A Multicenter, Open-Label Clinical Trial of RVU120 in Patients with Relapsed or Refractory High-Risk Myelodysplastic Syndrome or Acute Myeloid Leukemia with or without NPM1 Mutation (RIVER-52)

Prior treatment

• Concurrent participation in another therapeutic clinical trial
• Taking any medications, herbal supplements, or other substances that are known to be strong inhibitors or moderate/strong inducers or sensitive substrates of CYPXXX, within less than 5 half-lives prior to first dose of study drug (Section 10.9).
• Previous treatment with CDK8 and/or CDK19-targeted therapy
• Major surgery within 28 days prior to first dose of study drug
• Hematopoietic stem cell transplant within 120 days prior to first dose of study drug

Other illness

• Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of RVU120 (e.g., active inflammatory bowel disease, ulcerative disease, malabsorption syndrome, short bowel syndrome, uncontrolled nausea, vomiting or diarrhea).
• Ongoing drug-induced pneumonitis
• Prior history of malignancies other than AML, unless the participant has been free of the disease for 5 years or more prior to Screening, or the following apply:  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 stage of T1a or T1b).
• Active, ≥Grade 2 acute graft versus host disease (GVHD), active moderate-to-severe chronic GVHD, or requirement for systemic immunosuppressive medications for GVHD
• Evidence of ongoing and uncontrolled systemic bacterial, fungal, or viral infection and acute inflammatory conditions (including pancreatitis).
• Known seropositivity or history of active viral infection with human immunodeficiency virus (HIV).
• 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 or chronic hepatitis B virus (HBV) infection. Participants whose HBV infection status cannot be determined by serologic test results must be negative for HBV by PCR to be eligible for study participation. (https://www.cdc.gov/hepatitis/hbv/interpretationOfHepBSerologicResults.htm) - Acute or chronic hepatitis C virus (HCV) infection. Participants who are positive for HCV antibody must be negative for HCV by PCR to be eligible for study participation.

Lab values

• Significant cardiac dysfunction defined as myocardial infarction within 12 months of first dose of study drug, New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled dysrhythmias, poorly controlled angina (Section 10.10), or left ventricular ejection fraction <40% as per echocardiography or multiple gated acquisition (MUGA) scan.
• Taking medications that are documented in their drug package insert to have a risk of causing prolonged Q wave to T wave interval (QT) corrected for heart rate (QTc) or Torsades de pointes within 5 half-lives prior to first dose of study drug.
• History of ventricular arrhythmia, or QTc ≥470 ms (Bazett’s formula; Section 10.12).
• Any other prior or current medical condition, intercurrent illness, surgical history, physical or electrocardiogram (ECG) findings, laboratory abnormalities, or extenuating circumstance (e.g., alcohol or drug addiction) that, in the Investigator’s and Sponsor's opinion, could jeopardize participant safety or interfere with the objectives of the study.

Other

• Active central nervous system leukemia
• Pregnant or breast-feeding
• Diagnosis of acute promyelocytic leukemia, the M3 subtype of AML

• Written informed consent provided prior to any study-related procedure
• Life expectancy of at least 12 weeks.
• For women of childbearing potential (WOCBP), a negative pregnancy test must be confirmed during Screening and prior to first dose of ≤3 days prior to first dose of study drug. WOCBP must commit to using a highly effective method of contraception during study participation and until 28 weeks (approximately 6.5 months) after the last dose of study drug (Section 10.4) or For males, an effective barrier method of contraception must be used during study participation and until 28 weeks (approximately 6.5 months) after the last dose of study drug, if the participant is sexually active with a WOCBP (Section 10.4). Sexually active male participants are asked to advise their female partners of childbearing potential to also use highly effective contraception for the same time period.
• Agree not to donate blood, eggs (ova) or sperm, during study participation and until 28 weeks (approximately 6.5 months) after the last dose of study drug (Section 10.4).
• Investigator considers the participant to be suitable for participation in the clinical study by assessing that they: - understand the requirements of the clinical study and can give informed consent - can comply with study medication dosing requirements and all study-related procedures and evaluations - are not considered to be potentially unreliable and/or not cooperative.
• Has received all Coronavirus disease-19 (COVID-19) vaccinations per relevant national guidelines.
• Age ≥18 years at time of provision of informed consent.
• Diagnosis of AML or MDS as follows: • Cohort 1: AML according to the 2022 World Health Organization (WHO) classification (Arber 2022) in the absence of a mutation in the NPM1 or DNMT3A gene • Cohort 2: AML according to the 2022 WHO classification (Arber 2022) with a mutation in the NPM1 gene regardless of any other co-occurring mutation • Cohort 3: AML according to the 2022 WHO classification (Arber 2022) in the absence of a mutation in the NPM1 gene and with a mutation in the DNMT3A gene • Cohort 4: MDS according to the 2022 WHO classification (Arber 2022) confirmed as high risk with IPSS-R >4.5 following the most recent line of treatment (Section 10.6).
• Relapsed or refractory AML per the ELN 2022 (Döhner 2022) or relapsed or progressing HR-MDS per the International Working Group response criteria in MDS (Zeidan 2023). Participants with AML and <10% bone marrow cellularity may be enrolled where immunophenotyping of the bone marrow demonstrates this is due to underlying disease and not to potential myelotoxicity e.g., where >50% of cells have AML phenotype.
• Failed at least 1 line of therapy and no available alternative therapeutic options likely to produce clinical benefit.
• Eastern Cooperative Oncology Group (ECOG) performance score of 0-2 (Section 10.7).
• No other anti-cancer treatment received for 4 weeks or 5 half-lives, whichever is shorter, prior to first dose of study drug.
• Must have recovered from the toxic effects of previous treatments to at least Grade 1, except for neurotoxicity (which should return at least to Grade 2 or baseline), or alopecia.
• Clinical laboratory parameters as follows: a. peripheral white blood cell (WBC) count, no upper limit during Screening, but must be <30 x 109/L on Day 1 prior to first dose of study drug. b. platelet count >10,000 /μL Note: Platelet infusion permitted c. serum albumin ≥ 25 g/L (2.5 g/dL) d. normal coagulation (elevated international normalized ratio, prothrombin time or activated partial thromboplastin time [APTT] <1.3 x the upper limit of normal [ULN] acceptable) e. aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3 x ULN f. Direct bilirubin ≤1.5 x ULN g. creatinine clearance ≥30 mL/min (Cockcroft and Gault formula; Section 10.8).