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

• ClinicalTrials.gov Identifier: NCT03503968
• Recruitment Status: Terminated
• First Posted: April 20, 2018
• Last Update Posted: February 15, 2023
• Sponsor: Medigene AG
• Information provided by (Responsible Party): Medigene AG

Tracking Information

• First Submitted Date: March 21, 2018
• First Posted Date: April 20, 2018
• Last Update Posted Date: February 15, 2023
• Actual Study Start Date: March 27, 2018
• Actual Primary Completion Date: June 28, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 11, 2018)

• Phase I: Adverse Events and Dose Limiting Toxicities (Safety and Tolerability) [ Time Frame: 3 months ]
  Incidence and severity of adverse events according to the NCI CTCAE, v4.03; MTD and/or RP2D of IMP measured by dose-limiting toxicities (DLTs) up to 28 days post infusion
• Phase I: maximum tolerated dose (MTD) and/or recommended Phase II dose (RP2D) of MDG101 [ Time Frame: 28 days ]
• Phase I: For feasibility: percent of all subjects who receive the planned target dose of MDG1011 [ Time Frame: 3 months ]
• Phase II: Adverse Events (Safety) [ Time Frame: 3 months ]
  Incidence and severity of adverse events according to NCI CTCAE, v4.03
• Phase II: overall response rate (ORR) [ Time Frame: 3 months ]

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: July 3, 2019)

• Phase I: overall response rate (ORR) [ Time Frame: 3, 6 and 12 months ]
• Phase I: time to event and duration of response (DoR) rate [ Time Frame: 3, 6 and 12 months ]
• Phase I: time to event and time to progression (TTP) rate [ Time Frame: 3, 6 and 12 months ]
• Phase I: time to event and progression-free survival (PFS) rate [ Time Frame: 3, 6 and 12 months ]
• Phase I: time to event and overall survival (OS) rate [ Time Frame: 3, 6 and 12 months ]
• Phase I: Change in quality of life (QoL) [ Time Frame: baseline, 3, 6 and 12 months ]
  EQ-5D-5L questionaire
• Phase I: Change in quality of life (QoL) [ Time Frame: baseline, 3, 6 and 12 months ]
  EORTC-QLQ-C30 [AML/MDS] questionaire
• Phase I: Change in quality of life (QoL) [ Time Frame: baseline, 3, 6 and 12 months ]
  EORTC-MY20 [MM] questionaire
• Phase I: Correlation of PRAME expression with the antitumor response [ Time Frame: 3, 6 and 12 months ]
• Phase II: time to event and duration of response (DoR) rate [ Time Frame: 3, 6 and 12 months ]
• Phase II: time to event and time to progression (TTP) rate [ Time Frame: 3, 6 and 12 months ]
• Phase II: time to event and progression-free survival (PFS) rate [ Time Frame: 3, 6 and 12 months ]
• Phase II: time to event and overall survival (OS) rate [ Time Frame: 3, 6 and 12 months ]
• Phase II: changes in quality of life (QoL) [ Time Frame: baseline, 3, 6 and 12 months ]
  EQ-5D-5L questionaire
• Phase II: changes in quality of life (QoL) [ Time Frame: baseline, 3, 6 and 12 months ]
  EORTC-QLQ-C30 [AML/MDS] questionaire
• Phase II: changes in quality of life (QoL) [ Time Frame: baseline, 3, 6 and 12 months ]
  EORTC-MY20 [MM] questionaire
• Phase II: For feasibility, the percent of all subjects who receive the RP2D of MDG1011 [ Time Frame: 3 months ]
• Phase II: correlation of PRAME expression with the antitumor response [ Time Frame: 3, 6 and 12 months ]
• Phase I: Adverse Events (safety) [ Time Frame: 6 and 12 months ]
  Incidence and severity of adverse events according to NCI CTCAE, v4.03
• Phase II: Adverse Events (safety) [ Time Frame: 6 and 12 months ]
  Incidence and severity of adverse events according to NCI CTCAE, v4.03

Original Secondary Outcome Measures (submitted: April 11, 2018)

