IRB Study Number 25-491
Status Recruiting
Phase Phase 3
Locations Cleveland Clinic Main Campus, Cleveland Clinic Weston Hospital
Institute Taussig Cancer Institute
Description
Primary Objectives
To compare the efficacy of bleximenib and VEN+AZA vs VEN+AZA alone
Secondary Objectives
To further compare the efficacy of bleximenib and VEN+AZA vs VEN+AZA alone
To assess the safety profile
To assess symptoms, functioning, and HRQoL of bleximenib and VEN+AZA vs VEN+AZA alone
To characterize the PK of bleximenib
Exploratory Objectives
To characterize the PK of venetoclax using population approach when given with bleximenib.
Exposure-response relationship of bleximenib for safety, efficacy, and pharmacodynamic changes in bone
marrow or peripheral blood may be evaluated.
To assess the change in EQ-5D-5L health utility and VAS. To explore descriptive summaries of the
FACT-Leu symptom subscale items.
Inclusion Criteria
Be ≥18 years of age (or the legal age of majority in the jurisdiction in which the study is taking place, whichever is greater) at the time of informed consent.
Criterion modified as per Amendment 3
2.1 Criterion modified as per Amendment 3/USA-1
2.2 Previously untreated KMT2Aror NPM1mAML with ≥10% blasts per 2022 ICC criteria (Arber 2022; Appendix 7) based upon local testing.
Participants with KMT2A partial tandem duplications or amplifications are NOT eligible.
Participants with co-mutations (eg, IDH1 co-mutations) must receive approved SoC therapies unless they are ineligible for or have refused them.
Emergency leukapheresis or cytoreductive therapy with hydroxyurea and/or 1 dose of up to 2 g/m2 cytarabine is permitted prior to first dose of study treatment. Note: these treatments should not be given until after the screening bone marrow assessment. Leukapheresis and cytarabine must be discontinued 1 dayprior to first dose of study
treatment.
- Ineligible for intensive chemotherapy based on the following criteria:
≥75 years of age and ineligible per physician’s discretion, with ECOG performance status of0-2
≥18 to <75 years of age with ≥1 of the following comorbidities:
ECOG performance status of 2
Severe cardiac disorder (eg, congestive heart failure requiring treatment or chronic stable angina)
Severe pulmonary disorder (eg, DLCO ≤ 65% or FEV1 ≤65%)
Renal impairment defined as eGFR (MDRD formula) ≥30 mL/min to <60mL/min (KDIGO 2024)
Comorbidity that, in the investigator’s opinion, makes the participant unsuitable for intensive chemotherapy, which must be documented and approved by the sponsor before enrollment.
- Adequate renal and hepatic functions prior to randomization:
AST and ALT <3 × ULN; for participants with leukemic organ involvement (documented by biopsy or imaging) AST and ALT <5 × ULN is permitted.
Total bilirubin ≤1.5 × ULN, unless bilirubin rise is due to congenital nonhemolytic hyperbilirubinemia such as Gilbert’s syndrome or of non-hepatic origin.
eGFR (MDRD formula) ≥30 mL/min.
WBC count <25 x109/L.
While on study treatment and for at least 6 months after the last dose of study treatment, a participant must:
Not breastfeed or be pregnant.
Not donate gametes (ie, eggs or sperm) or freeze for future use for the purposes of assisted reproduction.
Wear an external condom.
If of childbearing potential, have a negative highly sensitive (eg, β-hCG) pregnancy test at screening and within 48 hours of the first dose of study treatment, and agree to further pregnancy tests, practice at least 1 highly effective method of contraception; if oral contraceptives are used, a barrier method of contraception must also be used.
Ifa participant’s partner is of childbearing potential, the partner must practice a highly effective method of contraception unless the participant is vasectomized for at least 6 months after the last dose of study treatment.
See Appendix 4 for details.
- Must sign an ICF indicating that the participant understands the purpose of, and procedures required for, the study and is willing to participate in the study.
Exclusion Criteria
Diagnosis of APL
Known active leukemic involvement of the CNS
History of myelofibrosis
Recipient of solid organ transplant
Criterion modified as per Amendment 3/USA-1
5.1 Cardiac disease:
a. Any of the following within 6 months of randomization: myocardial infarction, uncontrolled/unstable angina, congestive heart failure (NYHA Class III or IV), uncontrolled or symptomatic arrhythmias, stroke, or transient ischemic attack.
b. QTcF ≥470 msec. Participants with a family history of Long QT syndrome are excluded. For participants with documented wide QRS interval (eg, due to a bundle branch block), alternate methods of calculating a corrected QT interval may be appropriate for eligibility determination if recommended by a consulting cardiologist and approved by the sponsor, provided there is no evidence or history of a repolarization abnormality.
- Criterion modified as per Amendment 3/USA-1
6.1 Chronic respiratory disease requiring supplemental oxygen.
Active infection that is uncontrolled prior to first dose of study treatment and may interfere with the study objectives or expose the patient to undue risk by participating in the trial; an infection controlled with systemic therapy is allowed.
Any condition for which, in the opinion of the investigator, participation would not be in the best interest of the participant (eg, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments
Concurrent enrollment in another anticancer therapeutic investigational clinical study.
Criterion modified as per Amendment 3/USA-1
10.1 Any prior hypomethylating agent or any chemotherapeutic agent for MDS. Prior treatment with non-disease modifying agents (eg, luspatercept or imetelstat) for MDS is allowed if administered more than 5 half-lives prior to the first dose of study treatment.
Received strong CYP3A inducers or inhibitors within 14 days or 5 half-lives prior to first dose, whichever is longer.
Live, attenuated vaccine within 4 weeks of randomization. Non-live or non-replicating vaccines and those authorized for emergency use (eg, COVID-19) are allowed.
Criterion modified as per Amendment 2
13.1 Known to be positive or tests positive at screening for HIV. HIV positive participants with undetectable viral load, CD4 count >200 cell/mm3, and on stable highly active antiretroviral therapy that are not strong CYP3A4 inhibitors, which are contraindicated, are permitted.
- Active hepatitis of infectious origin.
a. Seropositive for hepatitis B: defined by a positive test for HBsAg. Participants with resolved infection (ie, participants with a history of HBV infections or who are HBsAg negative with positive antibodies to total hepatitis B core antigen [anti-HBc] must be screened using RT-PCR measurement of HBV DNA levels. Those who are RT-PCR positive will be excluded. Participants with serologic findings suggestive of HBV vaccination (anti-HBs positivity as the only serologic marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV DNA by RT-PCR. See Appendix 10.
b. Known hepatitis C infection or positive serologic testing for hepatitis C virus (anti-HCV) antibody. Participants with positive hepatitis C antibody due to prior resolved disease can be enrolled only if a confirmatory negative hepatitis C RNA test is obtained at screening or within 3 months prior to first dose of study treatment.
c. Other clinically active liver disease of infectious origin.
- Any active malignancy other than AML. The only allowed exceptions are:
a. Any malignancy that was not progressing nor requiring treatment change in the last 24 months (and not considered at high risk of recurrence requiring systemic therapy).
b. Malignancies treated within the last 12 months and considered at very low risk for recurrence:
i. Non-muscle invasive bladder cancer (solitary Ta-PUNLMP or low grade, <3 cm, no CIS).
ii. Non-melanoma skin cancers treated with curative therapy or localized melanoma treated with curative surgical resection alone
iii. Non-invasive cervical cancer.
iv. Breast cancer: adequately treated lobular carcinoma in situ or ductal carcinoma in situ, localized breast cancer and receiving antihormonal agents.
v. Localized prostate cancer (M0, N0) with a Gleason Score ≤7a, treated locally only (radical prostatectomy/radiotherapy/focal treatment).
Inability or difficulty swallowing capsules/tablets, malabsorption syndrome, or any disease or medical condition significantly affecting gastrointestinal function.
Known allergies, hypersensitivity, or intolerance of bleximenib excipients (refer to the IB).
Had major surgery or had significant traumatic injury within 2 weeks of randomization/enrollment.
NOTE: Investigators must ensure that all study enrollment criteria have been met at screening. If a participant's clinical status changes (including any available laboratory results or receipt of additional medical records) after screening but before the first dose of study treatment is given such that the participant no longer meets all eligibility criteria, then the participant must be excluded from participation in the study. Section 5.4, describes options for retesting.
