| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| Adult subjects with acute myeloid leukemia who are ineligible for intensive induction chemotherapy. |
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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 |
|
| 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 |
Safety Run-in, Arm 1, Arm 2:
To determine the recommended dose of siremadlin in combination with venetoclax plus azacitidine to be explored further in the expansion phase (RDE), separately in Arm 1 and Arm 2.
Safety Run-in and expansion, Arm 1:
To evaluate preliminary efficacy of siremadlin at the determined recommended dose for expansion (RDE) when administered in combination with venetoclax plus azacitidine in achieving Complete Remission (CR) (Arm 1 only). |
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|
| E.2.2 | Secondary objectives of the trial |
1. safety and tolerability profile of siremadlin when administered in combination with venetoclax plus azacitidine (Arms 1 and 2).
2. CR rate (Arm 2 only; for Arm 1, assessment of CR is a primary endpoint).
3. duration of CR in Arm 1 as well as in Arm 2.
4. CR/CRh and CR/CRi rates with CRh defined as CR with partial hematological recovery (neutrophils > 0.5 X109/L and platelet > 50X109/L) and CRi defined as CR with incomplete hematological recovery (neutrophils <1.0X109/L and/or platelets <100X109/L) (Arm 1
and 2).
5. duration of CR/CRh and CR/CRi (Arm 1 and 2).
6. Overall Survival (OS) (Arm 1 and 2).
7. Assessment of early mortality, defined by 30- and 60- day mortality from the start of study treatment (Arm 1 and 2).
8. PK of siremadlin, venetoclax and azacitidine administered in combination (Arms 1 and 2).
9. effect of siremadlin in combination with venetoclax plus azacitidine on measurable residual disease (MRD). |
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|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Participants eligible for inclusion in this study must meet all of the following criteria:
1. Signed informed consent must be obtained prior to participation in the study.
2. Age at the date of signing the informed consent form (ICF):
Arm 1 and Arm 2: = 18 years
3. Participants with AML based on WHO 2016 classification (Arber et al 2016) who are ineligible for chemotherapy and:
Arm 1 (sub-optimal responders): have received at least 2 cycles and not more than 4 cycles of first-line venetoclax plus azacitidine treatment and have not achieved a CR, CRi, CRh or MLFS. A participant can be enrolled
in the study after 2 cycles only if the participant is no better than in SD at the end of the 2nd cycle of venetoclax plus azacitidine treatment.Otherwise, the participants should be enrolled after cycle 3 of venetoclax
plus azacitidine treatment.
Arm 2 (newly diagnosed AML presenting with high-risk clinical features):
newly diagnosed AML with adverse-risk according to 2017 ELN genetic risk stratification (except TP53 mutation positive participants).
4. Participant (in both arms) must be considered ineligible for standard of care intensive induction chemotherapy (in Arm 1, ineligibility for standard induction chemotherapy must be determined by the investigator, prior to initiation of venetoclax plus azacitidine treatment) defined by the following:
= 75 years of age;
OR
= 18 to 74 years of age with at least one of the following co-morbidities:
Eastern Cooperative Oncology Group (ECOG) Performance Status of 2 or 3; Cardiac history of CHF requiring treatment or Ejection Fraction = 50% or chronic stable angina; DLCO = 65% or FEV1 = 65%;
5. Participants with antecedent of myelodysplastic syndromes (MDS), myelofibrosis, essential thrombocythemia, polycythemia vera or therapy related AML may be included in the study, provided no prior therapy, as
specified in exclusion criteria
6. Participants must have an ECOG performance status:
0 to 2 for participants = 75 years of age.
OR
0 to 3 for participants = 18 to 74 years of age.
