cAMeLot-2 - A Phase 3 Randomized, Double-Blind, Placebo-Controlled, Study of Bleximenib, Venetoclax and Azacitidine for the Treatment of Participants With Newly Diagnosed Acute Myeloid Leukemia Harboring KMT2A Rearrangements or NPM1 Mutations Who Are Ineligible for Intensive Chemotherapy (75276617AML3001)

Studio Clinico

Patologia: Neoplasie ematologiche

Osservazionale-Sperimentale: Sperimentale

Monocentrico-Multicentrico: Multicentrico

Randomizzato: Sì

Fase di studio: III

Linee di trattamento: Prima linea

Criteri di inclusione: 

Each potential participant must satisfy all of the following criteria to be enrolled in the study:

1. 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.
2. Criterion modified as per Amendment 3
2.1 Criterion modified as per Amendment 3/EEA-1
2.2 Criterion modified as per Amendment 3/EEA-2
2.3 Criterion modified as per Amendment 5/EEA-2
2.4 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.
- Emergency leukapheresis and/or cytoreductive therapy with hydroxyurea and/or up to a total of 2 g/m2 cytarabine (cytarabine may be administered over a maximum of 5 days, not to exceed 3 doses) is permitted prior to first dose of study treatment. Note:
cytoreductive therapywith cytarabine should not be given until after the screening bone marrow assessment. Leukapheresis and cytarabine must be discontinued 1 day prior to first dose of study treatment.
3. Criterion modified as per Amendment 3/EEA-1
3.1 Criterion modified as per Amendment 3/EEA-2
3.2 Criterion modified as per Amendment 5/EEA-2
3.3 Ineligible for intensive chemotherapy based on the following criteria:
    - ≥75 years of age and ineligible per physician’s discretion, with ECOG performance status of 0-2
    - ≥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 <60 mL/min (KDIGO 2024)
    - Moderate hepatic impairment with total bilirubin >1.5 to ≤3 × ULN
    - Comorbidity that, in the investigator’s opinion, makes the participant unsuitable for intensive chemotherapy, which must be documented before enrollment.
Ineligibility for intensive chemotherapy should be explicitly approved by a multidisciplinary team in countries in which this process is standard of care.
4. Criterion modified as per Amendment 5/EEA-2
4.1 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 ≤3 × ULN, unless of non-hepatic origin. If bilirubin rise is due to congenital nonhemolytic hyperbilirubinemia such as Gilbert’s syndrome, conjugated bilirubin needs to be within a clinically acceptable range with total bilirubin ≤3 × ULN.
- eGFR (MDRD formula) ≥30 mL/min.
5. WBC count <25 x109/L.
6. Criterion modified as per Amendment 5/EEA-2
6.1 Adhere to the following guidelines:
    - If of childbearing potential, while on study treatment and for at least 6 months after the
last dose of study treatment, a participant must:
        a) Not breastfeed or be pregnant.
        b) Not donate eggs or freeze for future use for the purposes of assisted reproduction.
        c) 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,
        d) Practice at least 1 highly effective method of contraception; if oral contraceptives are used, a barrier method of contraception must also be used.
   - If not of childbearing potential, while on study treatment and for at least 90 days after
the last dose of study treatment, a participant must:
       a) Not donate or freeze sperm for future use for the purposes of assisted reproduction.
       b) Wear an external condom.
   - If a 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 90 days after the last dose of study treatment.
See Appendix 4 for details.
7. 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.

Criteri di esclusione: 

Any potential participant who meets any of the following criteria will be excluded from participating in the study:
 Diagnosis of APL
2. Known active leukemic involvement of the CNS
3. History of myelofibrosis
4. Recipient of solid organ transplant
5. Criterion modified as per Amendment 5/EEA-2
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.
6. Criterion modified as per Amendment 5/EEA-2
6.1 Chronic respiratory disease requiring supplemental oxygen
7. 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.
8. Criteria modified as per Amendment 3/EEA-2
8.1 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. Participants must be able to travel easily to study sites or have access to alternative (local) hospitals/clinics that can provide appropriate care in case of emergency needs.
9. Criterion modified as per Amendment 3/EEA-1
9.1 Concurrent enrollment in another anticancer therapeutic investigational clinical study, and use of any other investigational medicinal product (IMP) within five times the half-life of the IMP/ relevant metabolites.
10. Criterion modified as per Amendment 5/EEA-2
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.
11. Received strong CYP3A inducers or inhibitors within 14 days or 5 half-lives prior to first dose, whichever is longer.
12. 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.
13. 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.
14. Criterion modified as per Amendment 5/EEA-2
14.1 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 28days prior to first dose of study treatment.
    c. Other clinically active liver disease of infectious origin.
15. Criterion modified as per Amendment 5/EEA-2
15.1 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 ≤7 (per ISUP Consensus Conference on Gleason grading of prostatic carcinoma [Epstein 2016]), treated locally only (radical prostatectomy/radiotherapy/focal treatment).
16. Inability or difficulty swallowing capsules/tablets, malabsorption syndrome, or any disease or medical condition significantly affecting gastrointestinal function.
17. Criterion modified as per Amendment 3/EEA-1
17.1 Criterion modified as per Amendment 5/EEA-2
17.2 Known allergies, hypersensitivity, or intolerance of bleximenib (refer to the IB), azacitidine, or venetoclax excipients (refer to the respective product label).
18. Had major surgery or had significant traumatic injury within 2 weeks of randomization/enrollment.
19. Participants with co-mutations (eg, IDH1) for which there are approved targeted therapies in the front-line setting, unless they do not have access to, or are ineligible for, the targeted therapy.

Trattamento sperimentale: 

I partecipanti effettueranno un incremento graduale di 3 giorni di venetoclax (100, 200 e 400 mg) a partire dal Giorno 1 del Ciclo 1 fino a una dose orale finale di 400 mg una volta al giorno durante il primo ciclo di trattamento di 28 giorni e, successivamente, nei cicli successivi. L’azacitidina 75 mg/m2 per via sottocutanea o endovenosa sarà somministrata dal Giorno 1 al Giorno 7 di ciascun ciclo di 28 giorni (è accettabile uno schema posologico alternativo). A partire dal Giorno 4 del Ciclo 1 (+3 giorni), i partecipanti riceveranno bleximenib o placebo (compressa da 50 o 100 mg) somministrato per via orale due volte al giorno (BID) durante il primo ciclo di 28 giorni e in seguito nei cicli successivi. Il trattamento continuerà fino a progressione della malattia o tossicità inaccettabile.

Trattamento di controllo: 

- 

Obiettivi primari dello studio: 

L’obiettivo primario è determinare se l’aggiunta di bleximenib a VEN+AZA migliori significativamente i duplici endpoint primari del tasso di CR o dell’OS rispetto a VEN+AZA nei partecipanti con LMA di nuova diagnosi con KMT2Ar o NPM1m non eleggibili alla chemioterapia intensiva. Saranno valutate la PK di bleximenib e la sicurezza complessiva.

Obiettivi secondari dello studio: 

Gli endpoint secondari includono EFS, durata della CR, tempo alla CR, tasso di CRMRD, indipendenza dalle trasfusioni, tasso di allo-HSCT e variazione rispetto al basale delle sottoscale EORTC QLQ-C30 e FACT-Leu.

Centri partecipanti

Nord Italia

Centro Italia

Sud Italia e isole

Informazioni Generali

Protocollo

Numero di iscrizione a registro: 2024-520154-38-00

Data di inserimento: 27.04.2026

Promotore

Janssen Research & Development, LLC

Principal Investigator ITALIA

Riferimento: Dr. - -

Telefono: 00000

Email: na@na.it

Localita: na