7,8-DIBROMO-5,6-DIHYDRO-9-METHYL-2-(1-PIPERAZINYL)-4H-IMIDAZO[4,5,1-IJ]QUINOLINE HYDROCHLORIDE for Myelodysplastic syndromes (MDS), lower-risk, with symptomatic anemia

Inclusion criteria

• {"criterion_text":"- 1. Written informed consent provided prior to any study-related procedure"}
• {"criterion_text":"- 6. 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))"}
• {"criterion_text":"- 7. Eastern Cooperative Oncology Group (ECOG) performance score of 0-2"}
• {"criterion_text":"- 8. 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."}
• {"criterion_text":"- 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 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"}
• {"criterion_text":"- 10. 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)."}
• {"criterion_text":"- 11. 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."}
• {"criterion_text":"- 12. 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"}
• {"criterion_text":"- 13. Has received all Coronavirus disease-19 (COVID-19) vaccinations per relevant national guidelines."}
• {"criterion_text":"- 2. Age ≥18 years"}
• {"criterion_text":"- 3. Diagnosis of de novo myelodysplastic neoplasms (MDS) according to WHO 2022 criteria. Diagnosis will be confirmed during screening assessment."}
• {"criterion_text":"- 4. 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."}
• {"criterion_text":"- 5. 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 • •\tthe Hb Mean over the baseline period (the 16 weeks before the first dose of IMP) will be less than 10 g/dL OR \t 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."}

Exclusion criteria

• {"criterion_text":"- 1. Inability to swallow and retain oral medications."}
• {"criterion_text":"- 18. 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."}
• {"criterion_text":"- 2. Patient does not accept bone marrow sampling during screening and after the treatment."}
• {"criterion_text":"- 19. Personal or family history of serious ventricular arrhythmia, or QT interval corrected for heart rate (QTc) ≥470 ms."}
• {"criterion_text":"- 20. 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."}
• {"criterion_text":"- 21. 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)."}
• {"criterion_text":"- 22. 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)."}
• {"criterion_text":"- 3. Prior treatment with azacitidine (injectable or oral) or decitabine."}
• {"criterion_text":"- 4. 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"}
• {"criterion_text":"- 5. 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."}
• {"criterion_text":"- 6. Previous treatment with CDK8-targeted therapy(s)."}
• {"criterion_text":"- 10. Prior hematopoietic stem cell transplantion."}
• {"criterion_text":"- 20. Active central nervous system (CNS) involvement."}
• {"criterion_text":"- 21. Patients who have undergone major surgery within 28 days prior to first dose of study drug."}
• {"criterion_text":"- 9. Evidence of ongoing and uncontrolled systemic bacterial, fungal, or viral infection and acute inflammatory conditions (including pancreatitis)"}
• {"criterion_text":"- 11. Known seropositivity or history of active viral infection with human immunodeficiency virus (HIV)."}
• {"criterion_text":"- 12. 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"}
• {"criterion_text":"- 13. 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)."}
• {"criterion_text":"- 14. Ongoing drug-induced pneumonitis."}
• {"criterion_text":"- 15. Concurrent participation in another investigational clinical trial."}
• {"criterion_text":"- 16. 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."}
• {"criterion_text":"- 17. 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."}

Primary endpoints

• {"endpoint_text":"- The primary efficacy endpoint is erythroid response (HI-E) according to IWG 2018 criteria. Measured after 8 full cycles of RVU120 administration (dose of 150 mg). In determining the response rate, patients who do not complete the treatment or are not assessable for response after treatment count as failures (non-responders).","definition_or_measurement_approach":"Erythroid response (HI-E) as defined by IWG 2018 criteria, measured after 8 full cycles of RVU120 at 150 mg. Non-completers or non-assessable patients are counted as non-responders."}

