High Risk Myeloid Neoplasms MedDRA version: 21.0 Level: LLT Classification code 10000886 Term: Acute myeloid leukemia System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 20.0 Level: HLT Classification code 10028536 Term: Myelodysplastic syndromes System Organ Class: 100000004851 MedDRA version: 21.0 Level: LLT Classification code 10028557 Term: Myeloid leukemia, acute System Organ Class: 10029104 - Neoplasms benign, malignant and
Conditions
Interventions
Product Code: MDG1011
Pharmaceutical Form: Dispersion for infusion
INN or Proposed INN: 11 Structurally Diverse Substance – Cell therapy
Current Sponsor code: MDG1011
Other descriptive name: PRAME-T-C
Sponsors
Medigene AG
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Key inclusion criteria include: 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) a. Phase I and Phase II (treatment group): Subjects positive for HLA-A*02:01 according to genotyping results b. 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 hematopoetic stem cell transplantation (HSCT) (e.g. based on disease characteristics or subject characteristics). Bridging to an allogeneic HSCT will be allowed. 8. Negative pregnancy test in women of childbearing potential (before leukapheresis and before administration of lymphodepleting chemotherapy). 9. For fertile men and women, agreement to use effective contraceptive methods during the clinical trial. Acute Myeloid Leukemia (AML)-specific inclusion criteria: 1. No complete remission response (CR) or no complete remission with incomplete heamatologic 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), 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/m² continuously or an equivalent regimen with cytarabine with total dose not less than 500 mg/m² per cycle and at least 2 days of an anthracycline (e.g. daunorubicin, 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 reponse (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; a. at least 100 days after transplant. b. no evidence of active acute or chronic GvHD at enrolment, in case of history of acute (> overall grade 1) or chronic GvHD (moderate/severe) requiring immunosuppressive treatment no immunosuppression within the last 3 months, c. no immunosuppression (with the exception of low-dose steroids =10 mg prednisone or equivalent) 4 weeks before enrollment and ongoing, and 7. Myeloid blasts must positively express PRAME Myelodysplastic Syndrome (MDS)-specific inclusion criteria: 1. International Prognostic Scoring System Intermediate-2 (IPSS INT-2) or High Grade MDS 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 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
Exclusion criteria
Exclusion criteria: Key exclusion criteria include: 1. Subjects with acute promyelocytic leukemia exhibiting t(15;17)(q22;q12); Promyelocytic Leukemia/Retinoic Acid Receptor Alpha (PML-RARA), or with variant translocations 2. Pregnant or lactating women 3. Known positive for human immunodeficiency virus (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 subjects at special risk, such as: a. Creatinine > 2.0 times the upper normal serum level b. total bilirubin, Alanine aminotransferase (ALT), Aspartate aminotransferase (AST) > 3.0 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 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 National Cancer Institute’s (NCI) Common Terminology Criteria for Adverse Events (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 Treatment Exemption Criterion: Unable to generate IMP for infusion; however, if a lower than planned number of cells is available (at least 1 x 105 T cells/kg), the subject in Phase I/II of the clinical trial will have the option to receive IMP and will be analyzed in the safety and full analysis set populations.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Phase I part: • To assess the safety and tolerability of MDG1011 • To establish the maximum tolerated dose (MTD) and/or recommended Phase II dose (RPD2) of MDG1011 • For feasibility, assess the percent of all subjects who receive the planned target dose of MDG1011 Phase II part: Primary: • To further assess the safety and tolerability of MDG1011 • To evaluate overall response rate (ORR) ;Secondary Objective: Phase I part: • To evaluate overall response rate (ORR) • To evaluate duration of response (DoR) • To evaluate time to progression (TTP) • To evaluate progression-free survival (PFS) • To assess overall survival (OS) • To evaluate quality of life (QoL) • To evaluate the correlation of PRAME expression with the antitumor response Phase II part: • To evaluate duration of response (DoR) • To evaluate time to progression (TTP) • To evaluate progression-free survival (PFS) • To assess overall survival (OS) • To evaluate quality of life (QoL) • For feasibility, assess the percent of all subjects who receive the RP2D of MDG1011 • To evaluate the correlation of PRAME expression with the antitumor response;Primary end point(s): Phase I • Incidence and severity of adverse events ([AEs] at 3 months) 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 II • Incidence and severity of adverse events ([AEs] at 3 months) according to NCI CTCAE, v4.03 • Overall response rate (ORR) at 3 months ;Timepoint(s) of evaluation of this end point: • Primary endpoint: Last Subject Last Visit 8 (month 3) | — |
Secondary
| Measure | Time frame |
|---|---|
| Timepoint(s) of evaluation of this end point: • Secondary endpoint: Last Subject Last Visit 9 (month 6) Last Subject Last EoT Visit (month 12);Secondary end point(s): Phase I • Incidence and severity of adverse events ([AEs] at 6 and 12 months) according to the NCI CTCAE, v4.03 • Overall response rate (ORR) at 3, 6 and 12 months • Time to event and OS rate at 3, 6 and 12 months • Time to event and PFS rate at 3, 6 and 12 months • Time to event and DoR rate at 3, 6 and 12 months • Time to event and TTP rate at 3, 6 and 12 months • Percent of subjects undergoing HSCT after receiving IMP • Quality of Life (before infusion of IMP and after 3, 6, and 12 months) • Correlation of PRAME expression with the antitumor response Phase II • Incidence and severity of adverse events ([AEs] at 6 and 12 months) according to NCI CTCAE, v4.03 • Overall response rate (ORR) at 6 and 12 months • Time to event and OS rate at 3, 6 and 12 months • Time to event and PFS rate at 3, 6 and 12 months • Time to event and DoR rate at 3, 6 and 12 months • Time to event and TTP rate at 3, 6 and 12 months • Percent (%) of subjects undergoing HSCT after receiving IMP • Quality of Life (before infusion of IMP and after 3, 6, and 12 months) • Correlation of PRAME expression with the antitumor response | — |
Countries
Germany
Contacts
Public ContactJan Laschinger
Medigene AG
Outcome results
None listed