A Phase 1B/2A Trial of Combination of ASTX727 With ASTX029 in 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.
• •2. Patient must be receiving protocol therapy as salvage 1 or 2.
• •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.
• •2. Patient must be receiving protocol therapy as salvage 1 or 2.
• •3. 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 brochures, 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 c: (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/m2 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 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 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 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
• •Serum biochemical values with the following limits:
• •1. 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) eGFR or measured by 24 hours' urine collection. For patients with BMI \>23, Adjusted body weight and not Ideal Body Weight is the recommended parameter29, 30.
• •2. Total bilirubin \<1.5 x ULN unless considered due to Gilbert's syndrome
• •3. 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 109/L. Hydroxyurea may be used to reduce the WBC count to ≤ 15x109/L.
• •Ability to understand and provide signed informed consent.
• •Females must be surgically or biologically sterile or postmenopausal (amenorrheic 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.