E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Relapsed refractory (R/R) or newly diagnosed acute myeloid leukemia (AML) |
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E.1.1.1 | Medical condition in easily understood language |
Cancer of the blood that has just been discovered and is untreated (1L AML) or that has previously been treated but did not respond to treatment or reoccurred since previous treatment (R/R AML) |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
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 |
The primary objective of Part 1 of this study is to determine RDE of HDM201 combined with CT in subjects with 1L and in subjects with R/R AML.
The primary objective of Part 2 of this study is to assess whether RDE of HDM201 combined with CT in 1L AML subjects enrolled to Expansion Cohort 1 (without documented FLT3 mutation) and in subjects with R/R AML enrolled to Expansion Cohort 4, respectively is the RP3D. For 1L AML subjects enrolled to Expansion Cohorts 2 and 3, the primary objective will be the safety and tolerability of HDM201 in combination with CT.
The primary objective of Part 3 of this study is to evaluate in DDI Cohort 1, the adjusted dose of HDM201 that may be needed when a strong cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) inhibitor (posaconazole) is used in subjects treated with HDM201, and to evaluate in DDI Cohort 2 the effect of multiple doses of HDM201 on the PK of a single oral dose of a sensitive CYP3A4 substrate (midazolam).
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E.2.2 | Secondary objectives of the trial |
The secondary objectives of Part 1 of this study are to assess PK, as well as safety and tolerability of HDM201 in combination with CT in both study populations (1L AML without documented FLT3 mutation and R/R AML subjects irrespective of FLT 3 mutation status).
The secondary objectives of Part 2 of this study are to assess PK of HDM201 at RDE, efficacy and blood count recovery of treatment with HDM201 in combination with CT in Expansion Cohorts 1, 3, and 4 and in combination with CT and midostaurin in Expansion Cohort 2. In Expansion Cohort 2 also the PK of midostaurin in combination with HDM201 at RDE and CT will be assessed. Minimal/measurable residual disease (MRD) negativity will be assessed in Expansion Cohorts 1 and 2.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
All subjects
1. Signed informed consent must be obtained prior to participation in the study.
2. Age ≥ 18 years at the date of signing the informed consent form (ICF).
3. Diagnosis of AML based on WHO 2016 classification (Arber et al 2016). Patients with APL (acute promyelocytic leukemia) with PML-RARA are not eligible.
4. Eastern Cooperative Oncology Group (ECOG) performance status (PS) that is 0 to 2
5. Adequate organ functions:
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 × upper limit of normal (ULN)
• Total bilirubin (TBL) ≤ 1.5 × ULN (except in the setting of isolated Gilbert syndrome)
• Glomerular Filtration Rate (estimation based on Cockcroft-Gault formula) ≥ 30 mL/min
6. Left ventricular ejection fraction (LVEF) > 45%
R/R AML subjects eligible for inclusion in this study must additionally meet the following criteria:
7. Diagnosis of relapsed or refractory AML
8. Suitable for treatment with intermediate dose cytarabine (IDAC) as per investigator judgement
9. For Part 3 only: willing and suitable to participate in DDI Cohort 1 or 2
1L AML subjects eligible for inclusion in this study must additionally meet the following criteria, as applicable to the part/cohort they are to be enrolled in:
For Part 1 or Part 2 Expansion Cohort 1 or Part 2 Expansion Cohort 2 only:
10. Subjects with de novo AML
11. Suitable for induction treatment with cytarabine and anthracyclines as per investigator judgement
For Part 2 Expansion Cohort 2 only:
12. Documented presence of FLT3 mutation (ITD or TKD)
13. Suitable for midostaurin treatment as per investigator judgement
For Part 3 Expansion Cohort 3 only:
14. Subjects with secondary AML (e.g. AML with Myelodysplasia-Related Changes/AML-MRC, AML secondary to myelodysplasia/MDS or therapy-related AML). Prior use of hypomethylating agents or other therapies with curative intent for treating previous hematological malignancies or therapy-related AML is allowed.
