ASTX029 and ASTX727 for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia

Inclusion Criteria

• PHASE 1B: Diagnosis of relapsed/refractory AML (excluding acute promyelocytic leukemia)
• PHASE 2A: Diagnosis of relapsed/refractory AML (excluding acute promyelocytic leukemia) with MAPK pathway mutations e.g. N or KRAS, PTPN11, NF1 etc.
• Patients aged >= 18 years old with relapsed/refractory AML are eligible if they are not eligible for potentially curative therapy such as more effective salvage therapy or hematopoietic stem cell transplantation or who refuse these options at the time of enrollment.
• Patient must be receiving protocol therapy as salvage 1 or 2.
• Patients aged >= 18 years old, with MDS or CMML treated with hypomethylating agent (HMA) therapies who progress to AML and have no available therapies or are not candidates for available therapies, will be eligible at the time of progression to AML.
• Eastern Cooperative Oncology Group (ECOG) Performance Status =< 2.
• Temporary prior measures such as apheresis while eligibility work-up is being performed are allowed and not counted as a prior salvage.
• In the absence of rapidly progressing disease, the interval from prior treatment to time of initiation of protocol therapy will be at least 2 weeks or at least 5 half-lives (whichever is longer). The half-life for the therapy in question will be based on published pharmacokinetic literature (abstracts, manuscripts, investigator’s brochure or drug-administration manuals) and will be documented in the protocol eligibility document.
• The toxicity from prior therapy should have resolved to grade =< 1, however alopecia and sensory neuropathy grade =< 2 not constituting a safety risk based on investigators judgement is acceptable.
• The use of chemotherapeutic or anti-leukemic agents is not permitted during the study with the following exceptions: (1) intrathecal (IT) therapy for patients with controlled CNS leukemia at the discretion of the PI. (2) Use of 1-2 doses of cytarabine (up to 1.5 g/m^2 each dose) for patients with rapidly proliferative disease is allowed up to 7 days before the start of study therapy (7 days washout). Since the anti-leukemia effect of hypomethylating agents (HMA)-therapies and kinase inhibitors may be delayed, use of hydroxyurea for patients with rapidly proliferative disease is allowed on study and before the start of study therapy and will not require a washout. These medications will be recorded in the case-report form. (Rationale: Patients with kinase mutations can have very proliferative disease and the combination can induce differentiation in patients as part of response).
• Concurrent therapy for central nervous system (CNS) prophylaxis or continuation of therapy for controlled CNS disease is permitted. Patients with a known history of CNS disease must have been treated with CNS directed therapy, have at least 2 consecutive lumbar punctures (LPs) with no evidence of CNS leukemia, and must be clinically stable for at least 4 weeks prior to enrollment and have no ongoing neurological symptoms that in the opinion of the treating physician are related to the CNS disease.
• Patients must have adequate renal function as demonstrated by a creatinine clearance (CrCl) >= 50 mL/min calculated by either the Cockcroft-Gault formula, Modification of Diet in Renal Disease (MDRD) estimated glomerular filtration rate (eGFR) or measured by 24 hours' urine collection. For patients with body mass index (BMI) >23, adjusted body weight and not ideal body weight is the recommended parameter.
• Total bilirubin < 1.5 x upper limit normal (ULN) unless considered due to Gilbert’s syndrome
• Aspartate aminotransferase or alanine aminotransferase =< 2.0 x ULN (aspartate aminotransferase or alanine aminotransferase =< 3.0 x ULN if deemed related to leukemia by the treating physician)
• White blood cell count < 15 x 10^9/L. Hydroxyurea may be used to reduce the white blood count (WBC) count to =< 15x10^9/L.
• Ability to understand and provide signed informed consent.
• Females must be surgically or biologically sterile or postmenopausal (amenorrhoeic for at least 12 months) or if of childbearing potential, must have a negative serum or urine pregnancy test within 72 hours before the start of the treatment.
• Women of childbearing potential must agree to use an adequate method of contraception during the study and until 4 months after the last treatment. Males must be surgically or biologically sterile or agree to use an adequate method of contraception during the study until 3 months after the last treatment.
• Adequate methods of contraception include: * Total abstinence when this is in line with the preferred and usual lifestyle of the patient. 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), hysterectomy with or without oophorectomy or tubal ligation at least six 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). For female patients on the study, the vasectomized male partner should be the sole partner for that patient. * Combination of any of the two following (a+b or a+c or b+c) ** Use of oral, injected or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception. ** Placement of an intrauterine device (IUD) or intrauterine system (IUS). ** Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal suppository In case of use of oral contraception, women should have been stable on the same pill before taking study treatment. *Note: Oral contraceptives are allowed but should be used in conjunction with a barrier method of contraception due to unknown effect of drug-drug interaction. * Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six 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. * Male patients who are sexually active with a woman of childbearing potential (WOCBP) and who have not had vasectomies must be willing to use a barrier method of contraception during the study and for 3 months after the last dose of ASTX727, ASTX029 whichever ends later. * Women who are pregnant or breastfeeding will not be eligible.

