Evaluation of RVU120 Monotherapy in Relapsed/Refractory High-Risk Myelodysplastic Syndrome and Acute Myeloid Leukemia with/without NPM1 Mutation

Trial ID: 2023-505910-10-00
Protocol: River-52
Sponsor: Ryvu Therapeutics S.A.

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Diseases & Conditions

Acute myeloid leukaemia Myelodysplastic syndrome

Objectives

The primary objective of this clinical trial is to provide an estimation of the **anti-tumor activity** of RVU120 monotherapy in patients with relapsed or refractory high-risk myelodysplastic syndrome or acute myeloid leukemia, with or without NPM1 mutation. This is clinically relevant as it aims to assess the potential efficacy of RVU120 in targeting these hematological malignancies, which are often resistant to standard treatments.

Secondary objectives include:

Evaluating the clinical benefit of RVU120 monotherapy.
Further characterizing the safety and tolerability profile of RVU120 monotherapy.
Further characterizing the pharmacokinetics (PK) of single and multiple doses of RVU120.
In Part 2 only, evaluating the effect of RVU120 on patient-reported outcomes and health-related quality of life.
Evaluating the depth of response to RVU120 monotherapy.

Participants

The clinical trial involves participants diagnosed with **Acute Myeloid Leukemia** (AML) with or without NPM1 mutation, and those with relapsed or refractory high-risk myelodysplastic syndrome (MDS). The study population includes both male and female subjects, aged 18 years and older, who are considered part of a vulnerable population. Participants were selected based on specific inclusion criteria, such as a confirmed diagnosis according to the 2022 World Health Organization classification, a life expectancy of at least 12 weeks, and an Eastern Cooperative Oncology Group performance score of 0-2. All participants must have received all COVID-19 vaccinations per relevant national guidelines. The trial does not provide information on the total number of participants. Lifestyle considerations, such as diet and physical activity, are not specified. The sponsor has not disclosed the total number of participants involved in the study.

Plans and Procedures

The clinical trial is designed to evaluate the **anti-tumor activity** of RVU120 monotherapy in patients diagnosed with **Acute Myeloid Leukemia** (AML) or **Relapsed or Refractory High-Risk Myelodysplastic Syndrome** (HR-MDS). This is a multicenter, open-label trial, which will not employ randomization or blinding. The trial is expected to commence on December 12, 2023, and conclude by February 4, 2026. Participants will be administered SEL120 monohydrochloride in capsule form, with a maximum daily dose of 250 mg and a total dose not exceeding 26,250 mg over a treatment period of 15 days.

Study visits will follow a structured sequence, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a life expectancy of at least 12 weeks, age of 18 years or older, and a confirmed diagnosis of AML or HR-MDS. Participants must have failed at least one line of therapy and have no alternative therapeutic options likely to produce clinical benefit. The screening visit will also include a negative pregnancy test for women of childbearing potential and confirmation of COVID-19 vaccinations as per national guidelines.

Following the screening, participants will undergo regular follow-up visits to monitor the **rate of complete response** (CR) and secondary endpoints such as overall response rate, duration of response, and progression-free survival. The trial will also assess the pharmacokinetics of RVU120, including parameters like Cmax and AUC. The end-of-study visit will evaluate the overall survival and any adverse events experienced during the trial.

Participant involvement is expected to last until the end of the study, with conditions for early termination including non-compliance with study procedures, withdrawal of consent, or any adverse events that may compromise participant safety. The trial aims to provide valuable insights into the efficacy and safety of RVU120 in treating high-risk hematological malignancies.

Treatment

The clinical trial involves the administration of **SEL120 monohydrochloride**, a chemical compound with the active substance **7,8-dibromo-5,6-dihydro-9-methyl-2-(1-piperazinyl)-4H-imidazo[4,5,1-ij]quinoline hydrochloride**. This experimental medication is provided in a **capsule** form and is intended for **oral** administration. The trial includes two dosage strengths: **RVU120 - 100mg** and **RVU120 - 25mg**. The maximum daily dose for each participant is set at **250 mg**, with a total maximum dose of **26,250 mg** over a treatment period of **15 days**. The medication is not formulated for pediatric use and is not classified as an orphan drug. The pharmaceutical product is developed by **RYVU THERAPEUTICS S.A.** and is identified by the European medicinal product numbers **PRD8279115** and **PRD8279114**.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus is solely on evaluating the anti-tumor activity of **RVU120** monotherapy in patients with relapsed or refractory high-risk myelodysplastic syndrome or acute myeloid leukemia, with or without **NPM1 mutation**. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed regimen.

Efficacy

Efficacy in the clinical trial of RVU120 for patients with relapsed or refractory high-risk **Myelodysplastic Syndrome** or **Acute Myeloid Leukemia** will be assessed using several primary and secondary endpoints. The primary endpoint is the rate of complete remission (CR). Secondary endpoints include overall response rate (ORR), which encompasses clinical benefits beyond CR, duration of response (DoR), transfusion independence, hematological improvement, 1-year progression-free survival (PFS), 1-year relapse-free survival (RFS), 1-year overall survival (OS), and the percentage of participants bridged to hematopoietic stem cell transplantation (HSCT). Additionally, the incidence and severity of adverse events (AE) will be monitored, along with pharmacokinetics (PK) parameters of RVU120, such as Cmax, tmax, AUCtau, AUCinf, and t½, data permitting. In Part 2 of the trial, changes in patient-reported outcomes will be evaluated through summary scores of the HM-PRO and QOL-E, and the rate of measurable residual disease (MRD) negativity will also be assessed.

Inclusion and Exclusion Criteria

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Inclusion Criteria

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

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Exclusion Criteria

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