Phase II Multicenter Study of RVU120 in Treating Anemia in Patients with Lower-Risk Myelodysplastic Syndromes Using SEL120 Monohydrochloride

Trial ID: 2023-509947-29-00
Protocol: REMARK_001
Sponsor: GCP-Service International West GmbH

Trial statistics

science

test molecules

location_city

research sites

public

countries

medical_information

diseases

person_search

investigators

handshake

vendors

Diseases & Conditions

Anaemia Myelodysplastic syndrome

Objectives

The primary objective of this phase II, open-label, multicenter study is to evaluate the proportion of patients with **anemia** in lower-risk myelodysplastic neoplasms (MDS) who achieve an erythroid response (HI-E) according to the IWG 2018 criteria. This is clinically relevant as it aims to determine the effectiveness of RVU120 in improving hematological parameters in this patient population, potentially reducing the need for transfusions and improving patient outcomes.

Secondary objectives include further assessment of the efficacy and safety of RVU120 through various measures:

Safety and toxicity profile of RVU120.
HI-E response duration and time to HI-E.
Changes in hemoglobin levels from baseline.
Red blood cell transfusion independence for ≥8 and ≥12 weeks.
Frequency of RBC transfusions in transfusion-dependent patients.
Neutrophil and platelet responses (HI-N and HI-P) according to IWG 2018 criteria.
Progressive disease (PD) and complete remission (CR) according to IWG 2023 criteria, specifically in patients with ≥5% myeloblasts at baseline.
Partial remission (PR) according to IWG 2023 criteria in the same patient subset.
Quality of life (QoL) assessment.
HI-E response after 8 cycles of treatment with a 250 mg dose following non-response to a 150 mg dose.

Participants

The clinical trial involves participants diagnosed with **anemia** in patients with very low, low, or intermediate risk myelodysplastic neoplasms (MDS). The study population includes both male and female subjects, aged 18 years and older. Participants are selected based on specific criteria, including a diagnosis of de novo myelodysplastic neoplasms according to WHO 2022 criteria and symptomatic anemia documented in the 16 weeks baseline period. The trial includes a vulnerable population, and participants must have received all COVID-19 vaccinations per relevant national guidelines. The sponsor has not provided information regarding the total number of participants. The selection process ensures that participants have no available option of an approved MDS therapy, as determined by the treating physician, and meet specific clinical laboratory parameters. Lifestyle considerations such as diet and physical activity are not specified. The trial population is characterized by an Eastern Cooperative Oncology Group (ECOG) performance score of 0-2, indicating a general good health status suitable for study participation.

Plans and Procedures

The clinical trial is a **phase II**, open-label, multicenter study designed to evaluate the efficacy and safety of orally administered RVU120 in treating anemia in patients with lower-risk myelodysplastic neoplasms (MDS). The primary objective is to assess the proportion of patients achieving an erythroid response (HI-E) according to the IWG 2018 criteria. The trial is expected to commence recruitment in May 2024 and conclude by May 2027, with a maximum treatment period of 315 days for each participant. The study involves the administration of RVU120, a small-molecule anticancer drug and CDK8 kinase inhibitor, in capsule form, with a maximum daily dose of 250 mg.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis of MDS, and previous treatment history. Following the screening, participants will receive RVU120 and attend regular follow-up visits to monitor efficacy and safety, including assessments of hemoglobin levels, red blood cell transfusion independence, and potential adverse events. The primary endpoint will be measured after eight full cycles of RVU120 administration. Secondary endpoints include safety measurements using NCI CTCAE v5.0 and various efficacy measurements such as hemoglobin changes and quality of life assessments.

The expected length of participant involvement is approximately 10.5 months, with conditions for early termination including failure to meet response criteria, unacceptable toxicity, or withdrawal of consent. The study is not low-intervention and does not include pediatric subjects. Participants must provide written informed consent and meet specific laboratory and clinical criteria to be eligible for the trial. The trial design does not include randomization or blinding, as it is an open-label study.

Treatment

The clinical trial involves the administration of **SEL120 monohydrochloride**, a small-molecule anticancer drug that functions as a **CDK8 kinase inhibitor**. The pharmaceutical form of SEL120 monohydrochloride is a capsule, and it is administered orally. The active substance in this medication is **7,8-dibromo-5,6-dihydro-9-methyl-2-(1-piperazinyl)-4H-imidazo[4,5,1-ij]quinoline hydrochloride**, which is of chemical origin. The maximum daily dose of SEL120 monohydrochloride is 250 mg, with a total maximum dose of 26,250 mg over a treatment period of up to 315 days. The medication is not formulated for pediatric use and is not classified as an orphan drug.

In this study, SEL120 monohydrochloride is the experimental treatment, and no additional non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The trial aims to evaluate the efficacy of SEL120 monohydrochloride in treating anemia in patients with lower-risk myelodysplastic neoplasms. Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the prescribed regimen.

Efficacy

Efficacy in this clinical trial will be assessed primarily through the **erythroid response (HI-E)** according to the IWG 2018 criteria. This primary endpoint will be measured after eight full cycles of RVU120 administration at a dose of 150 mg. Patients who do not complete the treatment or are not assessable for response after treatment will be considered non-responders. Secondary efficacy endpoints include the duration of HI-E response, time to HI-E, changes in hemoglobin levels from baseline, and red blood cell (RBC) transfusion independence for periods of 8 and 12 weeks. Additionally, the frequency of RBC transfusions in transfusion-dependent patients, neutrophil and platelet responses (HI-N and HI-P), and progressive disease according to IWG 2023 criteria will be evaluated. Complete remission (CR) and partial remission (PR) according to IWG 2023 criteria will also be assessed, along with quality of life using the EORTC QLQ-C30 (version 3) questionnaire. These efficacy parameters will be measured from the first administration of RVU120 (C1D1) until the end of treatment visit (EOT). The trial will also include assessments of progressive disease, defined by criteria such as disease progression by blasts, worsening cytopenia, and progression to acute myeloid leukemia (AML). The efficacy assessments will be conducted using validated scales and criteria, ensuring a comprehensive evaluation of the treatment's impact on patients with lower-risk myelodysplastic neoplasms (MDS).

