Navitoclax, Venetoclax, and Decitabine for the Treatment of High-Risk Myeloid Malignancies

Inclusion Criteria

• 18 years or older
• Subjects must have a diagnosis of one of the following: * Myelofibrosis in accelerated phase (AP-MF), defined by World Health Organization (WHO) as 10-19% blasts in either bone marrow or blood. There is no requirement for prior therapy. * Myelofibrosis in blast phase (BP-MF), defined as >= 20% blasts in either bone marrow or blood. MF-advanced disease with evidence of leukemic transformation (i.e. myeloid sarcoma/extramedullary) is also allowed. There is no requirement for prior therapy. * Untreated acute myeloid leukemia (AML) must be ineligible or not recommended for any available approved therapy as determined by the treating provider plus must have at least one of the following: ** Any prior anti-neoplastic cytotoxic therapy or radiation for an unrelated malignancy (i.e. therapy-related disease) ** Known antecedent myelodysplastic syndrome (MDS) or MDS/myeloproliferative neoplasm (MPN), overlap syndrome who has received at least one dose or cycle of HMA therapy for MDS or MDS/MPN overlap syndrome indication ** Essential thrombocythemia (ET) or polycythemia vera (PV), PV (may have or may have not received therapy for ET or PV indication) (i.e. secondary AML arising out of ET or PV) ** Acute erythroid leukemia as defined by erythroid predominance, typically ≥ 80% of the bone marrow elements, of which ≥ 30% are proerythroblasts or pronormoblasts * Any MDS/MPN overlap syndromes (e.g. not exclusive to the following examples chronic myelomonocytic leukemia [CMML], atypical chronic myeloid leukemia [CML], MDS/MPN-unclassifiable) with minimum >= 5% blasts in either bone marrow or blood. No requirements for prior therapy * MDS with excess blasts defined as >= 5% blasts in either bone marrow or blood must be ineligible for any available approved therapy including intensive chemotherapy and immediate allogeneic stem cell transplant per treating investigator and must meet at least one of the following criteria: 1) persistent disease despite prior exposure to venetoclax plus HMA for at least 3 cycles, 2) disease progression per International Working Group (IWG) 2006 criteria on venetoclax plus HMA or on M15-954 protocol, or 3) persistent disease after at least four cycles of any HMA-based therapy
• Eastern Cooperative Oncology Group (ECOG) performance status =< 2
• Baseline platelet count >= 25 x 10^9/L, with the exception (as of amendment version [v] 2.0) of AP/BP-MF patients who must have a baseline platelet count ≥ 75 x 10^9/L if entering study on concurrent ruxolitinib. Baseline platelet level must not be supported by platelet transfusions (<7 days) or TPO-mimetic.
• Aspartate transaminase (AST) and alanine transaminase (ALT) < 3 x upper limit of normal (ULN)
• Total bilirubin =< 1.5 x ULN (unless bilirubin rise is due to Gilbert’s syndrome or of non-hepatic origin)
• Subject must have adequate renal function as demonstrated by a creatinine clearance >= 45 mL/min; calculated by the Cockcroft Gault formula
• Activated partial thromboplastin time (aPTT) =< 1.5 x ULN
• International normalized ratio (INR) =< 1.5 x ULN
• Prior treatment-related toxicities must be grade 1 or baseline except for alopecia
• Moderate/strong inhibitors of CYP3A are allowed if they cannot be substituted; however, patients must be on these agents for at least 2-3 days prior to treatment start
• If female, subject must be either : * Postmenopausal (surgically sterile or age > 55 years with no menses for 12 or more months without an alternative medical cause or age greater than or equal to 55 or less with no menses for 12 or more months without an alternative medical cause and an follicle stimulating hormone (FSH) level > 40 IU/L); or * Of children bearing potential. These subjects must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Subject must agree to have a negative urine or serum beta-human chorionic gonadotropin (HCG) test result during screening and repeated within 7 days prior to study drug (local labs are allowed) to be eligible
• Subject must voluntarily sign and date an informed consent
• Subjects must be able to swallow pills

