RVU120 for Treatment of Anemia in Patients With Lower-risk Myelodysplastic Neoplasms

Inclusion Criteria:

1. Written informed consent provided prior to any study-related procedure

2. Age ≥18 years

3. Diagnosis of de novo myelodysplastic neoplasms (MDS) according to World HealthOrganization (WHO) 2022 criteria. Diagnosis will be confirmed during screening assessment.

4. Very low, low or intermediate risk disease MDS with up to 3.5 points according toInternational Prognostic Scoring System Score Revised (IPSS-R) classification (to beconfirmed during screening assessment). Patients with del(5q) and max. one further abnormality (excluding monosomy 7,del(7q), TP53mut) are eligible.

5. Symptomatic anemia: Symptomatic anemia (all non transfusion dependent (NTD), lowtransfusion burden (LTB), or high transfusion burden (HTB)) has to be documented inthe 16 weeks baseline period ending on the day of inclusion. Patients should be registered only if it is expected at time of registration that

• a valid and complete Hb (at least five measurements in the period of 16 weeksbefore the first dose of IMP) and transfusion history will be available atinclusion AND

• the Hb Mean over the baseline period will be less than 10 g/dL OR three or morered blood cell (RBC)-transfusions will have been given during the baselineperiod documenting transfusion dependence.

6. No available option of an approved MDS therapy according to decision of the treatingphysician and based on the following: Patients must be

• ESA exposed (and refractory or intolerant) or ESA naïve and serumerythropoietin level >200 U/L AND/OR

• Luspatercept exposed (and refractory or intolerant) or luspatercept naïve andnot eligible for treatment (e.g. not approved) AND/OR

• Lenalidomide exposed (and refractory or intolerant) or lenalidomide naïve andnot eligible for treatment (e.g. due to non-presence of del(5q))

7. Eastern Cooperative Oncology Group (ECOG) performance score of 0-2

8. Patients must have been off anti-cancer treatment for 2 weeks or 5 half-lives,whichever is longer

9. Clinical laboratory parameters as follows:

• Peripheral white blood cell (WBC) count, no upper or lower limit at screening,but must be <10 x 109/L prior to first dose of study drug

• Platelets count >25,000/μL

• Serum albumin ≥ 30 g/L (3.0 g/dL)

• Normal coagulation (elevated International Normalized Ratio (INR), prothrombintime or activated partial thromboplastin time (APTT) <1.3 x ULN acceptable)

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3 x theupper limit of normal (ULN)

• Total bilirubin ≤1.5 x ULN

• Creatinine clearance ≥60 mL/min

• Urine protein < 2+ (as measured by dipstick) or ≤1000 mg/24 hours urine

10. Adequate cardiac function confirmed by left ventricular ejection fraction (LVEF) ≥40% as per echocardiography or MUGA (Multiple Gated Acquisition) scan

11. For females of childbearing potential (FCBP), a negative serum pregnancy test mustbe confirmed before enrolment. FCBP must commit to use of highly effective method ofcontraception during study participation and until 28 weeks (6.5 months) after thelast dose of study drug. Females must also refrain from donating blood or egg (ovum)during the same time-period.

12. For males, an effective barrier method of contraception must be used during studyparticipation until 28 weeks (6.5 months) after the last dose of study drug, if thepatient is sexually active with a FCBP. Males must also refrain from donating bloodor sperm during the same time-period.

13. Investigator considers the patient to be suitable for participation in the clinicalstudy by assessing that they:

• Understand the requirements of the clinical study and can give informedconsent.

