TCR Modified T Cells MDG1011 in High Risk Myeloid and Lymphoid Neoplasms

NCT ID: NCT03503968

Last Updated: 2023-02-15

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 9 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-03-27
• Study Completion Date: 2022-07-15

Brief Summary

This is a multicentre, non-randomized, open-label, Phase I/II clinical trial of MDG1011, an investigational medicinal product (IMP), consisting of patient-derived autologous T cells, persistently transduced with a Preferentially Expressed Antigen in Melanoma (PRAME)-specific human leukocyte antigen (HLA)-A*02:01-restricted T cell receptor (TCR).

Detailed Description

Phase I:

The Phase I dose escalation part will establish the MTD/RP2D in subjects with high risk myeloid and lymphoid neoplasms, a total of 3 disease entities.

Phase I subjects will be enrolled into the following cohorts and treated with a single intravenous (i.v.) infusion of IMP:

• Cohort 1: target dose of 1 x 105 T cells/kg ± 20%
• Cohort 2: target dose of 1 x 106 T cells/kg ± 20%
• Cohort 3: target dose of 5 x 106 T cells/kg ± 20%
• Optional cohort 4: up to 1 x 107 T cells/kg + 20%

Phase II:

The Phase II part consists of two arms, each representing one disease entity. Within each arm, representing a disease entity, subjects will be enrolled in 2 different treatment groups to receive either:

1. IMP in the treatment group (up to 20 subjects who are positive for human leukocyte antigen (HLA)-A*02:01); Or

2. therapy as per Investigator's discretion in the concurrent control (up to 20 subjects who are negative for HLA-A*02:01).

Conditions

Safety; Tolerability; Feasibility; Treatment Efficacy

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Phase I - 3 disease entities

MDG1011 administration of escalating doses

Group Type: EXPERIMENTAL

MDG1011

Intervention Type: DRUG

PRAME-T-Cell Receptor Gene Modified Autologous T Cells

Phase II - HLA*02:01 - disease entity 1

MDG1011 administration of Phase II recommended dose

Group Type: EXPERIMENTAL

MDG1011

Intervention Type: DRUG

PRAME-T-Cell Receptor Gene Modified Autologous T Cells

Phase II - HLA*other - disease entity 1

Investigator Choice therapy

Group Type: ACTIVE_COMPARATOR

Investigator Choice therapy

Intervention Type: OTHER

Any intervention/therapy chosen by the investigator

Phase II - HLA*02:01 - disease entity 2

MDG1011 administration of Phase II recommended dose

Group Type: EXPERIMENTAL

MDG1011

Intervention Type: DRUG

PRAME-T-Cell Receptor Gene Modified Autologous T Cells

Phase II - HLA*other - disease entity 2

Investigator Choice therapy

Group Type: ACTIVE_COMPARATOR

Investigator Choice therapy

Intervention Type: OTHER

Any intervention/therapy chosen by the investigator

Interventions

MDG1011

PRAME-T-Cell Receptor Gene Modified Autologous T Cells

Intervention Type: DRUG

Investigator Choice therapy

Any intervention/therapy chosen by the investigator

Intervention Type: OTHER

Eligibility Criteria

Inclusion Criteria

1. Signed written informed consent prior to any clinical trial-related activities

2. Documented diagnosis with the last disease staging within the last 4 weeks prior to screening

3. Human leukocyte antigen (HLA):

1. Phase I and Phase II (treatment group): Subjects positive for HLA-A*02:01 according to genotyping results

2. Phase II (concurrent control group): Subjects negative for HLA-A*02:01 according to genotyping results

4. Age ≥ 18 years

5. Life expectancy of at least 4 months.

6. Eastern Cooperative Oncology Group (ECOG) performance status 0-2

7. Subjects not planned for allogeneic HSCT (e.g. based on disease characteristics or subject characteristics). Bridging to an allogeneic HSCT will be allowed.

8. Females of childbearing potential must have a negative serum beta human chorionic gonadotropin (β-hCG) pregnancy test result before leukapheresis and before administration of lymphodepleting chemotherapy. Females of non-childbearing potential are those who are postmenopausal greater than 2 years or who have had a bilateral tubal ligation or hysterectomy.

9. Females of childbearing potential and males who have partners of childbearing potential must agree to use an effective contraception method during the clinical trial and for 6 months following the last dose of IMP.

Effective birth control includes:

1. intrauterine device plus 1 barrier method; or (b) 2 barrier methods. Effective barrier methods are male or female condoms, diaphragms, and spermicides (creams or gels that contain a chemical to kill sperm).

1. No Complete remission/response (CR) or Complete remission with incomplete hematologic recovery (CRi) after completion of at least 2 cycles of intensive induction chemotherapy or 1 cycle of intensive induction and consolidation (intermediate or high dose cytarabine) chemotherapy each and/or

2. No CR or no CRi after completion of at least 1 cycle of intensive induction chemotherapy including at least 5 days of cytarabine 100-200 mg/m^2 continuously or an equivalent regimen with cytarabine with total dose not less than 500 mg/m^2 per cycle and at least 2 days of an anthracycline (e.g. daunorubicine, idarubicin), unable to undergo allogeneic HSCT and/or

3. Refractory disease (including stable disease [SD], progressive disease [PD]) or relapsed disease after hypomethylating agent therapy (e.g. azacitidine, decitabine) and/or

4. Any SD, partial response (PR), CRi, CR obtained after re-induction or salvage-therapy and/or

5. Relapsed AML patients unable to undergo allogeneic HSCT and/or

6. Relapsed AML after allogeneic HSCT

1. at least 100 days after transplant

2. no evidence of active acute or chronic GvHD at enrolment

3. in case of history of acute (> overall grade 1) or chronic GvHD (moderate/severe) requiring immunosuppression treatment, no immunosuppression within the last 3 months

