A Study of Bleximenib in Combination With Acute Myeloid Leukemia (AML) Directed Therapies
- Conditions
- Leukemia, Myeloid, Acute
- Interventions
- Registration Number
- NCT05453903
- Lead Sponsor
- Janssen Research & Development, LLC
- Brief Summary
The purpose of this study is to determine the recommended Phase 2 dose (RP2D) candidate(s) of bleximenib in combination with AML directed therapies (dose selection) and further to evaluate safety and tolerability of bleximenib in combination with AML directed therapies at the RP2D(s) (dose expansion).
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 200
- Adolescent participants (defined as greater than or equal to [>=] 12 and less than [<] 18 years of age) are only eligible for the relapsed/refractory (R/R) cohort (Arm A, cohort A4)
- Diagnosis of AML according to World Health Organization (WHO) criteria: a) De novo or secondary AML; b) relapsed/refractory (Arm A only); c) harboring KMT2A, NPM1, NUP98, or NUP214 alterations; d) Participants may receive emergency leukapheresis and/or cytarabine as cytoreductive therapy according to local practice guidelines
- Pretreatment clinical laboratory values meeting the following criteria -listed below: White blood cell (WBC) count: less than or equal to (<=) 25*10^9 per liter (/L), adequate liver and renal function
- Eastern Cooperative Oncology Group (ECOG) performance status grade of 0, 1 or 2. Adolescent participants only: Performance status >70 by Lansky scale (for participants <16 years of age) or >70 Karnofsky scale (for participants >16 years of age)
- A female of childbearing potential must have a negative highly sensitive serum beta-human chorionic gonadotropin at screening and within 48 hours prior to the first dose of study treatment
- Must sign an informed consent form (ICF) indicating participant (or their legally authorized representative) understands the purpose of the study and procedures required for the study and is willing to participate in the study
- Willing and able to adhere to the prohibitions and restrictions specified in this protocol
- Acute promyelocytic leukemia, diagnosis of Down syndrome associated leukemia or juvenile myelomonocytic leukemia according to WHO 2016 criteria
- Leukemic involvement of the central nervous system
- Recipient of solid organ transplant
- Cardiovascular disease that is uncontrolled, increases risk for Torsades de Pointes or that was diagnosed within 6 months prior to the first dose of study treatment including, but not limited to: (a) Myocardial infarction; (b) Severe or unstable angina; (c) Clinically significant cardiac arrhythmias, including bradycardia (<50 beats per minute); (d) Uncontrolled (persistent) hypertension: (example, blood pressure greater than [>] 140/90 millimeters of mercury [mm Hg]; (e) Acute neurologic events such as stroke or transient ischemic attack, intracranial or subarachnoid hemorrhage, intracranial trauma; (f) Venous thromboembolic events (example, pulmonary embolism) within 1 month prior to the first dose of study treatment ;(g) Congestive heart failure (NYHA class III to IV); (h) Pericarditis or clinically significant pericardial effusion; (i) Myocarditis; (j) Endocarditis (k) Clinically significant hypokalemia, hypomagnesemia, hypocalcemia (corrected for hypoalbuminemia)
- Any toxicity (except for alopecia, stable peripheral neuropathy, thrombocytopenia, neutropenia, anemia) from previous anticancer therapy that has not resolved to baseline or to grade 1 or less
- Pulmonary compromise that requires the need for supplemental oxygen use to maintain adequate oxygenation
- Participants with diagnosis of Fanconi anemia, Kostmann syndrome, Shwachman diamond syndrome, or any other known bone marrow failure syndrome
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Arm A: Relapsed/Refractory Setting Venetoclax (VEN) Participants with relapsed/refractory AML harboring NPM1, KMT2A, NUP98, or NUP214 alterations will receive bleximenib in combination with either venetoclax (VEN) (Cohort A1: bleximenib+VEN) or azacitidine (AZA) (Cohort A2: bleximenib +AZA) or VEN+AZA (Cohort A3: bleximenib+VEN+AZA) or VEN + AZA (Cohort A4: bleximenib + VEN + AZA) in adolescent participants aged greater than or equal to (\>=) 12 years and less than (\<) 18 years of age, to select the recommended phase 2 dose (RP2D) of bleximenib in combination with VEN, AZA or VEN+AZA (dose selection). In dose expansion portion of the study, participants will receive bleximenib in combination with AML directed therapies at the RP2D(s). Arm A: Relapsed/Refractory Setting Azacitidine (AZA) Participants with relapsed/refractory AML harboring NPM1, KMT2A, NUP98, or NUP214 alterations will receive bleximenib in combination with either venetoclax (VEN) (Cohort A1: bleximenib+VEN) or azacitidine (AZA) (Cohort A2: bleximenib +AZA) or VEN+AZA (Cohort A3: bleximenib+VEN+AZA) or VEN + AZA (Cohort A4: bleximenib + VEN + AZA) in adolescent participants aged greater than or equal to (\>=) 12 years and less than (\<) 18 years of age, to select the recommended phase 2 dose (RP2D) of bleximenib in combination with VEN, AZA or VEN+AZA (dose selection). In dose expansion portion of the study, participants will receive bleximenib in combination with AML directed therapies at the RP2D(s). Arm B: Newly Diagnosed Chemotherapy Ineligible Setting Venetoclax (VEN) Participants will receive bleximenib in combination with VEN+AZA as frontline chemo therapy for newly diagnosed AML participants harboring KMT2A, NPM1, NUP98, or NUP214 alterations who are \>=75 years of age or \>=18 years of age to \<75 years of age with comorbidities that preclude the use of intensive induction chemotherapy. Arm B: Newly Diagnosed Chemotherapy Ineligible Setting Azacitidine (AZA) Participants will receive bleximenib in combination with VEN+AZA as frontline chemo therapy for newly diagnosed AML participants harboring KMT2A, NPM1, NUP98, or NUP214 alterations who are \>=75 years of age or \>=18 years of age to \<75 years of age with comorbidities that preclude the use of intensive induction chemotherapy. Arm C: Newly Diagnosed Chemotherapy Eligible Setting Cytarabine Participants will receive combination of bleximenib with cytarabine+daunorubicin or idarubicin chemotherapy as frontline treatment regimen for participants \>= 18 to \<75 years of age with AML harboring NPM1, KMT2A, NUP98, or NUP214 alterations and eligible for intensive chemotherapy. Arm C: Newly Diagnosed Chemotherapy Eligible Setting Daunorubicin or Idarubicin Participants will receive combination of bleximenib with cytarabine+daunorubicin or idarubicin chemotherapy as frontline treatment regimen for participants \>= 18 to \<75 years of age with AML harboring NPM1, KMT2A, NUP98, or NUP214 alterations and eligible for intensive chemotherapy. Arm A: Relapsed/Refractory Setting Bleximenib Participants with relapsed/refractory AML harboring NPM1, KMT2A, NUP98, or NUP214 alterations will receive bleximenib in combination with either venetoclax (VEN) (Cohort A1: bleximenib+VEN) or azacitidine (AZA) (Cohort A2: bleximenib +AZA) or VEN+AZA (Cohort A3: bleximenib+VEN+AZA) or VEN + AZA (Cohort A4: bleximenib + VEN + AZA) in adolescent participants aged greater than or equal to (\>=) 12 years and less than (\<) 18 years of age, to select the recommended phase 2 dose (RP2D) of bleximenib in combination with VEN, AZA or VEN+AZA (dose selection). In dose expansion portion of the study, participants will receive bleximenib in combination with AML directed therapies at the RP2D(s). Arm B: Newly Diagnosed Chemotherapy Ineligible Setting Bleximenib Participants will receive bleximenib in combination with VEN+AZA as frontline chemo therapy for newly diagnosed AML participants harboring KMT2A, NPM1, NUP98, or NUP214 alterations who are \>=75 years of age or \>=18 years of age to \<75 years of age with comorbidities that preclude the use of intensive induction chemotherapy. Arm C: Newly Diagnosed Chemotherapy Eligible Setting Bleximenib Participants will receive combination of bleximenib with cytarabine+daunorubicin or idarubicin chemotherapy as frontline treatment regimen for participants \>= 18 to \<75 years of age with AML harboring NPM1, KMT2A, NUP98, or NUP214 alterations and eligible for intensive chemotherapy.
- Primary Outcome Measures
Name Time Method Number of Participants with Adverse Events (AEs) by Severity Up to 3 Years 3 months Number of Participants with AEs by severity will be reported. Severity will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. Severity scale ranges from Grade 1 (Mild) to Grade 5 (Death). Grade 1= Mild, Grade 2= Moderate, Grade 3= Severe, Grade 4= Life-threatening and Grade 5= Death related to adverse event.
Number of Participants with Adverse Events (AEs) Up to 3 Years 3 months An AE is any untoward medical occurrence in a participant participating in a clinical study that does not necessarily have a causal relationship with the pharmaceutical/biological agent under study.
Number of Participants with Dose-limiting Toxicity (DLT) End of Cycle 1 (28 days) Number of participants with DLT will be reported according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0.
- Secondary Outcome Measures
Name Time Method Plasma Concentration of Bleximenib Up to 3 Years 3 months Plasma samples will be analyzed to determine concentrations of bleximenib using a validated, specific, and sensitive method.
Percentage of Participants who Achieve Complete Remission with Incomplete Hematologic Recovery (CRi) Up to 3 Years 3 months Percentage of participants who achieve complete remission with incomplete hematologic recovery (CRi) will be reported. CRi is defined as All CR criteria except for residual neutropenia (\<1.0\*10\^9/L \[1,000/mcL\]) or thrombocytopenia (\<100 \* 10\^9/L \[100,000/mcL\]).
Number of Participants with Depletion of Leukemic Blasts Up to 3 Years 3 months Number of participants with depletion of leukemic blasts will be reported.
Percentage of Participants who Achieve Complete Remission (CR) Up to 3 Years 3 months Percentage of participants who achieve complete Remission (CR) will be reported. CR is defined as Bone marrow blasts less than (\<) 5 percent (%); Absence of circulating blasts; Absence of extramedullary disease; Absolute neutrophil count (ANC) greater than or equal to (\>=) 1.0\*10\^9/Liter (L) (1,000/microliter \[mcL\]); Platelet count \>= 100 \* 10\^9/L (100,000/mcL).
Percentage of Participants who Achieve Complete Remission with Partial Hematologic Recovery (CRh) Up to 3 Years 3 months Percentage of participants who achieve complete remission with partial hematologic recovery (CRh) will be reported. CRh is defined as All criteria of CR with both ANC \>0.5 \* 10\^9/L (500/mcL) and platelet count \>50 \* 10\^9/L (50,000/mcL).
Percentage of Participants who Achieved Overall Response Up to 3 Years 3 months Percentage of participants who achieve overall response will be reported. Overall response rate (ORR) is defined as the percentage of participants achieving CR, CRh, or CRi, morphologic leukemia-free state (MLFS) or partial remission (PR).
Trial Locations
- Locations (32)
Hosp. de La Santa Creu I Sant Pau
🇪🇸Barcelona, Spain
Hosp Clinic de Barcelona
🇪🇸Barcelona, Spain
Hosp Univ Vall D Hebron
🇪🇸Barcelona, Spain
Hosp Univ Fund Jimenez Diaz
🇪🇸Madrid, Spain
Clinica Univ. de Navarra
🇪🇸Pamplona, Spain
University College London Hospitals NHSFT
🇬🇧London, United Kingdom
Christie Hospital NHS Trust
🇬🇧Manchester, United Kingdom
ASST Grande Ospedale Metropolitano Niguarda
🇮🇹Milano, Italy
Universitatsklinikum Carl Gustav Carus Dresden
🇩🇪Dresden, Germany
IRCCS Istituto Clinico Humanitas
🇮🇹Rozzano, Italy
The University of Alabama at Birmingham
🇺🇸Birmingham, Alabama, United States
City of Hope
🇺🇸Duarte, California, United States
Massachusetts General Hospital
🇺🇸Boston, Massachusetts, United States
Albert Einstein College Of Medicine
🇺🇸New York, New York, United States
Novant Health
🇺🇸Charlotte, North Carolina, United States
Novant Health Forsyth Medical Center
🇺🇸Winston-Salem, North Carolina, United States
MD Anderson
🇺🇸Houston, Texas, United States
Monash Medical Centre
🇦🇺Clayton, Australia
Peter MacCallum Cancer Centre
🇦🇺Melbourne, Australia
Westmead Hospital
🇦🇺Westmead, Australia
Princess Margaret Cancer Centre University Health Network
🇨🇦Toronto, Ontario, Canada
Institut Paoli Calmettes
🇫🇷Marseille Cedex 9, France
Chu Rennes Hopital Pontchaillou
🇫🇷Rennes Cedex 9, France
Institut Universitaire du Cancer Toulouse Oncopole
🇫🇷Toulouse Cedex 9, France
CHU de Tours - Hôpital de Bretonneau
🇫🇷Tours, France
Charite Universitaetsmedizin Berlin
🇩🇪Berlin, Germany
Universitaetsklinikum Heidelberg
🇩🇪Heidelberg, Germany
Universitaetsklinikum Leipzig
🇩🇪Leipzig, Germany
Universitatsklinikum Ulm
🇩🇪Ulm, Germany
Azienda Opedaliero-Universitaria Policlinico Sant'orsola Malpighi di Bologna
🇮🇹Bologna, Italy
Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori
🇮🇹Meldola, Italy
Oxford University Hospitals NHS Trust
🇬🇧Oxfordshire, United Kingdom