Multiple Myeloma Clinical Trial
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
NCT number | NCT04464889 |
Other study ID # | CD-TCR-003 |
Secondary ID | |
Status | Withdrawn |
Phase | Phase 1 |
First received | |
Last updated | |
Start date | July 2, 2020 |
Est. completion date | July 2025 |
Verified date | September 2021 |
Source | Medigene AG |
Contact | n/a |
Is FDA regulated | No |
Health authority | |
Study type | Interventional |
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.
Status | Withdrawn |
Enrollment | 0 |
Est. completion date | July 2025 |
Est. primary completion date | July 2023 |
Accepts healthy volunteers | No |
Gender | All |
Age group | 18 Years and older |
Eligibility | 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 ß-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. |
Country | Name | City | State |
---|---|---|---|
Netherlands | Leiden University Medical Centre | Leiden | Zuid Holland |
Lead Sponsor | Collaborator |
---|---|
Medigene AG |
Netherlands,
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Other | 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 | |
Other | 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 | |
Other | 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 | |
Other | 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 | |
Other | 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 | |
Other | 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 | 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 | |
Primary | 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 | |
Primary | 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 | |
Primary | 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 | |
Primary | 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 | 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 | |
Secondary | 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 | |
Secondary | 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 | |
Secondary | 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 | |
Secondary | 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 | |
Secondary | 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 | |
Secondary | 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 |
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