AMLM30 (EVOLVE II)
ALLG AMLM30/EVOLVE II: Randomised study to assess revumenib in combination with azacitidine + venetoclax in adult patients with newly diagnosed NPM1-mutated or KMT2A-rearranged Acute Myeloid Leukaemia (AML) ineligible for intensive chemotherapy
Leukaemia – Acute myeloid leukaemia (AML)
The primary aim of this study is to assess the effectiveness and safety of revumenib combined with azacitidine and venetoclax in treating adult patients with newly diagnosed acute myeloid leukemia (AML) who have NPM1 mutations or KMT2A rearrangements and are ineligible for intensive chemotherapy. This patient population has an unmet clinical need for effective therapy.
Who is it for:
Adult patients, over 18 years of age, with newly diagnosed acute myeloid leukemia (AML) who have NPM1 mutations or KMT2A rearrangements and are ineligible for intensive chemotherapy.
STUDY DETAILS:
This is a randomised trial to determine if adding a new drug, revumenib, to the existing treatment with azacitidine and venetoclax will improve patient outcomes. Participants will be randomly divided into two groups. One group will receive the new combination of revumenib, azacitidine, and venetoclax, while the other group will receive azacitidine and venetoclax with a placebo. The study will involve multiple cycles of treatment, with each cycle lasting 28 days. After each cycle, a response will be assessed to evaluate the continuation of treatment.
It is hoped that this research will determine if the addition of a new drug, revumenib, can improve survival rates and patient outcomes in this AML patient population.
Key inclusion criteria:
In order to be eligible to participate in this study, a patient must meet all of the following criteria:
1. Patient with newly diagnosed NPM1-mutated AML, consistent with NPM1c, according to the 2022 International Consensus Classification (i.e. greater or equal to 10% blasts).
OR
Patient with newly diagnosed KMT2A-rearranged AML according to the 2022 International Consensus Classification (i.e. greater or equal to 10% blasts). KMT2A partial tandem duplications or deletions are NOT eligible.
2. Central confirmation of NPM1 mutation or KMT2A rearrangement in one of the dedicated central genetic laboratories.
3. Age greater or equal to 18 years, no upper age limit.
4. Patient is ineligible for intensive induction chemotherapy by meeting at least 1 of the following criteria:
• greater or equal to 75 years of age: ineligible for intensive chemotherapy per physician’s discretion (with an Eastern Cooperative Oncology Group (ECOG) performance status 0-2)
• 18-74 years: patient is not eligible for standard chemotherapy because any of the following co-morbidities:
o ECOG performance status 2 or 3
o Cardiac history of chronic heart failure requiring treatment; or with an ejection fraction less or equal to 50%; or chronic stable angina.
o Diffusing Capacity of Lung for Carbon Monoxide (DLCO) less or equal to 65% or Forced Expiratory Volume (in one second) (FEV1) less or equal to 65%.
o Creatinine clearance greater or equal to 30 mL per min to less than 45 ml per min calculated by the Cockcroft Gault formula.
o Moderate hepatic impairment with total bilirubin greater than 1.5 to less than 3.0 x upper limit of normal (ULN).
o Any other comorbidity that the local physician assesses to be incompatible with intensive chemotherapy.
5. Patient must have a projected life expectancy of at least 12 weeks (as assessed by the treating physician).
6. Patient must have a white cell blood (WBC) count of less than 25 x 109 per L. Hydroxyurea can be used prior to study enrolment to reduce the WBC count to meet this criterion.
7. Adequate renal function as evidenced by serum creatinine less or equal to 2.0 × upper limit of norm (ULN) or creatinine clearance greater than 30 mL per min based on the Cockcroft-Gault glomerular filtration rate (GFR).
8. Adequate hepatic function as evidenced by:
• Serum total bilirubin less or equal to 3.0 × ULN unless considered due to Gilbert’s disease, or leukemic involvement.
• Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) less or equal to 3.0 × ULN, unless considered due to leukemic involvement.
9. Female patient must:
• be of nonchildbearing potential:
o postmenopausal (defined as at least 1 year without any menses).
o documented surgically sterile (e.g. documented hysterectomy, or bilateral oophorectomy, bilateral salpingectomy) or status post hysterectomy (at least 1 month prior to screening).
• or, if of childbearing potential (not surgically sterile and not postmenopausal)
agree to avoid pregnancy during the study and for 6 months after the final study drug administration.
o and have a negative urine or serum pregnancy test at screening.
o and, if heterosexually active, agree to consistently apply one highly effective* method of birth control in combination to a barrier method for the duration of the study and for 6 months after the final study drug administration.
*Highly effective forms of birth control include
– Consistent and correct usage of established hormonal contraceptives that inhibit ovulation for at least 1 month prior to taking study drug. (hormonal contraception is only a highly effective method of birth control, if a combined [estrogen and progestogen containing] hormonal contraception or a progestogen-only hormonal contraception – both associated with inhibition of ovulation – is used.
– Established intrauterine device (IUD) or intrauterine system (IUS)
– Bilateral tubal occlusion
– Vasectomy – a vasectomy is highly effective contraception method provided the absence of sperm has been confirmed. If not, an additional highly effective method of contraception should be used.
– Male is sterile due to a bilateral orchiectomy.
– Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual activity during the entire period of risk associated with the study drug. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the patient.
List is not all inclusive. Prior to enrolment, the investigator is responsible for confirming patient will utilize highly effective forms of birth control in combination with a barrier method according to locally accepted standards during the protocol defined period.
Note: A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.
• agree not to breastfeed starting at screening and throughout the study period.
• agree not to donate ova starting at screening and throughout the study period, and for 6 months after the final study drug administration.
10. Men must use a latex condom during any sexual contact with women of childbearing potential (WOCBP), even if they have undergone a successful vasectomy and must agree to avoid to father a child (while on therapy and for 6 months after the final study drug administration). In addition, their female partners of childbearing potential must use a highly effective method of birth control.
11. Male patient must not donate sperm starting at screening and throughout the study period and for 6 months after the final study drug administration.
12. Able to understand and willing to sign an informed consent form (ICF).
13. Institutional Review Board/Independent Ethics Committee-approved written informed consent as per national regulations must be obtained from the patient prior to any study-related procedures (including consent for withdrawal of prohibited medication, if applicable).
1. Patient with newly diagnosed NPM1-mutated AML, consistent with NPM1c, according to the 2022 International Consensus Classification (i.e. greater or equal to 10% blasts).
OR
Patient with newly diagnosed KMT2A-rearranged AML according to the 2022 International Consensus Classification (i.e. greater or equal to 10% blasts). KMT2A partial tandem duplications or deletions are NOT eligible.
2. Central confirmation of NPM1 mutation or KMT2A rearrangement in one of the dedicated central genetic laboratories.
3. Age greater or equal to 18 years, no upper age limit.
4. Patient is ineligible for intensive induction chemotherapy by meeting at least 1 of the following criteria:
• greater or equal to 75 years of age: ineligible for intensive chemotherapy per physician’s discretion (with an Eastern Cooperative Oncology Group (ECOG) performance status 0-2)
• 18-74 years: patient is not eligible for standard chemotherapy because any of the following co-morbidities:
o ECOG performance status 2 or 3
o Cardiac history of chronic heart failure requiring treatment; or with an ejection fraction less or equal to 50%; or chronic stable angina.
o Diffusing Capacity of Lung for Carbon Monoxide (DLCO) less or equal to 65% or Forced Expiratory Volume (in one second) (FEV1) less or equal to 65%.
o Creatinine clearance greater or equal to 30 mL per min to less than 45 ml per min calculated by the Cockcroft Gault formula.
o Moderate hepatic impairment with total bilirubin greater than 1.5 to less than 3.0 x upper limit of normal (ULN).
o Any other comorbidity that the local physician assesses to be incompatible with intensive chemotherapy.
5. Patient must have a projected life expectancy of at least 12 weeks (as assessed by the treating physician).
6. Patient must have a white cell blood (WBC) count of less than 25 x 109 per L. Hydroxyurea can be used prior to study enrolment to reduce the WBC count to meet this criterion.
7. Adequate renal function as evidenced by serum creatinine less or equal to 2.0 × upper limit of norm (ULN) or creatinine clearance greater than 30 mL per min based on the Cockcroft-Gault glomerular filtration rate (GFR).
8. Adequate hepatic function as evidenced by:
• Serum total bilirubin less or equal to 3.0 × ULN unless considered due to Gilbert’s disease, or leukemic involvement.
• Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) less or equal to 3.0 × ULN, unless considered due to leukemic involvement.
9. Female patient must:
• be of nonchildbearing potential:
o postmenopausal (defined as at least 1 year without any menses).
o documented surgically sterile (e.g. documented hysterectomy, or bilateral oophorectomy, bilateral salpingectomy) or status post hysterectomy (at least 1 month prior to screening).
• or, if of childbearing potential (not surgically sterile and not postmenopausal)
agree to avoid pregnancy during the study and for 6 months after the final study drug administration.
o and have a negative urine or serum pregnancy test at screening.
o and, if heterosexually active, agree to consistently apply one highly effective* method of birth control in combination to a barrier method for the duration of the study and for 6 months after the final study drug administration.