15. Suitable for induction treatment with liposomal cytarabine/daunorubicin as per investigator judgement
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E.4 | Principal exclusion criteria |
All subjects
1. Prior exposure to MDM2 and MDM4 inhibitor (eg, idasanutlin)
2. Known CNS leukemia with signs or symptoms that are not controlled by adequate therapy.
3. Isolated extramedullary leukemia
4. For Part 1 only: subjects with a known favorable-risk AML subtype at screening
5. For Part 1 only: subjects with documented FLT3 mutation.
6. Subjects with prior malignancy, except for: a) Adequately treated solid tumor for which the subject has been disease free for at least 2 years and if no anticancer therapy is ongoing or required during the course of the study; b) Subjects with history of hematological malignancies leading to secondary AML (eg, myelodysplasia/ myelodysplastic syndrome (MDS)) and subjects with therapy-related AML will not be excluded in dose Expansion Cohort 3.
7. Any concurrent severe and/or uncontrolled medical condition eg, a) cardiovascular disease including congestive heart failure, or b) active uncontrolled infection requiring parenteral antibacterial, antiviral or antifungal therapy compromised by hemodynamic instability
8. QTcF > 470 ms at screening
9. Any other known disease that could compromise participation in the study including gastrointestinal (GI) disorders impacting absorption of HDM201, evidence of major active bleeding or history of bleeding diathesis or major coagulopathy not related to AML
10. Known confirmed diagnosis of human immunodeficiency virus (HIV) infection
11. Evidence of active hepatitis B (HBV) or hepatitis C (HCV) viral infection (hepatitis B surface antigen (HBsAg) in the absence of hepatitis B surface antibody (HBsAb) OR HCV Ab (antibody) positive with HCV RNA (ribonucleic acid) positive)
12. Subjects who require treatment with moderate or strong CYP3A4 inducers within 14 days prior to starting study treatment, or are expected to receive moderate or strong CYP3A4 inducers during the entire study
13. Subjects who require the use of herbal preparations/medications and dietary supplements (except for vitamins) within 7 days prior to first dose of study treatment or are expected to use such products during the entire study
14. Subjects who require treatment with substrates of CYP3A4/5 with a narrow therapeutic index (within 24 hours prior to, during and 48 hours after HDM201 administration).
15. Subjects taking medications with a known risk of prolonging the QT interval or inducing Torsade de pointes, if such medication cannot be discontinued or replaced safely with an alternative medication prior to starting first dose of HDM201
16. Subjects who require treatment with moderate or strong CYP3A4 inhibitors within 48 hours prior to, during and 48 hours post HDM201 administration. Of note, this is not applicable for Part 3 Cycle 1
17. Subject is pregnant or breastfeeding
18. Women of child-bearing potential (WOCBP), defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for 2 weeks after HDM201 discontinuation or for 4 months after midostaurin discontinuation (for 1L AML Expansion Cohort 2) or for 6 months after liposomal cytarabine/daunorubicin discontinuation (for 1L AML Expansion Cohort 3)
Highly effective contraception methods are described in the protocol.
Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (eg, age appropriate history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at least six weeks prior to start of study treatment. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow-up hormone level assessment is she considered not of child bearing potential.
19. Sexually active males unless they use a condom during intercourse while taking study drug and for 2 weeks after HDM201 discontinuation or for 4 months after midostaurin discontinuation (for 1L AML Expansion Cohort 2 only) or for 6 months after liposomal cytarabine/daunorubicin (for 1L AML Expansion Cohort 3 only) and thus do not attempt to father a child in this period. A condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid.
If local regulations deviate from the contraception methods listed in the protocol (for women of child bearing potential or male) to prevent pregnancy, local regulations apply and will be described in the ICF.
