A Multicenter, Open-Label, Dose-Finding Clinical Trial to Assess the Safety, Pharmacokinetics, Pharmacodynamics, and Clinical Efficacy of RVU120 in Combination with Venetoclax in Participants with Acute Myeloid Leukemia Who Failed Prior Therapy with Venetoclax and a Hypomethylating Agent (RIVER-81)

Prior treatment

• Concurrent participation in another investigational 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 7 days or 5 half-lives, whichever is longer, prior to first dose and during the treatment with study drug (Section 10.8).
• Taking medications, over-the-counter medications, foods or herbal supplements that are known to be strong or moderate inhibitors of CYP3A or P-gp, within 7 days or 5 half-lives, whichever is longer, prior to first dose of study drug (Section 5.3.1). Note: Azole antifungals used in clinical practice for prophylaxis or maintenance are allowed (following the Ven prescribing information), except during Cycle 1 for participants enrolled to Part 1.
• Systemic corticosteroids exceeding prednisone 10 mg/day (or equivalent) used as physiologic replacement are prohibited.
• Previous treatment with CDK8 and/or CDK19-targeted therapy.
• Major surgery within 28 days prior to first dose of study drug.
• Bone marrow stem cell transplant (BMT) or peripheral blood stem cell transplant (PBSCT) within 120 days prior to first dose of study drug.

Other illness

• 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 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 HCV infection. Participants who are positive for HCV antibody must be negative for HCV by PCR to be eligible for study participation.
• 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 at least 5 years before Screening. Malignancies that are not expected to interfere with the study objectives are allowed, including: - 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). Note: Eligibility of participants with history of malignancies other than AML must be discussed with the Medical Monitor.
• 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).

Lab values

• Known seropositivity or history of active viral infection with human immunodeficiency virus (HIV) infection defined as any of the following: •CD4+ T-cell count of less than 350 cells/µL at Screening •AIDS‑defining opportunistic infection within the past 12 months •On established antiretroviral therapy (ART) for less than 4 weeks or presenting with a viral load of more than 400 copies/mL prior to Screening •On ART or prophylactic antimicrobials that are expected to cause significant drug-drug interactions or overlapping toxicities with study treatment. Note: HIV testing is not required unless mandated locally.
• 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 10.9) or left ventricular ejection fraction (LVEF) <40% as per echocardiography or multiple gated acquisition (MUGA) scan.
• History of ventricular arrhythmia, or QTc ≥470 ms (Fridericia’s formula; Section 10.10).
• 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- or the Sponsor’s opinion, could jeopardize participant safety or interfere with the objectives of the study.

Other

• Active central nervous system (CNS) leukemia.
• Pregnant or breastfeeding.
• Diagnosis of acute promyelocytic leukemia (APL), the M3 subtype of AML, acute erythroid leukemia, the M6 subtype of AML, or acute megakaryoblastic leukemia, the M7 subtype of AML.

• Written informed consent provided prior to any study-related procedure.
• 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) and alopecia.
• Clinical laboratory parameters as follows: - Peripheral WBC count, no upper limit at Screening, but must be <25 x10^9/L on Day 1 prior to first dose of study drug (see acceptable methods of cytoreduction above) - Platelet (PLT) count >10^9/L at the time of first study drug administration (PLT count < 10^9/L, participant must receive a transfusion within a maximum 24 hours before study drug administration) - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3X the upper limit of normal (ULN) - Creatinine clearance ≥40 mL/min (Cockcroft and Gault formula; Section 10.7). - Total bilirubin ≤1.5X ULN Note: Participants with Gilbert’s syndrome may be enrolled provided that direct bilirubin is within the acceptable range as specified in this protocol, and there is no evidence of clinically significant hepatic dysfunction.
• Adequate cardiac function confirmed by left ventricular ejection fraction ≥40% as per echocardiography.
• For women of childbearing potential (WOCBP), a negative pregnancy test must be confirmed during Screening and within ≤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 RVU120 (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 RVU120, if the participant is sexually active with a WOCBP (Section 10.4).
• 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 RVU120 (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 vaccinations in accordance with institutional standards and local regulatory requirements, if applicable.
• Age ≥18 years at time of provision of informed consent.
• AML diagnosis according to the 2022 World Health Organization (WHO) classification (Arber 2022).
• Relapsed or refractory AML per the ELN 2022 (Döhner 2022) - Participants with <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 first-line treatment with Ven + HMA with or without additional targeted therapy specified as any of the following: - For Cohort B1: Participants who do not achieve at least morphologic leukemia-free state (MLFS) or partial remission (PR), or are progressing after at least 2 cycles of Ven + HMA - For Cohort B2: Participants must have achieved CR, CRh, or CRi, within 4 cycles of Ven + HMA and subsequently experienced relapse during treatment with Ven + HMA or experienced disease progression during or after subsequent salvage treatment. Note: If Ven was the participant’s most recent line of therapy, no more than 90 days may elapse between the last administered dose of Ven and the first study dose on C1D1.
• No alternative, approved therapeutic options likely to produce clinical benefit.
• Eastern Cooperative Oncology Group (ECOG) performance score of 0-2 (Section 10.6).
• Life expectancy of at least 12 weeks.
• No other anti-cancer treatment received for 14 days or 5 half-lives, whichever is shorter, prior to first dose of study drug. Note: Use of cytoreductive agents such as hydroxyurea or low dose (up to 40 mg/day) cytarabine is permitted, where discussed and agreed with the Medical Monitor, and provided that a 7-day washout period is observed prior to the first dose of study treatment (Section 6.8.1).