Overview

To find a recommended dose of HC-7366 that can be given in combination with azacitidine and venetoclax to patients with AML. The safety and effects of this drug combination will also be studied.

Eligibility

Inclusion Criteria:

1. Participants need to have a confirmed diagnosis of AML, or MDS/AML with 10% to 19% blasts, per the International Consensus Classification 2022 or the WHO 2022 classification.

   Dose escalation phase

2. Participants ≥18 years with R/R AML or R/R MDS/AML, other than acute promyelocytic leukemia (APL), with no available standard treatment options.
3. Relapsed or refractory disease defined by standard criteria as follows:
   1. Relapsed: Bone marrow blasts ≥5%, reappearance of blasts in the blood, or development of extramedullary disease following achievement of CR/CRi/MLFS b. 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% c. Appropriate prior therapy in order for patient to be deemed relapsed or refractory include any of the following: i. At least 1 cycle of purine analogue containing intensive induction chemotherapy regimen, e.g., FLAG-Ida, CLIA or CLAG-M or similar regimens with or without venetoclax.

             ii. At least 1 cycle of intensive induction chemotherapy with venetoclax, e.g., 7 + 3
             or CPX-251 with venetoclax or similar regimens iii. At least 2 cycles of intensive
             induction chemotherapy such as 7 + 3 or 5 + 2 or similar regimens without venetoclax
             iv. 2 cycles of venetoclax with HMA/LDAC +/- other agents v. 4 cycles of HMA alone d.
             Younger/fit patients in first relapse following intensive chemotherapy, will only be
             eligible if the first remission (CR1) duration was ≤12 months.
             e. Participants relapsing with persistent or new TP53 mutation will be eligible
             irrespective of CR1 duration.
             f. Older/unfit patients who relapse on HMA + venetoclax based maintenance regimen will
             be eligible irrespective of CR1 duration
          4. ECOG PS 0 to 2
          5. Participants relapsing after 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 GVHD. Physiologic ("replacement") dose of steroids (≤10 mg prednisone
             or equivalent) may be acceptable. Participants 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.
          6. Participants with actionable mutations with available FDA-approved therapies, e.g.,
             FLT3, IDH1/2 inhibitors may be enrolled after they have exhausted appropriate lines of
             FDA approved treatment options.
          7. Participants 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 phase.
             This is due to recognized poor outcomes in such patients with "treated secondary AML".
             All Participants
          8. Adequate hepatic function (total bilirubin ≤1.5 x upper limit of normal (ULN) unless
             increase is due to Gilberts's disease or leukemic involvement, and AST and/or ALT ≤
             2.5 x ULN unless considered due to leukemic involvement, in which case total bilirubin
             or AST and/or ALT ≤ 3 x ULN will be considered eligible).
          9. Adequate renal function with creatinine clearance ≥ 45 mL/min calculated by the
             Cockcroft-Gault formula or MDRD equation or measured by 24-hour urine collection.
         10. 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.
             a. This includes all female participants 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: i. Postmenopausal (no menses in greater than
             or equal to 12 consecutive months).
             ii. History of hysterectomy or bilateral salpingo-oophorectomy. iii. Ovarian failure
             (follicle-stimulating hormone and estradiol in menopausal range, who have received
             whole pelvic radiation therapy).
             iv. History of bilateral tubal ligation or another surgical sterilization procedure.
             b. 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.
             c. 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.
         11. Ability to understand and the willingness to sign a written informed consent document.
             Exclusion Criteria:
         12. Participants with t(15;17) karyotypic abnormality.
         13. Participant has a white blood cell count > 15 x 10 9/L. Hydroxyurea, and/or cytarabine
             (up to 2 g/m2 total) used as supportive care is permitted to meet this criterion.
         14. 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. Participants should have recovered from all prior therapy related
             toxicities. Participants may receive hydroxyurea or cytarabine for control of WBC
             count during this washout period.
         15. Participants with known symptomatic or uncontrolled CNS leukemia.
         16. Participant has systemic fungal, bacterial, viral or other infection that is
             exhibiting ongoing signs/symptoms related to the infection without improvement despite
             appropriate treatment.
         17. Participants with any severe gastrointestinal or metabolic condition which could
             interfere with the absorption of oral study medications as determined by the
             investigator.
         18. Active and uncontrolled comorbidities including decompensated congestive heart failure
             NYHA class III/IV, clinically significant, uncontrolled arrhythmia, acute respiratory
             failure, unstable or decompensated pulmonary disease, as judged by the treating
             physician.
         19. Known active hepatitis B (HBV) or Hepatitis C (HCV) infection with detectable viral
             DNA or RNA, respectively, or known HIV infection.
         20. 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.
         21. Any other medical, psychological, or social condition that may interfere with study
             participation or compliance, or compromise participant safety in the opinion of the
             investigator.
         22. Any previous malignancy, except when the participant has completed definitive
             curative-intent treatment with chemotherapy and/or surgery and/or radiotherapy at
             least 1 month prior to enrollment. Participants 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.
         23. Major surgery within 4 weeks prior to screening or a major wound that has not fully
             healed.
         24. Participants under legal protection measure (guardianship, trusteeship or safeguard of
             justice) and/or uncontrolled psychiatric comorbidities, ongoing illicit substance
             abuse, inability, any impairment or unwillingness to comply with the treatments,
             follow-up, requirements and procedures of this clinical trial.
         25. A known hypersensitivity or severe allergy to study drug components or diluents
         26. Nursing women, women of childbearing potential (WOCBP) with positive urine or serum
             pregnancy test, or WOCBP who are not willing to maintain adequate contraception.
         27. 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.
         28. The study will exclude first-degree relatives of the investigator, study staff or
             industry sponsor.