Inclusion and Exclusion Criteria

check_circle

Inclusion Criteria

Written informed consent provided prior to any study-related procedure
Adequate cardiac function confirmed by left ventricular ejection fraction (LVEF) ≥40% as per echocardiography or MUGA (Multiple Gated Acquisition) scan. In Germany, an echocardiogram will be performed (not MUGA scan).
For males, an effective barrier method of contraception must be used during study participation until 28 weeks (6.5 months) after the last dose of study drug, if the patient is sexually active with a female of childbearing potential (FCBP). Males must also refrain from donating blood or sperm during the same time-period.
Investigator considers the patient 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; and • 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
Diagnosis of de novo myelodysplastic neoplasms (MDS) according to WHO 2022 criteria. Diagnosis will be confirmed during screening assessment.
Very low, low or intermediate risk disease MDS with up to 3.5 points according to International Prognostic Scoring System Score Revised (IPSS-R) classification (to be confirmed during screening assessment). Patients with del(5q) and max. one further abnormality (excluding monosomy 7, del(7q), TP53mut) are eligible.
Symptomatic anemia: Symptomatic anemia (all NTD, LTB, or HTB) has to be documented in the 16 weeks baseline period ending on the day of the first IMP dose. 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 weeks before the first dose of IMP) and transfusion history will be available at inclusion AND • • the Hb Mean over the baseline period (the 16 weeks before the first dose of IMP) will be less than 10 g/dL OR three or more RBC-transfusions will have been given during the baseline period (the 16 weeks before the first dose of IMP) documenting transfusion dependence.
No available option of an approved MDS therapy according to decision of the treating physician and based on the following: Patients must be • ESA exposed (and refractory or intolerant) or ESA naïve and serum erythropoietin level >200 U/L AND/OR • Luspatercept exposed (and refractory or intolerant) or luspatercept naïve and not eligible for treatment (e.g. not approved) AND/OR • Lenalidomide exposed (and refractory or intolerant) or lenalidomide naïve and not eligible for treatment (e.g. due to non-presence of del(5q))
Eastern Cooperative Oncology Group (ECOG) performance score of 0-2
Patients must have been off anti-cancer treatment for 2 weeks or 5 half-lives, whichever is longer. Anti-cancer treatment also includes lenalidomide and luspatercept.
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 INR, prothrombin time or APTT <1.3 x ULN acceptable) • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3 x the upper limit of normal (ULN) • Total bilirubin ≤1.5 x ULN • Creatinine clearance ≥30 mL/min • Urine protein < 2+ (as measured by dipstick) or ≤1000 mg/24 hours urine

cancel

Exclusion Criteria

Inability to swallow and retain oral medications.
Prior hematopoietic stem cell transplantion.
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 PCR test results for acute or chronic HBV infection. Patients whose HBV infection status cannot be determined by serologic test results must be negative for HBV by PCR to be eligible for study participation. • Acute or chronic HCV infection. Patients 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 investigational clinical trial.
Taking any medications, herbal supplements or other substances (including smoking) that are known to be strong inhibitors or moderate/strong inducers or sensitive substrates of CYP1A2, within less than 5 half-lives, prior to first dose of study drug. Any exception should be discussed with the Coordinating Investigator. For clarity, vaping (use of e-cigarettes) is not considered smoking.
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, or poorly controlled angina.
Currently taking drugs that are documented, in the drug package insert, to have a risk 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.
Patient does not accept bone marrow sampling during screening and after the treatment.
Personal or family history of serious ventricular arrhythmia, or QT interval corrected for heart rate (QTc) ≥470 ms.
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 opinion, could jeopardize patient safety or interfere with the objectives of the study.
Prior history of malignancies other than AML or MDS, unless the patient has been free of the disease for 5 years or more prior to screening. The following conditions are exempt from the ≥5-year time limit, but the patient needs to be free disease before inclusion in the study: • 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).
Females of child-bearing potential including pregnant or breast-feeding females. FCBP is defined in this protocol as a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy or 2) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).
Prior treatment with azacitidine (injectable or oral) or decitabine.
The patient medically requires treatment with the following drugs that are forbidden during the trial or was exposed to one of these 14 days before the first dose of the IMP: • Erythropoiesis stimulating agent (ESA) or luspatercept • Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF) • Lenalidomide • Another investigational drug or device, or approved therapy for investigational use
Iron chelation therapy NOTE: if therapy was initiated 56 days or more prior to the first dose of the IMP, patient can be included. Recently initiated iron chelation [< 56 days prior to registration] might influence interpretation of hematological response after start of trial medication.
Previous treatment with CDK8-targeted therapy(s).
Active central nervous system (CNS) involvement.
Patients who have undergone major surgery within 28 days prior to first dose of study drug.
Evidence of ongoing and uncontrolled systemic bacterial, fungal, or viral infection and acute inflammatory conditions (including pancreatitis)

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
France	Not Recruiting	01 May 2024	10
Germany	Not Recruiting	01 May 2024	5
Italy	Not Recruiting	01 May 2024	10
Poland	Not Recruiting	01 May 2024	10
Spain	Not Recruiting	01 May 2024	10