A study of siremadlin in combination with venetoclax plus azacitidine in adult participants with AML who are ineligible for chemotherapy.
- Conditions
- Acute Myeloid LeukemiaMedDRA version: 21.0Level: LLTClassification code 10000886Term: Acute myeloid leukemiaSystem Organ Class: 100000004864Therapeutic area: Diseases [C] - Cancer [C04]
- Registration Number
- EUCTR2021-001165-21-IT
- Lead Sponsor
- OVARTIS PHARMA AG
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ot Recruiting
- Sex
- All
- Target Recruitment
- 55
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
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 10
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 45
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
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method
- Secondary Outcome Measures
Name Time Method