A Phase II, Open-Label Randomized Study of Intravenous Tambiciclib in Combination with the Standard of care Venetoclax and Azacitidine in Patients with Newly Diagnosed AML Who Failed to Achieve at Least MLFS After the First Two Cycles of Treatment with Venetoclax and Azacitidine Alone

Prior treatment

• Major surgery within 4 weeks prior to study entry.
• History of previous exposure to any other CDK9 inhibitors.
• Radiotherapy with wide field radiation within 28 days or radiotherapy with a limited field of radiation for palliation within 7 days of the first dose.
• Symptomatic central nervous system (CNS) involvement. Patients with asymptomatic CNS involvement who are radiologically and neurologically stable ≥ 4 weeks following CNS-directed therapy and are on a stable or decreasing dose of corticosteroids are eligible for study entry.
• Receiving any investigational agents in another clinical trial within 30 days prior to study screening.
• Ongoing therapy with corticosteroids greater than 25 mg of prednisone or its equivalent per day. Inhaled and topical steroids are allowed.
• Concurrent malignancy within 2 years prior to entry other than adequately treated cervical carcinoma-in-situ, localized squamous cell cancer of the skin, basal cell carcinoma, prostate cancer not requiring treatment, ductal carcinoma in situ of the breast, and superficial non-muscle invasive urothelial carcinoma (excluding T1 lesions and CIS).
• Known active hepatitis B or hepatitis C virus infection. Patients with chronic HBV infection with active disease who meet the criteria for anti HBV therapy have to be on a suppressive antiviral therapy prior to enrollment. Patients with HCV may be enrolled if the HCV is stable, and the patient is not at risk for hepatic decompensation.

Other illness

• Systemic therapy for AML (excluding ATRA if used for suspected APL, or hydroxyurea or cytarabine if used emergently for emergent cytoreduction or disease stabilization (a maximum total cumulative dose of cytarabine 1 g) and Ven+Aza), within 30 days.
• Any other uncontrolled intercurrent illness or condition that in the judgement of the investigator may endanger the patient
• Severe stroke or intracranial hemorrhage within 6 months.
• Known hypersensitivity to the study drug or excipients of the preparation or any agent given in association with this study.
• Uncontrolled hypertension with clinically meaningful episodes such as a history of recurrent hypertensive crisis, or a history of hypertensive encephalopathy.
• Severe cardiovascular disease within 6 months of study entry, including any of the following: a. Clinically significant heart disease such as congestive heart failure requiring treatment (NYHA class III or IV), or clinically significant arrhythmia. Subjects with pacemakers are eligible if they have no history of fainting or clinically relevant arrhythmias while using the pacemaker. b. Evidence of acute coronary syndromes (including myocardial infarction, and/or unstable angina). c. Average QTcF ≥ 480 msec on screening ECG. QTcF may be not considered if <500 msec in presence of complete or incomplete branch block or for subjects with pacemakers. Patients with a history of clinically significant venous or arterial thrombotic events that the investigator feels puts the patient at risk for participation in the study (based on overall status, medical history, or other factors) will be excluded.

Lab values

• Patients with known HIV infection except if: - They have CD4+ T-cell (CD4+) counts ≥ 350 cells/uL, and - No history of AIDS-defining opportunistic infections within the last 12 months preceding screening, and - Are on established ART for at least four weeks and have an HIV viral load less than 400 copies/mL prior to enrollment.
• Concomitant medications that are strong CYP3A4 inhibitors or strong inducers within 7 days prior to the first dose. Avoid consumption of Seville orange (and juice), grapefruit or grapefruit juice, grapefruit hybrids, pomelos, star citrus fruits or St. John’s wort within 7 days of first dose. Given that tambiciclib (SLS009) is a CYP3A4 substrate and the critical role of azole antifungals (commonly strong CYP3A4 inhibitors) in the treatment of patients with AML, if use of azole antifungals is necessary, and if azoles cannot be substituted with alternative antifungal drugs (e.g., caspofungin, amphotericin B etc.), use of isavuconazole, the only azole antifungal that is a moderate CYP3A4 inhibitors and does not prolong QT interval, is recommended. Other azoles are allowed if deemed necessary by the investigator. If azoles are used, patients receiving azole antifungals will adjust venetoclax dosing accordingly and receive enhanced monitoring
• Medications that are known to prolong the QT interval that could not be stopped prior to study entry judged by investigator, except azole antifungal medications.

Other

• Pregnant or breast-feeding females.

• Male or female ≥ 18 years
• Female patients of childbearing potential (WOBC) must accept and be compliant with a highly effective contraceptive method (APPENDIX F) during treatment and up to 6 months after last administration of study drug. Since no sufficient data are available on the interaction between tambiciclib and hormonal contraceptives, if hormonal contraceptive methods are used, also a barrier method (condom) is required.
• For woman of childbearing potential (WOCBP), a negative serum pregnancy test must be confirmed prior to first dose.
• Male patients whose partner is a pregnant woman or a WOBC must use a condom during treatment and up to 3 months after last administration of study drug.
• WOBC and male patients whose partner is a pregnant woman or a WOBC must be informed and must accept and be compliant with no gamete donation (sperm/egg) during treatment and through the full contraception follow up period.
• Participant is willing and able to give informed consent for participation in the study.
• Patients must have histologically or cytologically confirmed acute myeloid leukemia according to WHO2022 or ICC2022 definition. Patients must have ≥20 % blasts in the bone marrow and/or blood at diagnosis (excepting AML with defining genetic abnormalities according to WHO 2022).
• Patients should have received exactly 2 courses of the SOC venetoclax + azacitidine before study entry.
• Patients must have an insufficient response from standard of care treatment, defined as not having achieved at least morphological leukemia free state after course 2 of venetoclax + azacitidine (standard of care).
• Patients must have measurable disease, defined as at least 5% of bone marrow blast at the time of enrollment; extramedullary-only disease is excluded. Patients must have measurable disease, defined as at least 5% of bone marrow blast at the time of enrollment; extramedullary-only disease is excluded.
• ECOG performance status <2
• Patients must have normal organ function (- Total bilirubin ≤ 1.5 × upper limit of normal (ULN) except for patients with Gilbert’s syndrome, who are included if total bilirubin is < 3 × ULN or if direct bilirubin is < 1.5 × ULN. - Aspartate aminotransferase (AST), alanine aminotransferase (ALT) ≤ 2.5 × ULN. For those with known or suspected disease liver infiltration, AST and ALT ≤ 5 × ULN. - Measured or calculated (determined by the Cockcroft-Gault equation) serum creatinine clearance (CrCl) ≥ 50 mL/min (glomerular filtration rate can be alternative to CrCl) Whether the value is calculated by equation or measured directly can be based on institutional standard practice.)
• Peripheral WBC counts < 25,000/µL. Cytoreduction prior to study will be allowed with hydroxyurea; hydroxyurea use will also be permitted during treatment period in patients with proliferative, progressive disease. Use of leukapheresis for the purpose of lowering WBC counts to make the patient eligible for enrolment is not permitted.
• Recovery to grade ≤1 from adverse events related to the ongoing Ven+Aza SOC therapy occurring during the first two cycles of SOC except alopecia, fatigue, endocrinopathies and lab abnormalities controlled with medical therapy, and/or hematological toxicity.