Phase I Study of Q702 With Azacitidine and Venetoclax for Relapsed or Refractory Acute Myeloid Leukemia

Inclusion Criteria:

1. Patients 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 2022classification.23,24

2. Patients .18 years with R/R AML or R/R MDS/AML, other than acute promyelocyticleukemia (APL), with no available standard treatment options.

3. Relapsed or refractory disease defined by standard criteria as follows: a. Relapsed: Bone marrow blasts .5%, reappearance of blasts in the blood, ordevelopment of extramedullary disease following achievement of CR/CRi/MLFS b.Refractory: Failure to achieve CR/CRi/MLFS following initial treatment, withevidence 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 orrefractory include any of the following: i. At least 1 cycle of purine analoguecontaining intensive induction chemotherapy regimen, e.g., FLAG-Ida, CLIA or CLAG-Mor similar regimens with or without venetoclax.25,26 ii. At least 1 cycle ofintensive induction chemotherapy with venetoclax, e.g., 7 + 3 or CPX-351 withvenetoclax or similar regimens iii. At least 2 cycles of intensive inductionchemotherapy such as 7 + 3 or 5 + 2 or similar regimens without venetoclax iv. 2cycles of BCL2 inhibitor with HMA/LDAC +/- other agents v. 4 cycles of HMA-basedregimen without BCL2 inhibitor

• Younger/fit patients (<60 years) in first relapse following intensivechemotherapy, will only be eligible if the first remission (CR1) duration was .12 months. d. Patients relapsing with persistent or new TP53 mutation will be eligibleirrespective of CR1 duration. e. Older/unfit patients who relapse on HMA +venetoclax based maintenance regimen will be eligible irrespective of CR1 duration.

4. ECOG PS 0 to 1

5. Patients relapsing after allo-SCT may be eligible if they have recovered from alltransplant related toxicities and are off all immunosuppression, with no more thangrade 1 chronic GVHD. Physiologic ( greplacement h) dose of steroids (.10 mgprednisone or equivalent) may be acceptable. Patients must be off allimmunosuppression, including calcineurin inhibitors, for at least 2 weeks or 5half-lives, whichever is longer, prior to enrollment on study.

6. Patients with actionable mutations with available FDA-approved therapies, e.g.,FLT3, IDH1/2 inhibitors may be enrolled after they have exhausted appropriate linesof FDA approved treatment options.

7. Patients with antecedent hematological disorder (AHD), e.g., aplastic anemia,myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML) ormyeloproliferative disorder or neoplasm (MPD or MPN) who have previously received aregimen appropriate for AML for the antecedent hematological disorder, as describedabove, and have progressed to AML, will be eligible for the dose escalation andsalvage dose expansion cohorts. This is due to recognized poor outcomes in suchpatients with "treated secondary AML".27,28

8. Adequate hepatic function (total bilirubin . 1.5 x upper limit of normal (ULN), andAST and/or ALT . 2 x ULN). Patients with Gilbert disease will be eligible with totalbilirubin . 4.5 mg/dL.

9. Adequate renal function with creatinine clearance . 60 mL/min calculated by theCockcroft- 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 thisreason, 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, forthe duration of study participation, and for at least 90 days after last treatment. a. This includes all female patients between the onset of menses (as early as 8years of age) and 55 years unless the patient presents with an applicableexclusionary factor which may be one of the following: i. Postmenopausal (no mensesin 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 receivedwhole 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 postvasectomy, implantable or injectable contraceptives, and condoms plus spermicide.Not engaging in sexual activity for the total duration of the trial and the drugwashout period is an acceptable practice; however, periodic abstinence, the rhythmmethod, 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 partneris participating in this study, she should inform her treating physicianimmediately. c. Men treated or enrolled on this protocol must also agree to use adequatecontraception prior to the study, for the duration of study participation, and 4months after completion of treatment.

