRECTOR
References: