REVUMENIB for Acute myeloid leukemia | Acute myeloid leukemia with NPM1 mutation | Acute myeloid leukemia with KMT2A rearrangement

Inclusion criteria

• {"criterion_text":"- Patient with newly diagnosed NPM1-mutated AML, consistent with NPM1c, according to the 2022 International Consensus Classification (i.e. ≥ 10% blasts). OR Patient with newly diagnosed KMT2A-rearranged AML according to the 2022 International Consensus Classification (i.e. ≥ 10% blasts). KMT2A partial tandem duplications or deletions are NOT eligible. Of note: in case both NPM1 and IDH1 are mutated and both EVOLVE-1 (HO173) and EVOLVE-2 (HO177) are open for inclusion at your site, then patients can only be included in the EVOLVE-1 trial (HO173)\n- 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.\n- Male patient must not donate sperm starting at screening and throughout the study period and for 6 months after the final study drug administration.\n- Able to understand and willing to sign an informed consent form (ICF).\n- 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).\n- Central confirmation of NPM1 mutation or KMT2A rearrangement in one of the dedicated central genetic laboratories.\n- Age ≥ 18 years, no upper age limit.\n- Patient is ineligible for intensive induction chemotherapy by meeting at least 1 of the following criteria: ≥ 75 years of age: ineligible for intensive chemotherapy per physician’s discretion (with an ECOG performance status 0-2) 18-74 years: patient is not eligible for standard chemotherapy because any of the following co-morbidities: ECOG performance status 2 or 3 Cardiac history of chronic heart failure requiring treatment; or with an ejection fraction ≤50%; or chronic stable angina. DLCO ≤ 65% or FEV1 ≤ 65%. Creatinine clearance ≥ 30 mL/min to <45 ml/min calculated by the Cockcroft Gault formula. Moderate hepatic impairment with total bilirubin > 1.5 to < 3.0 x upper limit of normal (ULN). Any other comorbidity that the local physician assesses to be incompatible with intensive chemotherapy.\n- Patient must have a projected life expectancy of at least 12 weeks (as assessed by the treating physician).\n- Patient must have a white cell blood (WBC) count of < 25 x 109/L. Hydroxyurea can be used prior to study enrollment to reduce the WBC count to meet this criterion.\n- Adequate renal function as evidenced by serum creatinine ≤ 2.0 × upper limit of norm (ULN) or creatinine clearance >30 mL/min based on the Cockcroft-Gault glomerular filtration rate (GFR).\n- Adequate hepatic function as evidenced by: Serum total bilirubin ≤ 3.0 × ULN unless considered due to Gilbert’s disease, or leukemic involvement; Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) ≤ 3.0 × ULN, unless considered due to leukemic involvement.\n- Female patient must: be of nonchildbearing potential: 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; and have a negative urine or serum pregnancy test at screening; and, if heterosexually active, agree to consistently apply one highly effective method of birth control for the duration of the study and for 6 months after the final study drug administration; agree not to breastfeed starting at screening and throughout the study period, and for 1 week after the final study drug administration; agree not to donate ova starting at screening and throughout the study period, and for 6 months after the final study drug administration."}

Exclusion criteria

• {"criterion_text":"- 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 MDS-EB is not allowed; prior treatment with erythropoiesis-stimulating agents or luspatercept for MDS is allowed.\n- The patient is a pregnant or lactating woman, or plans to become pregnant during the study.\n- Patient who has once been screened and randomized into this HO177 trial but was considered ineligible cannot re-enter this trial at a later date.\n- Acute promyelocytic leukemia (APL) with t(15;17)(q24.1;q21.2); PML-RARA; or one of the other pathognomonic variant chromosomal translocations / fusion genes.\n- AML with BCR-ABL1; or myeloid blast crisis of CML.\n- Significant active cardiac disease within 3 months prior to the start of study treatment, including: New York Heart Association (NYHA) class III or IV congestive heart failure Myocardial infarction Unstable angina Severe cardiac arrhythmias Congenital long QT syndrome of family member with this condition QTcF >450 msec on screening electrogram for males and >470msec on screening electrogram for females (mean of triplicate recordings; calculated using Fridericia’s correction).\n- Severe obstructive or restrictive ventilation disorder.\n- History of stroke or intracranial hemorrhage within 6 months prior to randomization.\n- 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.\n- 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.\n- Immediate life-threatening, severe complications of leukemia such as uncontrolled bleeding and/or disseminated intravascular coagulation.\n- Conditions that limit the ingestion or gastrointestinal absorption of orally administered drugs.\n- Patient weighing <40 kg at registration.\n- 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 < 30% risk of relapse within one year. However, patients with the following history/concurrent conditions are allowed: Basal or squamous cell carcinoma of the skin; Carcinoma in situ of the cervix; Carcinoma in situ of the breast; Incidental histologic finding of prostate cancer.\n- 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).\n- Severe neurological or psychiatric disorder interfering with ability to give an informed consent.\n- Contraindication to azacitidine or venetoclax\n- Participation in other prospective studies with anti-leukemic and/or investigational agents.\n- Patient taking Dabigatran unless they can be transferred to other medications within ≥5 half-lives prior to dosing. Patients taking other P-gP transporter-sensitive medications should be properly monitored during the study if they cannot be transferred to other medications\n- Patients taking known strong cytochrome P450 (CYP) 3A4 inducers, unless they can be transferred to other medications within ≥5 half-lives prior to dosing."}

Primary endpoints

• {"endpoint_text":"- OS in adult patients with newly diagnosed NPM1-mutated AML ineligible for intensive chemotherapy, measured from the date of randomization to the date of death from any cause;","definition_or_measurement_approach":"Measured from the date of randomization to date of death from any cause (overall survival)."}
• {"endpoint_text":"- Rate of CR in adult patients with newly diagnosed NPM1-mutated AML ineligible for intensive chemotherapy, defined as the proportion of NPM1-mutated AML patients who achieve CR at any time-point during protocol therapy.","definition_or_measurement_approach":"Proportion of NPM1-mutated AML patients who achieve complete remission (CR) at any time-point during protocol therapy."}

Secondary endpoints

• {"endpoint_text":"- EFS in adult patients with newly diagnosed NPM1-mutated AML ineligible for intensive chemotherapy, measured from the date of randomization to the date of treatment failure, hematologic relapse from CR/CRh or death from any cause, whichever occurs first. Treatment failure is defined as lack of obtaining either CR or CRh by week 24","definition_or_measurement_approach":"Measured from randomization to treatment failure, hematologic relapse from CR/CRh, or death (whichever first). Treatment failure = lack of obtaining CR or CRh by week 24."}
• {"endpoint_text":"- Rate of CR/CRh in adult patients with newly diagnosed NPM1-mutated AML ineligible for intensive chemotherapy, defined as the proportion of NPM1-mutated AML patients who achieve CR or CRh at any time-point during protocol therapy.","definition_or_measurement_approach":"Proportion achieving CR or CRh at any time during protocol therapy."}
• {"endpoint_text":"- Rate of response (CRh and CR/CRi) in adult patients with newly diagnosed NPM1-mutated AML ineligible for intensive chemotherapy, defined as the proportion of NPM1-mutated AML patients with response at any time-point during protocol therapy.","definition_or_measurement_approach":"Proportion with response (CRh and CR/CRi) at any time during protocol therapy."}
• {"endpoint_text":"- Rates of CRMRD-, CR/CRhMRD- and CR/CRiMRD- assessed by quantitative PCR of bone marrow in adult patients with newly diagnosed NPM1-mutated AML ineligible for intensive chemotherapy, defined as the proportion of NPM1-mutated AML patients with CRMRD-, CR/CRhMRD- and CR/CRiMRD- by PCR in bone marrow, respectively, at any time-point during protocol therapy.","definition_or_measurement_approach":"Proportion with CRMRD-, CR/CRhMRD- and CR/CRiMRD- by quantitative PCR of bone marrow at any time-point during therapy."}
• {"endpoint_text":"- Time to achievement of response (CR, CR/CRh and CR/CRi) in adult patients with newly diagnosed NPM1-mutated AML ineligible for intensive chemotherapy, defined as time from the date of randomization to until the 1st occurrence of the response.","definition_or_measurement_approach":"Time from randomization to first occurrence of response (CR, CR/CRh, CR/CRi)."}
• {"endpoint_text":"- Duration of response (CR, CR/CRh and CR/CRi; DoR) in adult patients with newly diagnosed NPM1-mutated AML ineligible for intensive chemotherapy, measured from the date of achievement of response until the date of hematologic relapse or death from any cause; patients without any of these events will be censored on the date of the last clinical assessment.","definition_or_measurement_approach":"Measured from date of response to hematologic relapse or death; censoring at last clinical assessment if neither event occurs."}
• {"endpoint_text":"- OS, CR rate, EFS, rates of CR, CR/CRh, CR/CRi, and DoR across different patient subgroups in adult patients with newly diagnosed NPM1-mutated AML ineligible for intensive chemotherapy, where the groups are defined based on prognostic variables including clinical variables (e.g., age at randomization, sex, ECOG performance status, white blood cell count), risk category, geographical region as well as specific AML genotypes.","definition_or_measurement_approach":"Descriptive and comparative analyses of endpoints by prognostic subgroups defined by clinical variables, ELN risk groups, geographic region, and AML genotypes."}
• {"endpoint_text":"- Rates of CRMRD, CR/CRhMRD- and CR/CRiMRD- assessed by multiparameter flowcytometry of bone marrow at any time-point during protocol therapy in adult patients with newly diagnosed NPM1-mutated AML ineligible for intensive chemotherapy, defined as the proportion of NPM1-mutated AML patients with CRMRD-, CR/CRhMRD- and CR/CRiMRD- by multiparameter flowcytometry, respectively, at any time-point during protocol therapy.","definition_or_measurement_approach":"Proportion with MRD-negative responses assessed by multiparameter flow cytometry in bone marrow at any time-point."}
• {"endpoint_text":"- Resistance mechanisms after combined treatment with azacitidine/venetoclax/revumenib (e.g. MEN1 mutations, RAS mutations, TP53 mutations, FLT3 mutations).","definition_or_measurement_approach":"Molecular characterization of resistance mechanisms by sequencing/analysis of specified mutations after combined treatment."}
• {"endpoint_text":"- Quality of life (QoL) in adult patients with newly diagnosed NPM1-mutated AML ineligible for intensive chemotherapy as assessed by EORTC QLC-C30 and EQ-5D-5L questionnaires.","definition_or_measurement_approach":"Patient-reported QoL measured using EORTC QLQ-C30 and EQ-5D-5L instruments."}
• {"endpoint_text":"- OS, CR rate, EFS, rates of CR/CRh, CR/CRi, CRMRD-, CR/CRhMRD-, CR/CRiMRD-, time to response, DoR and QoL as assessed by EORTC QLQ-C30 and EQ-5D-5L questionnairesas defined above in adult patients with newly diagnosed KMT2A-rearranged AML ineligible for intensive chemotherapy.","definition_or_measurement_approach":"Same endpoint definitions as above applied in the KMT2A-rearranged AML subgroup."}
• {"endpoint_text":"- Descriptive summary of plasma concentrations and PK parameters of revumenib and the primary metabolites.","definition_or_measurement_approach":"Descriptive pharmacokinetic analysis of plasma concentrations and PK parameters for revumenib and primary metabolites."}
• {"endpoint_text":"- Descriptive summary of revumenib pharmacodynamics in relation to safety, efficacy and correlative biomarkers, which may include immunophenotyping of circulating peripheral blood mononuclear cells (PBMC) and/or bone marrow, gene expression, mutational analysis, and minimal residual disease (MRD).","definition_or_measurement_approach":"Descriptive pharmacodynamic analyses correlating revumenib exposure with safety, efficacy and biomarker readouts (immunophenotyping, gene expression, mutation analysis, MRD)."}
• {"endpoint_text":"- Frequency and severity of AE according to CTCAE version 5.0.","definition_or_measurement_approach":"Adverse events graded per CTCAE v5.0; frequency and severity summarized."}
• {"endpoint_text":"- Time to hematopoietic recovery (absolute neutrophil counts ≥0.5 and ≥1.0 x 109/L; platelets ≥50 and ≥100 x 109/L) after each treatment cycle (but at least for each of the first 6 cycles), defined as the time from the start of the cycle until recovery.","definition_or_measurement_approach":"Time from start of cycle to hematopoietic recovery thresholds (ANC and platelets) after each cycle; assessed for at least first 6 cycles."}
• {"endpoint_text":"- Number of patients requiring transfusions (platelet and RBC) and number of units transfused, rate and duration of transfusion independence, length of hospital stay, where transfusion independence is defined as a period of at least 56 days with no transfusion between the first dose of study drug and the last dose of study drug + 30 days.","definition_or_measurement_approach":"Counts and rates of transfusion use and independence (≥56 days without transfusion between first dose and last dose +30 days), number of units transfused, and hospital stay duration."}
• {"endpoint_text":"- Rates of CRMRD-, CR/CRhMRD-, and CR/CRiMRD- assessed by quantitative PCR of peripheral blood in adult patients with newly diagnosed NPM1-mutated AML ineligible for intensive chemotherapy, defined as the proportion of NPM1-mutated AML patients with CRMRD-, CR/CRhMRD- and CR/CRiMRD- by PCR in peripheral blood, respectively, at any time-point during protocol therapy.","definition_or_measurement_approach":"Proportion of patients with MRD-negative responses by quantitative PCR of peripheral blood at any time-point during therapy."}

Primary sponsor

Full Name

Hemato-Oncologie voor Volwassenen Nederland (Hovon) Stichting

Organisation Type

Hospital/Clinic/Other health care facility

Country Of Registered Address

Netherlands

Contract research organisations

Name

PPD Global Limited

Responsibilities

Sponsor duties codes: 1,12,3,5 (responsibilities listed in CTIS third-party entry: operational / monitoring / data management / other CRO functions as per sponsor duties fields)

Third parties

• {"country":"Netherlands","full_name":"Erasmus Universitair Medisch Centrum Rotterdam (Erasmus MC)","duties_or_roles":"Biobanking; contact: hovon@erasmusmc.nl","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"France","full_name":"Centre Hospitalier Universitaire De Lille","duties_or_roles":"Sponsor duties code: 4","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"United Kingdom","full_name":"PPD Global Limited","duties_or_roles":"Sponsor duties codes: 1,12,3,5 (roles/responsibilities as listed in CTIS entry)","organisation_type":"Pharmaceutical company"}
• {"country":"Netherlands","full_name":"Amsterdam UMC Stichting","duties_or_roles":"Biobanking; sponsor duties code: 4","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"Netherlands","full_name":"Allucent (NL) B.V.","duties_or_roles":"SAE coding","organisation_type":"Pharmaceutical company"}
• {"country":"Germany","full_name":"Medizinische Hochschule Hannover","duties_or_roles":"Biobanking; sponsor duties code: 4","organisation_type":"Educational Institution"}
• {"country":"United States","full_name":"Pci San Diego Inc.","duties_or_roles":"Sponsor duties code: 14","organisation_type":"Pharmaceutical company"}
• {"country":"Germany","full_name":"Universitaetsklinikum Ulm AöR","duties_or_roles":"Biobanking; sponsor duties code: 4","organisation_type":"Hospital/Clinic/Other health care facility"}