11. Ability to understand and the willingness to sign a written informed consentdocument.

Exclusion Criteria:

1. Patients with t(15;17) karyotypic abnormality.

2. Patient has a white blood cell count > 15 x 10./L. Hydroxyurea, and/or cytarabine (up to 2 g/m2 total) used as supportive care is permitted to meet this criterionprior to enrollment.

3. Prior use of any cytotoxic chemotherapy, targeted therapy, radiation therapy,immunotherapy, or other clinical trial therapies within 2 weeks or 5 half-lives,whichever is shorter, prior to first dose of study treatment. Patients should haverecovered from all prior therapy related toxicities. Patients may receivehydroxyurea or cytarabine for control of WBC count during this washout period.

4. Patients with known symptomatic or uncontrolled CNS leukemia.

5. Patient has systemic fungal, bacterial, viral or other infection that is exhibitingongoing signs/symptoms related to the infection without improvement despiteappropriate treatment.

6. 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:

7. Mild blurry vision, either age-related or due to ocular or systemic disorder (e.g., diabetes, dry eyes, cataracts, uncorrected refraction abnormality) maybe allowed at the discretion of an ophthalmologist if deemed as notconstituting evidence of preexisting retinopathy or a condition with thepotential to cause a predisposition to druginduced retinopathy.

8. Patients with only one assessable eye and no evidence of pre-existingretinopathy may be allowed at the discretion of the principal investigator.

9. Any known and active neurological disorder with residual neurological deficit orrequiring pharmacotherapy.

10. Patients with known acute or chronic liver disease, cirrhosis, hepatic steatosiswith elevated liver function tests or elevated LFTs of unknown etiology.

11. Active and uncontrolled comorbidities including decompensated congestive heartfailure NYHA class III/IV, clinically significant, uncontrolled arrhythmia, acuterespiratory failure, unstable or decompensated pulmonary disease, as judged by thetreating physician.

12. Decompensated congestive heart failure, hypokalemia, prolonged QT interval correctedfor heart rate (QTc) to greater than 470 msec or long QT syndrome, or history ofTorsades de pointes. Appropriate corrections may be applied for patients with bundlebranch block.

13. Patients with any severe gastrointestinal or metabolic condition which couldinterfere with the absorption of oral study medications as determined by theinvestigator.

14. Known active hepatitis B (HBV) or Hepatitis C (HCV) infection with detectable viralDNA or RNA, respectively, or known HIV or HTLV-1 infection.

15. Any other medical, psychological, or social condition that may interfere with studyparticipation or compliance, or compromise patient safety in the opinion of theinvestigator.

16. Any previous malignancy, except when the patient has completed definitivecurative-intent treatment with chemotherapy and/or surgery and/or radiotherapy atleast 1 month prior to enrollment. Patients having completed definitive treatmentfor the following conditions may be eligible immediately after completion ofdefinitive curative-intent therapy, after healing of wounds, and no evidence ofresidual disease by examination or imaging or cytology/pathology, e.g., non-melanomaskin cancers, or any carcinoma in-situ, e.g., ductal carcinoma in situ, urothelialcancer, cervical cancer, localized prostate cancer, pre-cancerous colon polyp, etc.

17. Major surgery within 4 weeks prior to screening or a major wound that has not fullyhealed.

18. Patients under legal protection measure (guardianship, trusteeship or safeguard ofjustice) and/or uncontrolled psychiatric comorbidities, ongoing illicit substanceabuse, any impairment or unwillingness to comply with the treatments, follow-up,requirements and procedures of this clinical trial.

19. A known hypersensitivity or severe allergy to study drug components or diluents

20. Nursing women, women of childbearing potential (WOCBP) with positive urine or serumpregnancy test, or WOCBP who are not willing to maintain adequate contraception.

21. Pregnant women are excluded from this study because study agents may have thepotential for teratogenic or abortifacient effects. Because there is an unknown butpotential risk for adverse events (Aes) in nursing infants secondary to treatment ofthe mother with study agents, breastfeeding should be discontinued if the mother istreated on this study.