Exclusion Criteria

• Patients with known allergy or hypersensitivity to ASTX727, ASTX029 or any of their components.
• Patients with any other known concurrent severe and/or uncontrolled medical condition including but not limited to diabetes, cardiovascular disease including hypertension, renal disease, or active uncontrolled infection, which could compromise participation in the study.
• Patients on active antineoplastic or radiation therapy for a concurrent malignancy at the time of screening. Maintenance therapy, hormonal therapy, or steroid therapy for well-controlled malignancy is allowed.
• Prior organ transplantation including allogenic stem-cell transplantation within 3 months prior to planned enrollment, active graft versus host disease (GVHD) > grade 1, or requiring transplant-related immunosuppression with the exception of low dose cyclosporine and tacrolimus.
• Prior treatment with an ERK inhibitor.
• History or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR) including: * Presence of predisposing factors to RVO or CSR (eg, uncontrolled glaucoma or ocular hypertension, uncontrolled diabetes mellitus) or * Visible retinal pathology as assessed by ophthalmic examination at screening that is considered a risk factor for RVO or CSR such as: ** Evidence of optic disc cupping or ** Evidence of new visual field defects on automated perimetry or ** Intraocular pressure > 21mmHg as measured by tonography.
• Patients with symptomatic CNS leukemia or patients with poorly controlled CNS leukemia.
• Patients with a known human immunodeficiency virus (HIV) infection that is not well controlled (i.e. any detectable circulating viral load) at the time of enrollment.
• Patients with known positive hepatitis B or C infection by serology, with the exception of those with an undetectable viral load within 3 months (Hepatitis B or C testing is not required prior to study entry). Subjects with serologic evidence of prior vaccination to hepatitis B virus (HBV) (i.e., hepatitis B surface antigen negative [HBs Ag-], and anti-hepatitis B surface antigen positive [HBs+]) may participate.
• Patients who have consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or Starfruit within 3 days prior to the initiation of study treatment.
• Patients who have had any major surgical procedure within 14 days of day 1.
• Other severe acute or chronic medical conditions that is active and not well controlled including colitis, inflammatory bowel disease, or psychiatric conditions including recent (within the past year) or active suicidal ideation or behavior; or laboratory abnormalities that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.
• Active and uncontrolled disease (active infection requiring systemic therapy or fever likely secondary to infection within prior 48 hours): prophylactic antibiotics or prolonged course of intravenous (IV) antibiotics for controlled infection are allowed, uncontrolled hypertension despite adequate medical therapy, active and uncontrolled congestive heart failure New York Heart Association (NYHA) class III/IV, clinically significant and uncontrolled arrhythmia) as judged by the treating physician.
• Patients unwilling or unable to comply with the protocol.
• Screening 12-lead electrocardiogram (ECG) showing a baseline average QT interval as corrected by Fridericia’s formula (QTcF) > 470 msec. Subjects with left or right bundle branch block, where QT cannot be accurately assessed, will be allowed into the study after assessment by institutional cardiologist.