7. AST and ALT = 3 × upper limit of normal (ULN)
8. Total bilirubin = 1.5 × ULN (except in the setting of isolated Gilbert syndrome, in which case higher total bilirubin is allowed provided that conjugated bilirubin is = 3.0 x ULN)
9. Estimated Glomerular Filtration Rate (eGFR) = 60 mL/min/1.73 m2 (estimation based on Modification of Diet in Renal Disease (MDRD) formula, by local laboratory)
10. WBC < 25x109/L (may be reduced with leukopheresis or hyroxyurea)
11. Participant is able to communicate with the investigator, and has the ability to comply with the requirements of the study procedures |
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|
| E.4 | Principal exclusion criteria |
1. Prior exposure to MDM-inhibitor therapy at any time
2. Participants with TP53 mutation positive, as defined by local TP53 testing
3. Participants with del17p
4. Previous treatment at any time, with any of the following antineoplastic agents, approved or investigational; checkpoint inhibitors, venetoclax and hypomethylating agents (HMAs) such as decitabine or azacitidine. Previous treatment for AML, MDS, myelofibrosis, essential thrombocythemia, or polycythemia vera, with the exception of hydroxyurea, growth factors, ruxolitinib, and supportive care. In Arm 1, as defined in the inclusion criteria pre-treatment with venetoclax and azacitidine is allowed provided the participant is enrolled in the study within 28 days from their last dose of venetoclax and/or azacitidine treatment.
5. Participants with AML-M3 / APL (Acute promyelocytic leukemia) with PML-RARA or with AML secondary to Down's syndrome
6. Participants treated with FLT3 inhibitors
7. Participants with known active CNS leukemia or neurologic symptoms suggestive of CNS leukemia (unless CNS leukemia has been excluded by at least one lumbar puncture showing negativity prior to starting
protocol therapy)
8. Participants with concurrent or prior malignancy, except:
• Participant with history of MDS, myelofibrosis, essential thrombocythemia, or polycythemia vera, aplastic anemia or other antecedent hematologic disorder
• Participant with history of adequately treated malignancy for which the participant has been disease free (absence of residual disease) for at least 1 years and if no anticancer systemic therapy (namely chemotherapy, radiotherapy or surgery) is ongoing or required during the course of the study. Participants who are receiving adjuvant therapy such as hormonal therapy or long-term maintenance therapy who have had no residual disease for at least 1 year are eligible
9. Other protocol-defined exclusion criteria may apply |
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
• Proportion of participants with DLT as per investigator assessment reported during the first cycle.
• Proportion of participants achieving a complete remission (CR) as per investigator assessment (Cheson et al 2003, Döhner et al 2017). |
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|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Analysis for primary safety endpoint (proportion of participants with DLT) will be conducted conducted for each cohort when participants have received siremadlin plus azacitidine plus venetoclax for at least one cycle.
The primary efficacy analysis (proportion of participants achieving CR) will be performed on all participant data (from both safety run-in at RDE and expansion parts in Arm 1) at the time all participants who are still receiving study treatment will have completed at least 7 cycles or discontinued earlier. |
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|
| E.5.2 | Secondary end point(s) |
1.Incidence and severity of AEs and SAEs, changes in laboratory values and vital signs, incidence of notable ECG abnormalities.
2.Proportion of participants achieving a CR as per investigator assessment (Cheson et al 2003, Döhner et al 2017).
3.Time from the date of the first documented CR to the date of first documented relapse or death due to any cause, whichever occurs first.
4.Proportion of participants achieving a CR or CRh, Proportion of participants achieving a CR or CRi.
5.Time from the date of the first documented CR/CRh and CR/CRi to the date of first documented relapse or death due to any cause, whichever occurs first.
6.The time from start of treatment to death due to any cause.
7.Proportion of participants died due to any cause from start of treatment until 30- and 60-day.
8.Pharmacokinetic parameters (e.g., AUC, Cmax, Tmax) and concentration vs time profiles of siremadlin, venetoclax and azacitidine.
9.Proportion of CR-MRD negative overall and in participants achieving a CR, CR/CRh, and CR/CRi. |
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|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Timepoint of evaluation will be at evaluation of primary efficacy analysis and final analysis, respectively. |
| - |
|
| 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 | 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 |
| Phase Ib/II proof of concept study |
| - |
|
| 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 | No |
| 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.8.2.4 | 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 32 |
| 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 | Information not present in EudraCT |
| 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 |
| Hong Kong |
| Hungary |
| Israel |
| Italy |
| Japan |
| Malaysia |
| Russian Federation |
| Switzerland |
| Turkey |
| United States |
|
| 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
|
|
| 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 | 8 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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