Study of Monzosertib In Patients With R/R AML Or High-Risk Myelodysplastic Syndrome

Primary Objective:

To study the safety and tolerability of monzosertib in terms of treatment emergent adverse events (TEAE) and dose limiting toxicities (DLT).

To establish the RP2D of monzosertib based on the totality of the data.

Secondary Objectives:

• To estimate rate of CR/CRh by 4 cycles of treatment
• To estimate overall response rate (ORR) by 4 cycles of treatment. ORR will be defined as CR/CRh/CRi/MLFS/PR for AML and MDS/AML, and CR/CR equivalent/PR/CRL/CRh/HI for MDS or CMML
• To determine duration of response (DOR) of CR/CRh
• To determine overall survival (OS)

Exploratory Objective:

• To characterize the pharmacokinetics (PK) and drug-drug interactions with azole antifungals.
• To characterize pharmacodynamic (PD) biomarkers with monzosertib treatment
• To explore biomarkers of response and resistance

Inclusion criteria

• Patients need to be adults ≥18 years with R/R AML, 'MDS/AML', MDS, or CMML, per the ICC 2022 or the WHO 2022 with ≥5% blasts at screening. 6,7
• Relapsed or refractory disease is defined as: patient having received and have progressed or relapsed or intolerant to standard regimens, e.g., as listed in NCCN guidelines, or declined treatment with such therapies.

a. This may include at least one cycle of intensive chemotherapy for AML, or for AML/MDS/CMML at least 2 cycles of BCL2 inhibitor based lower intensity regimen or 4 cycles of HMA-based regimens without BCL2 inhibitor, or clear progression during such treatment.

• "Treated secondary AML" i.e., patients with antecedent hematological disorder, e.g., MDS, CMML, MPD/MPN, who progress to AML despite receiving treatment adequate for AML (per NCCN) for the antecedent hematological disorder, will be eligible due to recognized poor outcomes similar to R/R AML.

8,9

• Patients with actionable mutations with available FDA-approved therapies, e.g., FLT3, IDH1/2, menin inhibitors may be enrolled after they have exhausted or ineligible for appropriate lines of FDA approved treatment options.
• ECOG PS 0 to 2
• Adequate hepatic function (total bilirubin ≤ 1.5 x upper limit of normal (ULN) unless increase is due to Gilbert'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).
• Adequate renal function with creatinine clearance ≥ 30 mL/min calculated by the CockcroftGault formula or MDRD equation.
• Patients relapsing after allo-SCT may be eligible if they have recovered from all transplantrelated 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. 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.
• 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 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: 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.

• Ability to understand and the willingness to sign a written informed consent document.

Exclusion criteria

• Patient has a white blood cell count > 15 x 10⁹/L. Hydroxyurea, and/or cytarabine use as supportive care is permitted to meet this criterion.10
• Prior use of any cytotoxic chemotherapy, targeted therapy, immunotherapy, or investigational therapies within 2 weeks or 5 half-lives (whichever is shorter), 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 WBC count during this washout period.
• Patient has uncontrolled systemic fungal, bacterial, viral or other infection with ongoing signs/symptoms despite appropriate treatment.
• Decompensated congestive heart failure, clinically significant, uncontrolled arrhythmia prolonged QT interval corrected for heart rate (QTcF) to greater than 450 msec, or long QT syndrome, or history of Torsades de pointes. Patients with bundle branch block or pacemaker and prolonged QTc interval are permitted after appropriate correction, (e.g., Bogossian formula, or others) or after discussion with the PI and/or cardiologist. Acute respiratory failure, unstable or decompensated pulmonary disease
• Patients with any severe gastrointestinal or metabolic condition or gastric bypass, which could interfere with absorption of oral drug.
• Active hepatitis B (HBV) or Hepatitis C (HCV) infection with detectable viral DNA or RNA, respectively, or known HIV infection. Patients with history of hepatitis with undetectable viral load will be eligible.
• 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, inability, any impairment or unwillingness to comply with the treatments, follow-up, requirements and procedures of this clinical trial.
• 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.