Phase 3 Study of Tamibarotene Plus Azacitidine in Patients Selected for RARA-positive Higher-risk MDS (SELECT-MDS-1)

Prior treatment

• Patients have not adequately recovered from a major surgery within 4 weeks of starting study drug administration.
• Patients with a diagnosis of hypervitaminosis A or patients taking vitamin A supplements >10,000 IU/day, unless treatment is discontinued at least 7 days prior to the first dose of the study drug.
• Patients received strong inducers of CYP3A4 within 2 weeks prior to the first tamibarotene/placebo administration.
• Patients received any other investigational agents within 4 weeks of the Screening Visit, or <5 half-lives since completion of previous investigational therapy have elapsed, whichever is shorter.
• Patients require concurrent treatment with any investigational or approved oncology agent, other than the agents described in exclusion criterion #3.
• Patients received prior treatment for MDS with any hypomethylating agent, chemotherapy (including lenalidomide), or allogeneic HSCT, with the exception of prior treatment with growth factors or hydroxyurea. Growth factor treatment must be discontinued at least 2 weeks prior to starting study drug. Hydroxyurea treatment must be discontinued prior to starting study drug.
• Patients for whom treatment with tamibarotene or azacitidine is contraindicated.
• Patients with clinically significant cardiovascular disease, including unstable angina, acute myocardial infarction within 3 months prior to the start of study drug administration, or New York Heart Association Class III or IV congestive heart failure, cerebral vascular accident within 3 months prior to the start of study drug administration, or cardiac arrhythmia associated with hemodynamic instability.
• Patients have a known active or chronic hepatitis B or active HCV infection. Patients with a history of HCV infection who have completed curative therapy for HCV at least 12 weeks before the Screening Visit and have a documented undetectable viral load at the Screening Visit are eligible for enrollment.
• Patients received prior treatment with ATRA or systemic retinoid for a hematologic malignancy.

Other illness

• Patients who have a hypersensitivity to tamibarotene, azacitidine, or to any of their excipients
• Patients with history of cancer are excluded if they are in active treatment (with radiation, chemotherapy, antibodies, immunotherapies, or molecularly targeted therapies) or unless they are disease free for at least 2 years prior to the Screening Visit, following completion of a prior treatment. Exceptions include: localized prostate cancer treated with hormone monotherapy; localized breast cancer treated with adjuvant hormone monotherapy; or localized basal cell carcinoma, non-melanoma skin cancer, or cervical carcinoma in situ.
• Patients have an active, life-threatening, or clinically-significant, uncontrolled systemic infection requiring hospitalization.
• Patients have a known malabsorption syndrome or other condition that may impair absorption of study medication (e.g., gastrectomy).

Lab values

• Patients known to be refractory to platelet or packed red blood cell transfusions per Institutional Guidelines, or patients who refuse blood product support.
• Patients with Grade > or = 2 hypertriglyceridemia, defined as >300 mg/dL (CTCAE, version 5)
• QTc >450 msec for male patients, QTc >470 msec for female patients, or QTc >480 msec in male or female patients with bundle branch block based on triplicate electrocardiogram (ECG) readings at the Screening Visit. NOTE: The QTc in this study should be the QT interval corrected for heart rate according to Fridericia formula (QTcF).
• Immunocompromised patients with increased risk of opportunistic infections, including known HIV-positive patients with CD4 counts < or =350 cells/mm3 or history of opportunistic infection in the last 12 months. Note: To ensure that effective ART, when used in eligible HIV-positive patients, is tolerated and that toxicities are not confused with investigational drug toxicities, patients should be on an established ART for at least 4 weeks and have an HIV viral load less than 400 copies/mL prior to the Screening Visit.
• Patients have other severe acute or chronic medical conditions (and/or psychiatric conditions or laboratory abnormalities) that may increase the expected risk to the patient (i.e., the risk associated with the study participation or investigational product administration), or that may interfere with the interpretation of study results or, in the judgment of the investigator, would make the patient inappropriate for entry into this study.

Other

• Patients are suitable for and agree to undergo allogeneic HSCT at the time of screening.
• Patients with > or = 20% blasts in peripheral blood or bone marrow or evidence of myeloid sarcoma (extramedullary AML).
• Pregnant females, breastfeeding females, and males not willing to comply with contraceptive requirements or females of childbearing potential not willing to comply with contraceptive requirements.

• Patients must be at least 18 years old at the time of signing of an informed consent
• Patients must be RARA-positive based on the investigational assay
• Patients must be newly diagnosed with HR-MDS as follows: Diagnosis of MDS according to the WHO classification (Arber 2016) and classified by the IPSS-R risk category as: a. Very High (risk score >6), b. High (risk score >4.5 to 6), OR c. Intermediate (risk score >3 to 4.5).
• Patients must have measurable disease with bone marrow blasts >5% at the Screening Visit.
• Patients must have ECOG Performance Status of ≤2.
• Patients must have adequate organ function, as defined by: a. total bilirubin ≤3.0 × the ULN b. ALT and AST ≤3 × ULN, and c. creatinine clearance ≥30 mL/min based on the Cockcroft-Gault Glomerular Filtration Rate estimation.
• Patients must have a serum/high-sensitivity urine pregnancy test (for females of childbearing potential) that is negative at the Screening Visit and immediately prior to initiation of treatment (first dose of study drug).
• Patients must be willing and able to comply with the scheduled study visits, treatment plans, laboratory tests, use of 2 methods of birth control (including a barrier method) for WOCBP and male patients (as described in Appendix 4), and other procedures.
• Patients must be capable of giving signed and dated IRB or IEC approved informed consent document.