E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Adverse genetic Acute Myeloid Leukaemia |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10000878 |
E.1.2 | Term | Acute myeloblastic leukemia |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
1. To evaluate the safety and tolerability of a multiple infusion schedule of UCART123 in patients with CD123+ adverse genetic risk AML who do not achieve morphologic or cytogenetic complete remission after induction chemotherapy. 2. To determine the Maximum Tolerated Dose (MTD) of UCART123.
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E.2.2 | Secondary objectives of the trial |
To assess the efficacy and tolerability of UCART123 in patients with CD123+ adverse genetic risk AML who do not achieve morphologic or cytogenetic complete remission after induction chemotherapy, by measuring: • Rate and severity of cytokine release syndrome, • Rate and severity of UCART123 related adverse events, • Rate of morphological CR at Day 28 after each UCART123 infusion, • Rate of cytogenetic CR at Day 28 after each UCART123 infusion, • Rate of CR without MRD at Day 28 after each UCART123 infusion, and • Leukaemia-free survival (LFS) and overall survival (OS).
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1.Aged between 18 and 65 years; 2. Weight ≥42 kg; 3. Patients newly diagnosed with CD123 positive adverse genetic risk acute myeloid leukaemia (AML), including patients with CD123 positive AML secondary to MDS, who do not achieve complete remission, and whose bone marrow blast content is < 20% after 1 or 2 courses of standard intensive induction chemotherapy. Adverse genetic risk is defined as per ELN guidelines (Döhner et al., 2017). 4. Patients must have received either a “3+7” regimen (consisting of 3 days of an IV anthracycline: daunorubicin at least 60 mg/m²; idarubicin 12 mg/m²; or mitoxantrone 12 mg/m², and 7 days of continuous infusion cytarabine (100-200 mg/m²)) ; or FLAG-Ida regimen (consisting of fludarabine 30 mg/m² from Day 2 to Day 6, cytarabine 1500-2000 mg/m² IV, Day 2 to Day 6; idarubicin 10 mg/m², Day 2 to Day 4); 5. Availability of a suitable sibling or unrelated HLA matched donor; 6. Adequate organ function defined as: i. Creatinine clearance ≥60mL/minute (assessed as glomerular filtration rate using the Cockcroft & Gault formula or MDRD); and ii. Alanine aminotransferase <3 × upper limit of normal (ULN) or aspartate aminotransferase <3 × upper limit of normal (ULN); and iii. Bilirubin < 2 times ULN (except for patients with documented history of Gilbert’s syndrome confirmed by UGT1A1 mutation); and iv. Cardiac ejection fraction >50% as assessed by echocardiography; and v. Must have a minimum level of pulmonary reserve defined as Grade <2 dyspnoea and pulse oxygenation ≥92% on room air. 7. Women of childbearing potential must have a negative highly sensitive serum pregnancy test performed within 7 days prior to enrolment. Within the frame of this study, female patients of childbearing potential and male patients with partners of childbearing potential must use a highly effective method of birth control, as well as their partners, from the screening period for a duration of 12 months after UCART123 administration. Nonchildbearing potential is defined as being postmenopausal for at least 1 year, or women with documented infertility (natural or acquired). Highly effective birth control methods include combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal), progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable), intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomized partner, and sexual abstinence
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E.4 | Principal exclusion criteria |
1. Patients with ≥20% blasts in bone marrow after 1 or 2 courses of standard intensive induction chemotherapy; 2. Patients with AML transformed from previously diagnosed myeloproliferative disorder; 3. Patients with APL; 4. Evidence of uncontrolled CNS leukaemia or evidence of CNS leukaemia on CSF examination; 5. AML relapsing after first complete remission; 6. Prior allogeneic stem cell transplant; 7. Therapy-related AML; 8. Favourable or intermediate risk AML; 9. Prior gene or experimental cellular therapy; 10. Active uncontrolled infection or organ dysfunction that in the opinion of the investigator precludes intensive induction chemotherapy or cellular therapy; 11. Use of other investigational products within five half-lives or within 14 days prior to start of lymphodepletion, whichever is longer; participation in non-interventional registries or epidemiological studies is allowed. In addition, treatment-related toxicities should have resolved to no more than Grade 1; 12. Use of rituximab and other anti-CD20 antibodies known to have the same epitope as rituximab or anti-CD20 antibodies for which the epitope is unknown within 3 months or 5 half-lives prior to enrolment, whichever is longer. Any contraindication to or safety concern preventing the potential use of rituximab; 13. Patients may not receive ≥ 20 mg of prednisone or equivalent between Day -7 and Day 28 of UCART123 administration. Hydrocortisone required for mineralocorticoid replacement therapy is authorized at all times as needed clinically. Topical, inhaled, or nasal route of steroids are permitted; 14. Known infection with human immunodeficiency virus or human T-cell leukaemia/lymphoma virus type 1; 15. A known hypersensitivity to any of the test materials or related compounds including murine and bovine products; 16. Any planned medical/surgical treatment that might interfere with the ability to comply with the study requirements; or 17. Evidence of another uncontrolled malignancy within 2 years prior to Screening (except in situ non-melanoma skin cell cancers and in situ cervical carcinoma).
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E.5 End points |
E.5.1 | Primary end point(s) |
-Safety Endpoint • Evaluation of DLT, Incidence, nature, and severity of adverse events and serious adverse events (SAEs) throughout the study (CTCAE v4.03; Lee et al., 2014 for CRS; Cairo and Bishop 2004 for TLS, New consensus criteria 2016 for GvHD).
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
• DLT at Day 28 post first UCART123 infusion and adverse events are assessed throughout the study
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E.5.2 | Secondary end point(s) |
-Efficacy Endpoints • Antileukemic activity, as measured by European Leukaemia Net (ELN) Response Criteria in AML (Döhner et al., 2017). |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
• Antileukemic Response will be assessed following each UCART123 administration at Day 14 and Day 28, at EOT visit and as clinically relevant
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
Safety and Efficacy Trial |
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E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 3 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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15 years long-term follow-up participation. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 18 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 19 |