*Highly effective forms of birth control include
– Consistent and correct usage of established hormonal contraceptives that inhibit ovulation for at least 1 month prior to taking study drug. (hormonal contraception is only a highly effective method of birth control, if a combined [estrogen and progestogen containing] hormonal contraception or a progestogen-only hormonal contraception – both associated with inhibition of ovulation – is used.
– Established intrauterine device (IUD) or intrauterine system (IUS)
– Bilateral tubal occlusion
– Vasectomy – a vasectomy is highly effective contraception method provided the absence of sperm has been confirmed. If not, an additional highly effective method of contraception should be used.
– Male is sterile due to a bilateral orchiectomy.
– Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual activity during the entire period of risk associated with the study drug. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the patient.
List is not all inclusive. Prior to enrolment, the investigator is responsible for confirming patient will utilize highly effective forms of birth control in combination with a barrier method according to locally accepted standards during the protocol defined period.
Note: A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.
• agree not to breastfeed starting at screening and throughout the study period.
• agree not to donate ova starting at screening and throughout the study period, and for 6 months after the final study drug administration.
10. Men must use a latex condom during any sexual contact with women of childbearing potential (WOCBP), even if they have undergone a successful vasectomy and must agree to avoid to father a child (while on therapy and for 6 months after the final study drug administration). In addition, their female partners of childbearing potential must use a highly effective method of birth control.
11. Male patient must not donate sperm starting at screening and throughout the study period and for 6 months after the final study drug administration.
12. Able to understand and willing to sign an informed consent form (ICF).
13. Institutional Review Board/Independent Ethics Committee-approved written informed consent as per national regulations must be obtained from the patient prior to any study-related procedures (including consent for withdrawal of prohibited medication, if applicable).
Minimum age: 18 Years
Maximum age: No limit
Sex: Both males and females
Healthy volunteers: No
Key exclusion criteria:
1. Subject has previously been treated for AML; a treatment period with hydroxyurea to control WBC counts is allowed; prior treatment with a hypomethylating agent for Myelodysplastic Syndrome with Excess Blasts (MDS-EB) is not allowed; prior treatment with erythropoiesis-stimulating agents or luspatercept for Myelodysplastic Syndrome (MDS) is allowed.
2. Acute promyelocytic leukemia (APL) with t(15;17)(q22;q12); PML-RARA; or one of the other pathognomonic variant chromosomal translocations / fusion genes.
3. AML with BCR-ABL1; or myeloid blast crisis of Chronic Myeloid Leukemia (CML).
4. Significant active cardiac disease within 3 months prior to the start of study treatment, including:
o New York Heart Association (NYHA) class III or IV congestive heart failure
o Myocardial infarction
o Unstable angina
o Severe cardiac arrhythmias
o Congenital long QT syndrome of family member with this condition
o Corrected QT interval by Fridericia (QTcF) greater than 450 msec on screening electrogram for males and greater than 470 msec on screening electrogram for females (mean of triplicate recordings; calculated using Fridericia’s correction).
5. Severe obstructive or restrictive ventilation disorder.
6. History of stroke or intracranial hemorrhage within 6 months prior to randomisation.
7. Clinical symptoms suggestive of active central nervous system (CNS) leukemia or known CNS leukemia. Evaluation of cerebrospinal fluid (CSF) during screening is only required if there is a clinical suspicion of CNS involvement by leukemia during screening.
8. Active infection, including hepatitis B or hepatitis C or Human Immunodeficiency Virus (HIV) infection, that is uncontrolled prior to first dose of study treatment and may interfere with the study objectives or which could expose the patient to undue risk through the participation in the clinical trial; an infection controlled with an approved antibiotic/ antiviral/ antifungal treatment that is not a strong or moderate CYP3A inducer is allowed. Patients with COVID-19 infection can be enrolled, if the patient has no symptoms and was tested negative twice by polymerase chain reaction (PCR) test prior to inclusion in the trial.
9. Immediate life-threatening, severe complications of leukemia such as uncontrolled bleeding and/or disseminated intravascular coagulation.
10. Conditions that limit the ingestion or gastrointestinal absorption of orally administered drugs.
11. Patient with a currently active second malignancy. Patients are not considered to have a currently active malignancy, if they have completed therapy and are considered by their physician to be at less than 30% risk of relapse within one year. However, patients with the following history/concurrent conditions are allowed:
o Basal or squamous cell carcinoma of the skin;
o Carcinoma in situ of the cervix;
o Carcinoma in situ of the breast;
o Incidental histologic finding of prostate cancer.