Exclusion Criteria

• Subject cannot have had prior navitoclax or any BCL-XL therapy. Otherwise, there are no restrictions on any other prior therapies. Prior venetoclax is allowed
• Subject is eligible and willing to receive intensive chemotherapy for their specific disease if it is recommended by the treating provider.
• Systemic anti-leukemic therapy within 14 days of first day of study treatment. If on venetoclax, then a wash-out period of at least five times the half-life of the treatment. Exceptions: No wash-out required for intrathecal chemotherapy, hydroxyurea, or palliative radiation therapy to painful sites of leukemic disease. JAK inhibitors other than ruxolitinib can be used up until the day before study start (a taper strategy may be considered by treating investigator prior to study start), but must be discontinued by study start. Ruxolitinib may continue while on study in patients that have received this for > 4 weeks prior to first dose on study
• Subject with known and active concurrent malignancy requiring treatment. Subjects with basal or squamous skin cancers or carcinomas in situ are allowed. Exception: hormonal or topical therapies are allowed
• Subject has known active/uncontrolled human immunodeficiency virus (HIV) and on contraindicated medication due to drug-drug CYP inducer interaction. HIV testing is not required
• Subject has known and active central nervous system (CNS) involvement with AML
• Evidence of other clinically significant uncontrolled condition(s) including, but not limited to: * Uncontrolled and/or active systemic infection (viral, bacterial or fungal). Controlled infections are allowed. * Chronic, active hepatitis B virus (HBV) or hepatitis C (HCV) requiring treatment. Note: subjects with serologic evidence of prior vaccination to HBV (i.e. hepatitis B surface [HBs] antigen negative, anti-HBs antibody positive and anti-hepatitis B core [HBc] antibody negative) or positive anti-HBc antibody from intravenous immunoglobulins (IVIG) may participate. Subjects that have prior HCV that has been definitively treated with negative HCV viral load prior to study initiation and no evidence of cirrhosis are allowed to participate. Hepatitis serologies are recommended, but not required at baseline unless otherwise clinically indicated
• Recent diagnosis of myocardial infarction or worsening heart failure (symptomatic) within the last six months
• Treatment with any moderate or strong CYP3A inducers within 7 days prior to the first dose of study drug
• Administration or consumption of any of the following within 3 days prior to the first dose of study drug: * Grapefruit or grapefruit products * Seville oranges (including marmalade containing Seville oranges) * Star fruit
• White blood cell count (WBC) greater than or equal to 25 x 10^9/L. Exception: Subjects with myelofibrosis or MDS/MPN overlap syndrome may enter study with WBC greater than or equal 25 x 10^9/L on the first day of therapy only if the absolute blast count is < 5 x 10^9/L; hospitalization for these subjects with WBC > 25 is required during dose ramp-up of venetoclax for tumor lysis syndrome (TLS) monitoring. This criterion is intended to exclude AML patients at high risk of TLS, but permit entry of patients with myelofibrosis (MF) or CMML or MDS/MPN who frequently have leukocytosis without AML transformation who are at lower risk for TLS
• Ongoing requirement for anticoagulation with the exception of low-dose anticoagulation medications used to maintain patency of a central venous catheter or for deep venous thrombosis prophylaxis. Antiplatelet agents such as aspirin and clopidogrel are not recommended if platelet count < 50 x 10^9/L
• Known history of immune thrombocytopenia that previously required therapy
• Known history of platelet refractoriness and human leukocyte antigen (HLA) alloimmunization prior to study start
• Known history of serious or life-threatening bleeding in last 12 months that has not been definitively treated
• Uncontrolled, systemic infection (viral, bacterial, or fungal). Antibiotic use for controlled conditions or prophylaxis is permitted
• Active and known severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection * Subjects positive for active SARS-CoV-2 infection may re-screen after resolution of fever without use of antipyretics and improvement in symptoms
• Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that in the opinion of the investigator may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and/or would make the subject inappropriate for enrollment into this study
• Vaccination with live, attenuated vaccines =< 4 weeks prior to initiation of study treatment or anticipation of need for such a vaccine during the study. All other recommended vaccinations including coronavirus disease 2019 (COVID19) is permitted