Q702 with Azacitidine and Venetoclax for Relapsed or Refractory Acute Myeloid Leukemia

Inclusion Criteria

• Patients need to have a confirmed diagnosis of AML, or myelodysplastic syndrome (MDS)/AML with 10% to 19% blasts, per the International Consensus Classification 2022 or the World Health Organization (WHO) 2022 classification
• Patients ≥ 18 years with relapsed/refractory (R/R) AML or R/R MDS/AML, other than acute promyelocytic leukemia (APL), with no available standard treatment options
• Relapsed or refractory disease defined by standard criteria as follows: * Relapsed: Bone marrow blasts ≥ 5%, reappearance of blasts in the blood, or development of extramedullary disease following achievement of CR/CRi/morphologic leukemia-free state (MLFS) * Refractory: Failure to achieve CR/CRi/MLFS following initial treatment, with evidence of persistent leukemia by blood and/or bone marrow evaluation with blasts ≥ 5% * Appropriate prior therapy in order for patient to be deemed relapsed or refractory include any of the following: ** At least 1 cycle of purine analogue containing intensive induction chemotherapy regimen, e.g., idarubicin, fludarabine, high-dose cytarabine and filgrastim (FLAG-Ida), cladribine, idarubicin, and cytarabine (CLIA) or cladribine, cytarabine, filgrastim, and mitoxantrone (CLAG-M) or similar regimens with or without venetoclax ** At least 1 cycle of intensive induction chemotherapy with venetoclax, e.g., 7 + 3 or liposome-encapsulated daunorubicin-cytarabine (CPX-351) with venetoclax or similar regimens ** At least 2 cycles of intensive induction chemotherapy such as 7 + 3 or 5 + 2 or similar regimens without venetoclax ** 2 cycles of venetoclax with hypomethylating agent (HMA)/low-dose cytarabine (LDAC) +/- other agents ** 4 cycles of HMA alone * Younger/fit patients (< 60 years) in first relapse following intensive chemotherapy, will only be eligible if the first remission (CR1) duration was ≤ 12 months * Patients relapsing with persistent or new TP53 mutation will be eligible irrespective of CR1 duration * Older/unfit patients who relapse on HMA + venetoclax based maintenance regimen will be eligible irrespective of CR1 duration
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 to 1
• Patients relapsing after allogeneic stem cell transplantation (allo-SCT) may be eligible if they have recovered from all transplant-related toxicities and are off all immunosuppression, with no more than grade 1 chronic graft versus host disease (GVHD). Physiologic ("replacement") dose of steroids (=< 10 mg prednisone or equivalent) may be acceptable. Patients must be off all immunosuppression, including calcineurin inhibitors, for at least 2 weeks or 5 half-lives, whichever is longer, prior to enrollment on study
• Patients with actionable mutations with available Food and Drug Administration (FDA)-approved therapies, e.g., FLT3, IDH1/2 inhibitors may be enrolled after they have exhausted appropriate lines of FDA approved treatment options
• Patients with antecedent hematological disorder (AHD), e.g., aplastic anemia, myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML) or myeloproliferative disorder or neoplasm (MPD or MPN) who have previously received a regimen appropriate for AML for the antecedent hematological disorder, as described above, and have progressed to AML, will be eligible for the dose escalation and salvage dose expansion cohorts. This is due to recognized poor outcomes in such patients with “treated secondary AML"
• Total bilirubin ≤ 1.5 x upper limit of normal (ULN) unless increase is due to Gilbert’s disease
• Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) ≤ 2 x ULN
• Creatinine clearance ≥ 45 mL/min calculated by the Cockcroft-Gault formula or Modification of Diet in Renal Disease (MDRD) equation or measured by 24-hour urine collection
• The effects of these agents on the developing human fetus are unknown. For this reason, and because other therapeutic agents used in this trial may be teratogenic, women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for at least 90 days after last treatment * This includes all female patients between the onset of menses (as early as 8 years of age) and 55 years unless the patient presents with an applicable exclusionary factor which may be one of the following: ** Postmenopausal (no menses in greater than or equal to 12 consecutive months) ** History of hysterectomy or bilateral salpingo-oophorectomy ** Ovarian failure (follicle-stimulating hormone and estradiol in menopausal range, who have received whole pelvic radiation therapy) ** History of bilateral tubal ligation or another surgical sterilization procedure * Approved methods of birth control are as follows: hormonal contraception (i.e., birth control pills, injection, implant, transdermal patch, vaginal ring), intrauterine device (IUD), tubal ligation or hysterectomy, subject/partner post vasectomy, implantable or injectable contraceptives, and condoms plus spermicide. Not engaging in sexual activity for the total duration of the trial and the drug washout period is an acceptable practice; however, periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of birth control. 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 * Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of treatment
• Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria

• Patients with t(15;17) karyotypic abnormality
• Patient has a white blood cell count > 15 x 10^9/L. Hydroxyurea, and/or cytarabine (up to 2 g/m^2 total) used as supportive care is permitted to meet this criterion prior to enrollment
• Prior use of any cytotoxic chemotherapy, targeted therapy, radiation therapy, immunotherapy, or other clinical trial therapies within 2 weeks, prior to first dose of study treatment. Patients should have recovered from all prior therapy related toxicities. Patients may receive hydroxyurea or cytarabine for control of white blood cell (WBC) count during this washout period
• Patients with known symptomatic or uncontrolled central nervous system (CNS) leukemia
• Patient has systemic fungal, bacterial, viral or other infection that is exhibiting ongoing signs/symptoms related to the infection without improvement despite appropriate treatment
• Active ophthalmological disorders, e.g., retinal pigment epithelium (RPE)/photoreceptor disorders such as retinitis pigmentosa, cone-rod dystrophies, Bests dystrophy, Stargardt disease (STGD), macular degeneration. Exceptions: * Mild blurry vision, either age-related or due to ocular or systemic disorder (e.g., diabetes, dry eyes, cataracts, uncorrected refraction abnormality) may be allowed at the discretion of an ophthalmologist if deemed as not constituting evidence of pre-existing retinopathy or a condition with the potential to cause a predisposition to drug-induced retinopathy * Patients with only one assessable eye and no evidence of pre-existing retinopathy may be allowed at the discretion of the principal investigator
• Patients with known acute or chronic liver disease, cirrhosis, hepatic steatosis with elevated liver function tests or elevated liver function tests (LFTs) of unknown etiology
• Active and uncontrolled comorbidities including decompensated congestive heart failure New York Heart Association (NYHA) class III/IV, clinically significant, uncontrolled arrhythmia, acute respiratory failure, unstable or decompensated pulmonary disease, as judged by the treating physician
• Decompensated congestive heart failure, hypokalemia, prolonged QT interval corrected for heart rate (QTc) (as calculated using Fridericia’s formula) to greater than 450 msec for males, or to greater than 470 msec for females or long QT syndrome, or history of Torsades de pointes
• Patients with any severe gastrointestinal or metabolic condition which could interfere with the absorption of oral study medications as determined by the investigator
• Known active hepatitis B (hepatitis B virus [HBV]) or hepatitis C (hepatitis C virus [HCV]) infection with detectable viral deoxyribonucleic acid (DNA) or ribonucleic acid (RNA), respectively, or known HIV or human T-lymphotropic virus-1 (HTLV-1) infection
• Any other medical, psychological, or social condition that may interfere with study participation or compliance, or compromise patient safety in the opinion of the investigator
• Any previous malignancy, except when the patient has completed definitive curative-intent treatment with chemotherapy and/or surgery and/or radiotherapy at least 1 month prior to enrollment. Patients having completed definitive treatment for the following conditions may be eligible immediately after completion of definitive curative-intent therapy, after healing of wounds, and no evidence of residual disease by examination or imaging or cytology/pathology, e.g., non-melanoma skin cancers, or any carcinoma in-situ, e.g., ductal carcinoma in situ, urothelial cancer, cervical cancer, localized prostate cancer, pre-cancerous colon polyp, etc
• Major surgery within 4 weeks prior to screening or a major wound that has not fully healed
• Patients under legal protection measure (guardianship, trusteeship or safeguard of justice) and/or uncontrolled psychiatric comorbidities, ongoing illicit substance abuse, any impairment or unwillingness to comply with the treatments, follow-up, requirements and procedures of this clinical trial
• A known hypersensitivity or severe allergy to study drug components or diluents
• Nursing women, women of childbearing potential (WOCBP) with positive urine or serum pregnancy test, or WOCBP who are not willing to maintain adequate contraception
• Pregnant women are excluded from this study because study agents may have the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events (AEs) in nursing infants secondary to treatment of the mother with study agents, breastfeeding should be discontinued if the mother is treated on this study