4. no immunosuppression (with the exception of low dose steroids <= 10 mg prednisone or equivalent) 4 weeks before enrolment and ongoing and

7. Myeloid blasts must positively express PRAME

1. IPSS INT-2 or High Grade MDS Excess Blasts-2 (EB-2) not responding to at least 6 courses of azacitidine or 4 courses of decitabine and/or

2. IPSS INT-1, INT-2 or High Grade MDS with recurrence after initial response and

3. Blasts must positively express PRAME

1. Relapsed and refractory multiple myeloma:

• Progressive MM, also defined as relapsed disease, defined as:

1. A 25% increase from baseline in the serum M-protein (absolute increase

• 0.5 g/dL), urine M-protein (absolute increase > 200 mg/day), and/or the difference between involved and uninvolved free light chain levels (absolute increase ≥ 10 mg/dL).

2. The presence of definite new bone lesions and/or soft tissue plasmacytomas with a clear increase in the size of existing plasmacytomas, or hypercalcemia, that cannot be attributed to another cause. • Relapsed and refractory MM is defined as disease progression within 60 days of a patient's last treatment where at least a minimal response was achieved. • Primary refractory MM is defined as disease that fails to achieve at least a minimal response with any therapy. and

2. At least 3 previous therapy lines with at least one proteasome inhibitor and one immunomodulatory derivate (IMiDs). Induction with or without hematopoietic stem cell transplant and with or without maintenance therapy is considered a single regimen. and

3. Myeloma cells must positively express PRAME

CRITERIA FOR PRE-EMPTIVE LEUKAPHERESIS PROCEDURE

• subject is positive for HLA-A*02:01 and their blasts/myeloma cells express PRAME

• subject does not fulfill any exclusion criterion that would be considered permanent (i.e.

irreversible organ function impairment) and therefore would certainly preclude the subject from receiving the IMP in the future

Exclusion Criteria

<!-- -->

1. Subjects with acute promyelocytic leukemia exhibiting t(15;17)(q22;q12); PML-RARA, or with variant translocations

2. Pregnant or lactating women

3. Known positive for HIV, active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection

4. Any clinically significant, advanced or unstable disease or inadequate main organ function that may put the subject at special risk, such as: a. creatinine > 2.0 times the upper normal serum level b. total bilirubin, ALT, AST >3 times the upper normal serum level c. cardiac left ventricular ejection fraction < 40% at rest d. severe restrictive or obstructive lung disease

5. History of haploidentical allogeneic stem cell transplantation

6. Subjects both with urinary outflow obstructions and on dialysis or subjects for whom cyclophosphamide is contraindicated for other reasons

7. Clinical significant and ongoing immune suppression including, but not limited to: immunosuppressive agents such as cyclosporine or corticosteroids (at an equivalent dose of >= 10 mg prednisone per day). Inhaled steroid and physiological replacement for adrenal insufficiency is allowed.

8. Subjects with currently active autoimmune disease.

9. Subjects with a history of primary immunodeficiency.

10. Subjects with a currently active second malignancy other than non- melanoma skin cancers or subjects with history of prior malignancy and previously treated with a curative intent therapy less than 1 year ago

11. Known or suspected hypersensitivity or intolerance to IMP, cyclophosphamide, fludarabine and/or tocilizumab or to any of the excipients

12. Participation in any clinical trial < 60 days prior to first IMP administration in case of antibodies and < 14 days for all other IMPs

13. Vulnerable subjects and/or subjects unwilling or unable to comply with procedures required in this clinical trial protocol

1. Prior therapy with IMiDs within 14 days prior to leukapheresis and/or infusion of IMP

2. Prior therapy with corticosteroids within 7 days prior to leukapheresis or 7 days prior to infusion of IMP

1. Uncontrolled central nervous system (CNS) disease

2. Uncontrolled infections or uncontrolled disseminated intravascular coagulation; however, if these problems resolve, the start of treatment can be initiated on a delayed schedule

3. Ongoing 3 grade cardiac, renal, pulmonary, gastrointestinal or hepatic toxicities according to CTCAE v4.03; however, if these problems resolve, the start of treatment can be initiated on a delayed schedule

4. Evidence of acute or chronic GvHD

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Medigene AG

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Simone Thomas, PD Dr. med.

Role: PRINCIPAL_INVESTIGATOR

University Hospital Regensburg

Locations

University Hospital Dresden

Dresden, , Germany

University Hospital Erlangen

Erlangen, , Germany

University Hospital Frankfurt

Frankfurt, , Germany

University Hospital Freiburg

Freiburg im Breisgau, , Germany

University Hospital Heidelberg

Heidelberg, , Germany

University Hospital Leipzig

Leipzig, , Germany

University Hospital Mainz

Mainz, , Germany

University Hospital Regensburg

Regensburg, , Germany

University Hospital Wuerzburg

Würzburg, , Germany

Countries

Germany

References

Burdek M, Prinz PU, Mutze K, Tippmer S, Geiger C, Longinotti G, Schendel DJ. Characterization of a 3S PRAME VLD-Specific T Cell Receptor and Its Use in Investigational Medicinal Products for TCR-T Therapy of Patients with Myeloid Malignancies. Cancers (Basel). 2025 Jan 13;17(2):242. doi: 10.3390/cancers17020242.

Reference Type: DERIVED

PMID: 39858024 (View on PubMed)

Other Identifiers

CD-TCR-001

Identifier Type: -

Identifier Source: org_study_id