Secondary endpoints

• {"endpoint_text":"- Safety Measurements: Toxicity as measured by NCI CTCAE v5.0","definition_or_measurement_approach":"Toxicity graded by NCI CTCAE version 5.0."}
• {"endpoint_text":"- Efficacy Measurements: HI-E response duration - Measured from the time measurement criteria are met for HI-E (IWG 2018 HI criteria) until the first date at which loss of response is objectively documented.","definition_or_measurement_approach":"Duration measured from meeting IWG 2018 HI-E criteria to objectively documented loss of response."}
• {"endpoint_text":"- Efficacy Measurements: Time to HI-E - Defined as the time from first administration of RVU120 (C1D1) until the time measurement criteria are met for HI-E (IWG 2018 HI criteria).","definition_or_measurement_approach":"Time (days) from first dose (C1D1) to first time HI-E criteria (IWG 2018) are met."}
• {"endpoint_text":"- Efficacy Measurements: Hemoglobin changes from baseline - Defined as changes in hemoglobin measurement from first administration of RVU120 (C1D1) until end of treatment visit (EOT).","definition_or_measurement_approach":"Change in hemoglobin values from baseline (C1D1) to end-of-treatment visit."}
• {"endpoint_text":"- Efficacy Measurements: Red blood cell transfusion (RBC) independence ≥ 8 and ≥ 12 weeks - Defined as lack of need for RBC transfusions until after 8 weeks of treatment and beyond and after 12 weeks of treatment and beyond.","definition_or_measurement_approach":"Absence of RBC transfusions for ≥8 weeks and for ≥12 weeks, measured from treatment start."}
• {"endpoint_text":"- Efficacy Measurements: Frequency of RBC transfusions in transfusion dependent patients - Defined as the number of RBC units transfused from first RVU120 administration (C1D1) until end of treatment visit (EOT).","definition_or_measurement_approach":"Count of RBC units transfused from C1D1 to EOT."}
• {"endpoint_text":"- Efficacy Measurements: Neutrophil and platelet (HI-N and HI-P) responses according to IWG 2018 criteria - Measured from first RVU120 administration (C1D1).","definition_or_measurement_approach":"HI-N and HI-P defined per IWG 2018 criteria, measured from first administration (C1D1)."}
• {"endpoint_text":"- Efficacy Measurements: Progressive disease (PD) according to IWG 2023 criteria. Defined by any of the following criteria: - Disease progression by blasts: ≥ 50% relative increase in blasts and absolute increase of blast percentage by at least 5% from pretreatment sample taken before current line of therapy","definition_or_measurement_approach":"PD by blast criteria per IWG 2023: ≥50% relative increase and ≥5% absolute increase in blasts vs pretreatment sample."}
• {"endpoint_text":"- Efficacy Measurements: Progressive disease (PD) according to IWG 2023 criteria. Defined by any of the following criteria: - Disease progression by worsening cytopenia: new, repeated (more than once and separated by ≥ 7 days) need for RBC or platelet transfusions within 8 weeks, not related to acute intercurrent illness (eg, sepsis, gastrointestinal tract bleed) or treatment effect, in the absence of HI of at least one other blood lineage as defined above","definition_or_measurement_approach":"PD by worsening cytopenia per IWG 2023: repeated need for transfusions within 8 weeks not due to intercurrent illness or treatment effect, with absence of HI in other lineages."}
• {"endpoint_text":"- Efficacy Measurements: Progressive disease (PD) according to IWG 2023 criteria. Defined by any of the following criteria: - Progression to AML: ≥ 50% increase in blasts from baseline assessment to ≥ 20% blasts.","definition_or_measurement_approach":"Progression to AML defined as ≥50% increase in blasts from baseline to ≥20% blasts."}
• {"endpoint_text":"- Efficacy Measurements: Complete remission (CR) according to IWG 2023 criteria (only patients with ≥ 5% myeloblasts at baseline). Defined as follows: - BM: < 5% myeloblasts, dysplasia may persist - PB: Hb ≥ 10 g/dL, platelets ≥100 × 10(9)/L; neutrophils ≥1.0 × 10(9)/L; blasts 0%","definition_or_measurement_approach":"CR per IWG 2023: marrow <5% myeloblasts; peripheral blood thresholds as specified."}
• {"endpoint_text":"- Efficacy Measurements: Partial remission (PR) according to IWG 2023 criteria (only patients with ≥ 5% myeloblasts at baseline). Defined as follows: - All CR criteria except: ▪ BM blasts decreased by ≥ 50% over pretreatment but still ≥ 5% ▪ Cellularity and morphology not relevant","definition_or_measurement_approach":"PR per IWG 2023: meets CR criteria except marrow blasts decreased ≥50% but remain ≥5%."}
• {"endpoint_text":"- Efficacy Measurements: Quality of life assessment - Scores of EORTC QLQ-C30 (version 3) ▪ Global health status / QoL ▪ Functional scales ▪ Symptom scales / items ▪ Assessment in paper form","definition_or_measurement_approach":"QoL assessed using EORTC QLQ-C30 v3 (global health, functional and symptom scales), collected on paper."}
• {"endpoint_text":"- Efficacy Measurements: Only for pEP type 2 responders and non-responders: • Erythroid response (HI-E) after 8 cycles of treatment at 250 mg dose according to IWG 2018 criteria","definition_or_measurement_approach":"HI-E after 8 cycles at 250 mg in specified subset, per IWG 2018 criteria."}