• Phase I: overall response rate (ORR) [ Time Frame: 3, 6 and 12 months ]
• Phase I: duration of response (DoR) [ Time Frame: 3, 6 and 12 months ]
• Phase I: time to progression (TTP) [ Time Frame: 3, 6 and 12 months ]
• Phase I: progression-free survival (PFS) [ Time Frame: 3, 6 and 12 months ]
• Phase I: overall survival (OS) [ Time Frame: 3, 6 and 12 months ]
• Phase I: Change in quality of life (QoL) [ Time Frame: baseline, 3, 6 and 12 months ]
  EQ-5D-5L questionaire
• Phase I: Change in quality of life (QoL) [ Time Frame: baseline, 3, 6 and 12 months ]
  EORTC-QLQ-C30 [AML/MDS] questionaire
• Phase I: Change in quality of life (QoL) [ Time Frame: baseline, 3, 6 and 12 months ]
  EORTC-MY20 [MM] questionaire
• Phase I: Correlation of PRAME expression with the antitumor response [ Time Frame: 3, 6 and 12 months ]
• Phase II: duration of response (DoR) [ Time Frame: 3, 6 and 12 months ]
• Phase II: time to progression (TTP) [ Time Frame: 3, 6 and 12 months ]
• Phase II: progression-free survival (PFS) [ Time Frame: 3, 6 and 12 months ]
• Phase II: overall survival (OS) [ Time Frame: 3, 6 and 12 months ]
• Phase II: changes in quality of life (QoL) [ Time Frame: baseline, 3, 6 and 12 months ]
  EQ-5D-5L questionaire
• Phase II: changes in quality of life (QoL) [ Time Frame: baseline, 3, 6 and 12 months ]
  EORTC-QLQ-C30 [AML/MDS] questionaire
• Phase II: changes in quality of life (QoL) [ Time Frame: baseline, 3, 6 and 12 months ]
  EORTC-MY20 [MM] questionaire
• Phase II: For feasibility, the percent of all subjects who receive the RP2D of MDG1011 [ Time Frame: 3 months ]
• Phase II: correlation of PRAME expression with the antitumor response [ Time Frame: 3, 6 and 12 months ]
• Phase I: Adverse Events (safety) [ Time Frame: 6 and 12 months ]
  Incidence and severity of adverse events according to NCI CTCAE, v4.03
• Phase II: Adverse Events (safety) [ Time Frame: 6 and 12 months ]
  Incidence and severity of adverse events according to NCI CTCAE, v4.03

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: TCR Modified T Cells MDG1011 in High Risk Myeloid and Lymphoid Neoplasms
• Official Title: A Phase I/II, Open-Label, Non-Randomized, Multicentre, Dose-Escalation Clinical Trial With Control Group to Evaluate the Safety, Feasibility and Preliminary Efficacy of PRAME TCR Modified T Cells, MDG1011, in Subjects With High Risk Myeloid and Lymphoid Neoplasms
• 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).

• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Safety
• Tolerability
• Feasibility
• Treatment Efficacy

Intervention

• Drug: MDG1011
  PRAME-T-Cell Receptor Gene Modified Autologous T Cells
• Other: Investigator Choice therapy
  Any intervention/therapy chosen by the investigator

Study Arms

• Experimental: Phase I - 3 disease entities
  MDG1011 administration of escalating doses
  Intervention: Drug: MDG1011
• Experimental: Phase II - HLA*02:01 - disease entity 1
  MDG1011 administration of Phase II recommended dose
  Intervention: Drug: MDG1011
• Active Comparator: Phase II - HLA*other - disease entity 1
  Investigator Choice therapy
  Intervention: Other: Investigator Choice therapy
• Experimental: Phase II - HLA*02:01 - disease entity 2
  MDG1011 administration of Phase II recommended dose
  Intervention: Drug: MDG1011
• Active Comparator: Phase II - HLA*other - disease entity 2
  Investigator Choice therapy
  Intervention: Other: Investigator Choice therapy

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: February 13, 2023): 9
• Original Estimated Enrollment (submitted: April 11, 2018): 92
• Actual Study Completion Date: July 15, 2022
• Actual Primary Completion Date: June 28, 2022 (Final data collection date for primary outcome measure)

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).

   AML-SPECIFIC INCLUSION CRITERIA:

   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

   MDS-SPECIFIC INCLUSION CRITERIA:

   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

   MM-SPECIFIC INCLUSION CRITERIA:

   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 fulfills at least some inclusion criteria and, based on the judgement of the investigator, have a likelihood of being eligible for IMP administration in the further course of the subjects disease

      • 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

   MM-SPECIFIC EXCLUSION CRITERIA FOR PHASE I AND PHASE II (TREATMENT GROUP):

   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

   EXCLUSION CRITERIA FOR TREATMENT WITH IMP IN PHASE I AND PHASE II (TREATMENT GROUP):

   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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Germany

Administrative Information

• NCT Number: NCT03503968
• Other Study ID Numbers: CD-TCR-001
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Medigene AG
• Original Responsible Party: Same as current
• Current Study Sponsor: Medigene AG
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Simone Thomas, PD Dr. med.; University Hospital Regensburg

• PRS Account: Medigene AG
• Verification Date: February 2023