E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Relapsed/Refractory FLT3 Mutated Acute Myeloid Leukemia (AML) |
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E.1.1.1 | Medical condition in easily understood language |
Relapsed/Refractory Mutated Blood Cancer |
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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 | 21.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10000886 |
E.1.2 | Term | Acute myeloid leukemia |
E.1.2 | System Organ Class | 100000004864 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10060558 |
E.1.2 | Term | Acute myeloid leukemia recurrent |
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 |
To evaluate the effect of adding crenolanib versus placebo to salvage chemotherapy, consolidation (HiDAC and/or allo-HCT) and as single-agent maintenance therapy on event-free survival (EFS) |
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E.2.2 | Secondary objectives of the trial |
To evaluate the effect of adding crenolanib versus placebo to salvage chemotherapy, consolidation (HiDAC and/or allo-HCT) and as single-agent maintenance therapy on:
• Overall survival (OS) • Relapse-free survival (RFS) • Complete remission (CR) rate • Composite complete remission (CRc) rate • MRD-negative complete remission (CR MRD-) rate |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Confirmed diagnosis of AML according to WHO 2016 classification 2. Presence of FLT3-ITD and/or D835 mutation(s) 3. Subjects must be primary refractory or relapsed to 1st line intensive treatment for AML or refractory or relapsed after second line of treatment for AML as defined by: 3a. Primary refractory is defined as no CR or CRi after two courses of intensive induction chemotherapy. 3b. Relapse after first line treatment for AML is defined as the first hematologic relapse after one line of treatment for AML that includes at least one course of intensive chemotherapy with or without a tyrosine kinase inhibitor. 3c. Relapse after second line treatment for AML is defined as a hematologic relapse after two lines of treatment for AML. Subjects may be refractory to or relapse after the first line treatment but must have achieved a CR/CRi after second line treatment and subsequently relapse. First line treatment must include at least one course of intensive chemotherapy. Second line treatment may be one of the following: i. Intensive or non-intensive salvage therapy with or without tyrosine kinase inhibitor or other targeted therapy ii. Tyrosine kinase inhibitor alone iii. Hypomethylating agent iv. One experimental therapy for treatment of AML 3d. Refractory after second line treatment for AML is defined as no CR or CRi after second line of treatment for AML. Subjects who are refractory after a second line treatment for AML must have must have achieved a CR/CRi after first line treatment and subsequently relapsed. First line treatment must include at least one course of intensive chemotherapy. Second line treatment may be one of the following: i. Non-intensive salvage therapy with or without tyrosine kinase inhibitor or other targeted therapy ii. Tyrosine kinase inhibitor alone iii. Hypomethylating agent iv. One experimental therapy for treatment of AML 4. Eligible for pre-selected induction chemotherapy specified in the protocol 5. Age ≥ 18 years and ≤ 75 years 6. Adequate hepatic function 7. Adequate renal functions 8. ECOG performance status ≤ 3 9. Female subjects with reproductive potential must have negative serum or urine pregnancy test. 10. Adequate contraception, if heterosexually active 11. Written informed consent before any study-specific procedure is performed |
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E.4 | Principal exclusion criteria |
1. Subjects with any of the following current or previous diagnoses: • Treatment related AML secondary to prior chemotherapy • AML secondary to prior myelodysplastic syndrome (MDS) • AML secondary to prior myeloproliferative syndrome (MPN) including polycythemia vera, essential thrombocythemia, myelofibrosis, mastocytosis and chronic myeloid leukemia • Acute promyelocytic leukemia (APL) • AML secondary to MDS/MPN syndromes including chronic myelomonocytic leukemia • DNA fragility or bone marrow failure syndromes • Blastic plasmacytoid dendritic cell neoplasm • Acute leukemia of ambiguous lineage • B-lymphoblastic leukemia/lymphoma • T-lymphoblastic leukemia/lymphoma, including early T-cell precursor lymphoblastic leukemia (ETP-ALL) 2. Known clinically active central nervous system (CNS) leukemia 3. Subjects who have received more than 1 prior allogeneic HSCT. 4. Subjects who are refractory to first-line (induction and re-induction) and a second-line (1st salvage) treatment for AML. 5. Severe liver disease 6. Active infections including known mycobacterial infections. Subjects with positive blood cultures for virus, bacteria, or fungi, or sepsis will not be eligible. 7. Inadequate pulmonary function (subjects requiring assisted ventilation will not be eligible) 8. Hemodynamically unstable (subjects requiring pressor support will not be eligible) 9. Active infection with hepatitis B virus (HBV), defined as a positive test for HBV surface antigen (HBsAg), and/or active infection with hepatitis C virus (HCV), defined as a positive test for HCV ribonucleic acid (RNA) 10. Clinically significant bleeding diathesis and coagulation disorder independent of leukemia 11. Subjects with a “currently active” second malignancy other than non-melanoma skin cancers. 12. Inadequate cardiac function, including greater than Grade 2 decreased ejection fraction, clinically significant prolonged QTc interval, congestive heart failure class III or IV by the NYHA, unstable angina (angina symptoms at rest), new onset angina (began within the last 3 months) or myocardial infarction within the past 6 months 13. Any disorder that compromises the subject’s ability to give written informed consent and/or to comply with study procedures 14. Any substance abuse, severe and/or uncontrolled medical, social or psychiatric conditions that may prevent the subject from completing the study, interfere with the evaluation of safety and/or efficacy, or interfere with the interpretation of the study results 15. Grade 2 or above graft-versus-host disease (GvHD), including acute, chronic, or overlap; or escalation of therapy for GvHD within 14 days prior to randomization 16. Major surgical procedures within the 28 days prior to randomization (does not include line placement as needed for chemotherapy administration). 17. Prior anti-leukemia therapy within the 14 days prior to randomization. Prior use of quizartinib or gilteritinib must be discontinued 21 days prior to randomization. Prior use of hydroxyurea or other palliative treatment for leukocytosis is allowed. 18. Previous treatment with crenolanib or prior participation in clinical trial involving crenolanib. 19. Concurrent use of other investigational agents. 20. Female subject who is pregnant or breastfeeding, or planning to become pregnant while receiving treatment and within 6 months after ending treatment 21. Known or suspected hypersensitivity to the study drugs and/or any excipients |
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E.5 End points |
E.5.1 | Primary end point(s) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
From the date of randomization to the date of failure to achieve a complete remission, relapse or death of any cause (whichever occurs first) |
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E.5.2 | Secondary end point(s) |
• Overall survival (OS) • Relapse-free survival (RFS) • Complete remission (CR) rate • Composite complete remission (CRc) rate • MRD-negative complete remission (CR MRD-) rate |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
• OS: from the date of randomization to the date of death of any cause for all randomized subjects • RFS: from the date of achievement of CRc to the date of relapse or death of any cause • CR, CRc, CR MRD-: throughout the study |
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
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 | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 30 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Czech Republic |
France |
Germany |
Hungary |
Italy |
Poland |
Spain |
United States |
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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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 6 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 6 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |