Clinical Trials

Inclusion Criteria:

• Signed informed consent must be obtained prior to participation in the study.
• Age ≥ 18 years at the date of signing the informed consent form (ICF).
• Newly diagnosed with AML based on 2016 WHO classification (Arber et al 2016) and not suitable for intensive chemotherapy defined as:
  • age ≥ 75;
  • ECOG performance Status 2 or 3, or any of the following comomorbitities: severe cardiac comorbities (including congestive heart failure, LVEF ≤ 50%, chronic stable Angina) , pulmonary comorbidity (DLCO ≤ 65% or FEVI ≤ 65%);
  • moderate hepatic impairment (with total Bilirubin >1.5 to 3x ULN);
  • renal impairment (eGFR ≥ 30 ml/min/1.73m^2 to 45 30 ml/min/1.73m^2); or
  • any other comorbidity (to be documented in the CRF) that the physician judges to be incompatible with intensive chemotherapy must be reviewed and approved by the Novartis Medical Monitor before study enrollment.
• Not planned for hematopoietic stem-cell transplantation (HSCT).
• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 , 2 or 3.
• AST and ALT ≤ 3 × upper limit of normal (ULN).
• Total bilirubin ≤ 3.0 × ULN (except in the setting of isolated Gilbert syndrome, in which case higher total bilirubin is allowed provided that conjugated bilirubin is ≤ 3.0 x ULN).
• Estimated Glomerular Filtration Rate (eGFR) ≥ 30 mL/min/1.73 m^2 (estimation based on Modification of Diet in Renal Disease (MDRD) formula, by local laboratory)
• Subject is able to communicate with the investigator, and has the ability to comply with the requirements of the study procedures.
• WBC < 25 x10^9 /L (may be reduced with leukopheresis or hyroxyurea).

Exclusion Criteria:

• Previous treatment at any time, with any of the following antineoplastic agents, approved or investigational; checkpoint inhibitors, venetoclax and hypomethylating agents (HMAs) such as decitabine or azacitidine. Previous treatment for AML, MDS, myelofibrosis, essential thrombocythemia, or polycythemia vera, with the exception of hydroxyurea, growth factors, and supportive care ruxolitinib.
• Prior exposure to TIM-3 directed therapy.
• Subjects with AML-M3 / APL (Acute promyelocytic leukemia) with PML-RARA and patients with AML secondary to Down's syndrome.
• Subjects with CNS leukemia or neurologic symptoms suggestive of CNS leukemia (unless CNS leukemia has been excluded by a lumbar puncture).
• Subjects with concurrent or prior malignancy, except:
  • subject with history of MDS, myelofibrosis, essential thrombocythemia, or polycythemia vera;
  • subject with history of adequately treated malignancy for which the subject has been disease free (absence of residual disease) for at least 1 year and if no anticancer systemic therapy (namely chemotherapy, radiotherapy or surgery) is ongoing or required during the course of the study. Patients who are receiving adjuvant therapy such as hormonotherapy are eligible.
• History of severe hypersensitivity reactions to any ingredient of study drug(s) (azacitidine, venetoclax or MGB453) or monoclonal antibodies (mAbs) and/or their excipients.
• Any concurrent severe and/or uncontrolled medical condition; e.g., active uncontrolled infection or severe infectious disease requiring parenteral antibacterial, antiviral or antifungal therapy (such as severe pneumonia, meningitis, or septicemia).
• Active autoimmune disease requiring systemic therapy (e.g., corticosteroids).
• Subject has consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or Starfruit within 3 days prior to the initiation of study treatment (C1D1).
• Current use, or use within 14 days prior to randomization of systemic, steroid therapy (> 10 mg/day prednisone or equivalent) or any immunosuppressive therapy.
• Live vaccine administered within 30 days prior to the first day of study treatment (C1D1).
• Cardiac or cardiac repolarization abnormality, including but not limited to any of the following:
  • History of myocardial infarction (MI), angina pectoris, or coronary artery bypass graft (CABG) within 6 months prior to starting study treatment;
  • QTcF > 470 ms at screening (based on mean of triplicate ECG), long QT syndrome or family history of unexplained cardiac death;
  • Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block, high-grade AV block (e.g., bifascicular block, Mobitz type II and third degree AV block);
• HIV infection not controlled by standard therapy and/or with known history of opportunistic infection. For countries where HIV status is mandatory: HIV status will be tested during screening using a local test.
• Active Hepatitis B (HBV) or Hepatitis C (HCV) infection. Subjects whose disease is controlled under antiviral therapy should not be excluded.
• Other co-morbidity that, in the opinion of the investigator, predisposes the subject to high risk of noncompliance with the protocol.
• Sexually active males unless they use a condom during intercourse while taking azacitidine and for 3 months after stopping this drug. They should not father a child in this period. A condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid. In addition, male participants must not donate sperm for the time period specified above.
• Subject is pregnant or breastfeeding.
• Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during study treatment and for 30 days after the last dose of venetoclax, 90 days after the last dose of azacitidine (or as per their respective local labels, whichever is longer) and 150 days after the last dose of MBG453. It is currently unknown whether venetoclax may reduce the effectiveness of hormonal contraceptives, and therefore women using hormonal contraceptives should add a barrier method. Highly effective contraception methods include:
  • Total abstinence (when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception;
  • Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy or bilateral tubal ligation at least 6 weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment;
  • Male sterilization (at least 6 months prior to screening/baseline). For female subjects on the study the vasectomized male partner should be the sole partner;
  • Use of oral (estrogen and progesterone), injected or implanted combined hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS) or other forms of hormonal contraception that have comparable efficacy (failure rate < 1%), for example hormone vaginal ring or transdermal hormone contraception.
• In case of use of oral contraception women should have been stable on the same pill for a minimum of 3 months before taking study treatment. Women are considered post-menopausal and not of child bearing potential if they have had over 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age appropriate [generally age from 40 to 59 years], history of vasomotor symptoms) in the absence of other medical justification or have had surgical bilateral oophorectomy (with or without hysterectomy) or bilateral tubal ligation at least 6 weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential. If local regulations deviate from the contraception methods listed above to prevent pregnancy, local regulations apply and will be described in the ICF.

Eligibility last updated 11/4/21. Questions regarding updates should be directed to the study team contact.