Additional exclusion criteria apply for R/R AML subjects and for 1L AML subjects as per protocol
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E.5 End points |
E.5.1 | Primary end point(s) |
Part 1:
1L AML subjects
• Incidence of DLT and time to DLT in subjects receiving induction therapy
• Incidence and severity of AEs in 1L AML subjects
R/R AML subjects
• Incidence of DLT and time to DLT
• Incidence and severity of AEs in R/R AML subjects
Part 2:
1L AML subjects
• Incidence and severity of AEs, SAEs and abnormal laboratory values, ECG and vital signs (Expansion Cohort 1)
• Proportion of CR/CRi with ABCR at the end of induction treatment (Expansion Cohort 1)
• Incidence and severity of AEs, SAEs and abnormal laboratory values, ECG and vital signs (Expansion Cohort 2)
• Incidence and severity of AEs, SAEs and abnormal laboratory values, ECG and vital signs (Expansion Cohort 3)
R/R AML subjects
• Incidence and severity of AEs, SAEs and abnormal laboratory values, ECG and vital signs
• Proportion of CR/CRi with ABCR at the end of treatment
Part 3:
DDI Cohort 1
• PK parameters for HDM201 such as AUClast, Cmax, cumulative AUC (Cycle 1) and average plasma concentration (Cycle 1)
DDI Cohort 2
• PK parameters of midazolam (e.g., AUClast, AUCinf, Cmax)
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Part 1:
1L AML subjects
- D1 of study treatment (ST) to 3 m after start of ST
- D1 of ST to 3 m after start of ST
R/R AML subjects
- D1 of ST to 3 m after start of ST
- D1 of ST to 3 m after start of ST
Part 2:
1L AML subjects
- D1 of ST until 8.5 m after start of ST
- D1 of ST until 4.5 m after start of ST
- D1 of ST until 8.5 m after start of ST
- D1 of ST until 8.5 m after start of ST
R/R AML subjects:
- D1 of ST until 8.5 m after start of ST
- D1 of ST until 8.5 m after start of ST
Part 3:
DDI Cohort 1:
- D1 of HDM201 dose to 10d after start of HMD201
DDI Cohort 2:
- first dose of midazolam (D2) to 8 days after start of ST (HMD201) |
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E.5.2 | Secondary end point(s) |
Part 1:
1L AML and R/R AML subjects
• PK parameters of HDM201 (e.g., AUC, Cmax, Tmax)
• Incidence of AEs, SAEs and abnormal laboratory values, ECG and vital signs
Part 2:
Expansion Cohort 1
• OS, DFS, CIR , EFS
• Proportion of subjects receiving HSCT
• Proportion of subjects with MRD negativity
Expansion Cohort 2
• OS, DFS, CIR , EFS, proportion of subjects with CR/CRi with ABCR
• Proportion of subjects receiving HSCT
• Proportion of subjects with MRD negativity
• PK parameters of midostaurin (e.g., AUC, Cmax, Tmax)
Expansion Cohort 3
• OS, DFS, CIR , EFS, proportion of CR/CRi with ABCR
• Proportion of subjects receiving HSCT
Expansion Cohort 4
• OS, EFS
• Proportion of subjects receiving HSCT
All Expansion Cohorts
• PK parameters of HDM201 (e.g., AUC, Cmax, Tmax)
• Time to platelet recovery, time to neutrophil recovery
Part 3:
DDI Cohort 1
• Overall safety information in subjects in DDI Cohort 1
DDI Cohort 2
• Overall safety information in subjects in DDI Cohort 2
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Part 1:
1L AML and R/R AML subjects
- D1 of ST to 7.5 m after start of ST
- D1 of ST to 8.5 m after start of ST
Part 2:
Expansion Cohort 1
- D1 of ST to 3 y after last patients is enrolled in Part 2
- D1 of ST to 3 y after last patients is enrolled in Part 2
- D1 of ST to 7.5 m after start of ST |
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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 | 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) | 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 |
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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 | 20 |
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 |
Australia |
Belgium |
Canada |
Finland |
France |
Germany |
Hong Kong |
Israel |
Italy |
Japan |
Lebanon |
Singapore |
Spain |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
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 | 3 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | 13 |
E.8.9.2 | In all countries concerned by the trial years | 4 |