12. Receipt of live, attenuated vaccine within 30 days prior to the study inclusion (NOTE: patient, if enrolled, should not receive live vaccine during the study and until 6 months after the therapy).
13. Severe neurological or psychiatric disorder interfering with ability to give an informed consent.
14. Contraindication to azacitidine or venetoclax (as per Summary of Product Characteristics (SmPC).
15. Patient weighing less than 40 kg at registration.
16. Participation in other prospective studies with anti-leukemic and/or investigational agents.
17. Patient taking Dabigatran unless they can be transferred to other medications within greater than 5 half-lives prior to dosing. Patients taking other P-glycoprotein (P-gP) transporter-sensitive medications should be properly monitored during the study if they cannot be transferred to other medications.
18. Patients taking known strong cytochrome P450 (CYP) 3A4 inducers, unless they can be transferred to other medications within greater than 5 half-lives prior to dosing.
19. The patient is a pregnant or lactating woman, or plans to become pregnant during the study.
20. Patient who has once been screened and randomized into this trial but was considered ineligible cannot re-enter this trial at a later date.
2. Acute promyelocytic leukemia (APL) with t(15;17)(q22;q12); PML-RARA; or one of the other pathognomonic variant chromosomal translocations / fusion genes.
3. AML with BCR-ABL1; or myeloid blast crisis of Chronic Myeloid Leukemia (CML).
4. Significant active cardiac disease within 3 months prior to the start of study treatment, including:
o New York Heart Association (NYHA) class III or IV congestive heart failure
o Myocardial infarction
o Unstable angina
o Severe cardiac arrhythmias
o Congenital long QT syndrome of family member with this condition
o Corrected QT interval by Fridericia (QTcF) greater than 450 msec on screening electrogram for males and greater than 470 msec on screening electrogram for females (mean of triplicate recordings; calculated using Fridericia’s correction).
5. Severe obstructive or restrictive ventilation disorder.
6. History of stroke or intracranial hemorrhage within 6 months prior to randomisation.
7. Clinical symptoms suggestive of active central nervous system (CNS) leukemia or known CNS leukemia. Evaluation of cerebrospinal fluid (CSF) during screening is only required if there is a clinical suspicion of CNS involvement by leukemia during screening.
8. Active infection, including hepatitis B or hepatitis C or Human Immunodeficiency Virus (HIV) infection, that is uncontrolled prior to first dose of study treatment and may interfere with the study objectives or which could expose the patient to undue risk through the participation in the clinical trial; an infection controlled with an approved antibiotic/ antiviral/ antifungal treatment that is not a strong or moderate CYP3A inducer is allowed. Patients with COVID-19 infection can be enrolled, if the patient has no symptoms and was tested negative twice by polymerase chain reaction (PCR) test prior to inclusion in the trial.
9. Immediate life-threatening, severe complications of leukemia such as uncontrolled bleeding and/or disseminated intravascular coagulation.
10. Conditions that limit the ingestion or gastrointestinal absorption of orally administered drugs.
11. Patient with a currently active second malignancy. Patients are not considered to have a currently active malignancy, if they have completed therapy and are considered by their physician to be at less than 30% risk of relapse within one year. However, patients with the following history/concurrent conditions are allowed:
o Basal or squamous cell carcinoma of the skin;
o Carcinoma in situ of the cervix;
o Carcinoma in situ of the breast;
o Incidental histologic finding of prostate cancer.
12. Receipt of live, attenuated vaccine within 30 days prior to the study inclusion (NOTE: patient, if enrolled, should not receive live vaccine during the study and until 6 months after the therapy).
13. Severe neurological or psychiatric disorder interfering with ability to give an informed consent.
14. Contraindication to azacitidine or venetoclax (as per Summary of Product Characteristics (SmPC).
15. Patient weighing less than 40 kg at registration.
16. Participation in other prospective studies with anti-leukemic and/or investigational agents.
17. Patient taking Dabigatran unless they can be transferred to other medications within greater than 5 half-lives prior to dosing. Patients taking other P-glycoprotein (P-gP) transporter-sensitive medications should be properly monitored during the study if they cannot be transferred to other medications.
18. Patients taking known strong cytochrome P450 (CYP) 3A4 inducers, unless they can be transferred to other medications within greater than 5 half-lives prior to dosing.
19. The patient is a pregnant or lactating woman, or plans to become pregnant during the study.
20. Patient who has once been screened and randomized into this trial but was considered ineligible cannot re-enter this trial at a later date.
Dr. Carolyn Grove
Australasian Leukaemia & Lymphoma Group
Phase 3
ALLG AMLM30/EVOLVE II
ACTRN12625000964415p