• Can comply with study medication dosing requirements and all study-relatedprocedures and evaluations; and

• Are not considered to be potentially unreliable and/or not cooperative

14. Has received all Coronavirus disease-19 (COVID-19) vaccinations per relevantnational guidelines.

Exclusion Criteria:

1. Inability to swallow and retain oral medications.

2. Patient does not accept bone marrow sampling during screening and after thetreatment.

3. Prior treatment with azacitidine (injectable or oral) or decitabine.

4. The patient medically requires treatment with the following drugs that are forbiddenduring the trial or was exposed to one of these 14 days before the first dose of theIMP:

• Erythropoiesis stimulating agent (ESA) or luspatercept

• Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colonystimulating factor (GM-CSF)

• Lenalidomide

• Another investigational drug or device, or approved therapy for investigationaluse

5. Iron chelation therapy NOTE: if therapy was initiated 56 days or more prior to thefirst dose of the IMP, patient can be included. Recently initiated iron chelation [< 56 days prior to registration] might influence interpretation of hematologicalresponse after start of trial medication.

6. Previous treatment with CDK8-targeted therapy(s).

7. Active central nervous system (CNS) involvement.

8. Patients who have undergone major surgery within 28 days prior to first dose ofstudy drug.

9. Evidence of ongoing and uncontrolled systemic bacterial, fungal, or viral infectionand acute inflammatory conditions (including pancreatitis)

10. Hematopoietic stem cell transplant within 120 days prior to first dose of studydrug.

11. Active Grade 2-4 acute graft versus host disease (GVHD), active moderate-to-severechronic GVHD, or requirement for systemic immunosuppressive medications for GVHD.

12. Known seropositivity or history of active viral infection with humanimmunodeficiency virus (HIV).

13. Ongoing significant liver disease such as cirrhosis, drug-induced liver injury,active hepatitis or chronic persistent hepatitis B and/or C:

• Positive serologic or polymerase chain reaction (PCR) test results for acute orchronic Hepatitis B virus (HBV) infection. Patients whose HBV infection statuscannot be determined by serologic test results must be negative for HBV by PCRto be eligible for study participation.

• Acute or chronic Hepatitis C virus (HCV) infection. Patients who are positivefor HCV antibody must be negative for HCV by PCR to be eligible for studyparticipation

14. Impairment of gastrointestinal function or gastrointestinal disease that maysignificantly alter the absorption of RVU120 (e.g. active inflammatory boweldisease, ulcerative disease, malabsorption syndrome, short bowel syndrome,uncontrolled nausea, vomiting or diarrhea).

15. Ongoing drug-induced pneumonitis.

16. Concurrent participation in another investigational clinical trial.

17. Taking any medications, herbal supplements or other substances (including smoking)that are known to be strong inhibitors or moderate/strong inducers or sensitivesubstrates of CYP1A2, within less than 5 half-lives, prior to first dose of studydrug. Any exception should be discussed with the Coordinating Investigator. Forclarity, vaping (use of e-cigarettes) is not considered smoking.

18. Significant cardiac dysfunction defined as myocardial infarction within 12 months offirst dose of study drug, New York Heart Association (NYHA) Class III or IV heartfailure, uncontrolled dysrhythmias, or poorly controlled angina.

19. Currently taking drugs that are documented, in the drug package insert, to have arisk of causing prolonged QTc or torsades de pointes (TdP) within 5 half-lives,prior to first dose of study drug. Any exception should be discussed with the Coordinating Investigator.

20. Personal or family history of serious ventricular arrhythmia, or QT intervalcorrected for heart rate (QTc) ≥470 ms.

21. Any other prior or current medical condition, intercurrent illness, surgicalhistory, physical or electrocardiogram (ECG) findings, laboratory abnormalities, orextenuating circumstance (e.g. alcohol or drug addiction) that, in theInvestigator's opinion, could jeopardize patient safety or interfere with theobjectives of the study.

22. Prior history of malignancies other than Acute myeloid leukemia (AML) or MDS, unlessthe patient has been free of the disease for 5 years or more prior to screening.Exceptions to the ≥5-year time limit include history of the following:

• basal cell carcinoma of the skin

• non-metastatic squamous cell carcinoma of the skin

• carcinoma in situ of the cervix

• carcinoma in situ of the breast

• carcinoma in situ of the bladder

• incidental histological finding of prostate cancer (Tumor/Node/Metastasis [TNM]stage of T1a or T1b).

23. Pregnant or breast-feeding females