Germany

Earliest CTIS Part Ii Submission Date

27-06-2024

Latest Decision Or Authorization Date

08-07-2024

Processing Time Days

11

Number Of Sites

2

Number Of Participants

5

France

Earliest CTIS Part Ii Submission Date

04-06-2024

Latest Decision Or Authorization Date

07-08-2024

Processing Time Days

64

Number Of Sites

5

Number Of Participants

10

Italy

Earliest CTIS Part Ii Submission Date

12-06-2024

Latest Decision Or Authorization Date

09-09-2024

Processing Time Days

89

Number Of Sites

6

Number Of Participants

10

Poland

Earliest CTIS Part Ii Submission Date

18-06-2024

Latest Decision Or Authorization Date

06-09-2024

Processing Time Days

80

Number Of Sites

4

Number Of Participants

10

Spain

Earliest CTIS Part Ii Submission Date

25-06-2024

Latest Decision Or Authorization Date

05-11-2024

Processing Time Days

133

Number Of Sites

6

Number Of Participants

10

Primary sponsor

Full Name

GCP-Service International West GmbH

Organisation Type

Pharmaceutical company

Country Of Registered Address

Germany

Third parties

• {"country":"France","full_name":"Groupe Francophone Des Myelodysplasies","duties_or_roles":"13|2","organisation_type":"Patient organisation/association"}
• {"country":"Germany","full_name":"GCP-Service International Limited & Co. KG","duties_or_roles":"1|10|12|13|2|5|6|8|9","organisation_type":"Pharmaceutical company"}
• {"country":"Italy","full_name":"FISiM Fondazione Italiana Sindromi Mielodisplastiche Ets","duties_or_roles":"1|15 (contracts with sites)","organisation_type":"Patient organisation/association"}
• {"country":"Germany","full_name":"Universitaet Leipzig","duties_or_roles":"4","organisation_type":"Educational Institution"}
• {"country":"Sweden","full_name":"Viedoc Technologies AB","duties_or_roles":"7","organisation_type":"Non-Pharmaceutical company"}
• {"country":"Germany","full_name":"Universitaet Leipzig","duties_or_roles":"13","organisation_type":"Educational Institution"}
• {"country":"Germany","full_name":"Bremen Briteline GmbH","duties_or_roles":"15 (archiving)","organisation_type":"Non-Pharmaceutical company"}
• {"country":"Spain","full_name":"Red De Apoyo A La Investigacion Clinica En Hematologia Y Hemoterapia S.L.","duties_or_roles":"1|15 (contracts with sites)","organisation_type":"Pharmaceutical company"}