Clinical Research
assignment
Recruiting

Evaluation of RVU120 and Venetoclax Combination Therapy in Acute Myeloid Leukemia Patients Refractory to Prior Venetoclax and Hypomethylating Agent Treatment

Trial ID
2023-505911-19-00
Protocol
RIVER-81
Sponsor
Ryvu Therapeutics S.A.

Trial statistics

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5
test molecules
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32
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4
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1
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31
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6
vendors

Diseases & Conditions

Acute myeloid leukaemia

Objectives

The primary objective of this clinical trial is to determine the recommended dose (RD) of RVU120 in combination with Venetoclax (Ven) for patients with Acute Myeloid Leukemia (AML) who have not responded to prior treatment with Venetoclax and a hypomethylating agent (HMA). Additionally, the trial aims to evaluate the anti-leukemic activity of RVU120 combined with Venetoclax, including the assessment of measurable residual disease (MRD) response where applicable. This is clinically relevant as it seeks to establish an effective treatment regimen for AML patients who have limited options after failing standard therapies. Secondary objectives include:
  • Determining the safety and tolerability of RVU120 when administered with Venetoclax in AML patients who have failed previous Venetoclax and HMA therapy.
  • Evaluating further efficacy endpoints of RVU120 in combination with Venetoclax in the same patient population.
  • Characterizing the pharmacokinetics (PK) of single and multiple doses of RVU120 when given with Venetoclax.
  • Assessing the effect of RVU120 combined with Venetoclax on patient-reported outcomes and health-related quality of life (HRQOL).
These secondary objectives are crucial for understanding the broader impact of the treatment on patient safety, efficacy, and quality of life.

Participants

The clinical trial involves participants diagnosed with Acute Myeloid Leukemia (AML) who have failed prior treatment with Venetoclax (Ven) and hypomethylating agents (HMA). The study population includes both male and female subjects aged 18 years and older, with no upper age limit specified. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) performance score of 0-2, indicating they are ambulatory and capable of self-care. The trial includes individuals who are considered a vulnerable population. Participants must have a life expectancy of at least 12 weeks and must not have received any other anti-cancer treatment for 14 days or 5 half-lives, whichever is shorter, prior to the first dose of the study drug. The sponsor has not provided information regarding the total number of participants. Key lifestyle considerations include the requirement for women of childbearing potential to use highly effective contraception and for all participants to refrain from donating blood, eggs, or sperm during the study and for 28 weeks after the last dose of RVU120. Participants must have received all COVID-19 vaccinations per institutional standards. The selection criteria ensure that participants have adequate cardiac function and have recovered from the toxic effects of previous treatments to a specified degree. The trial does not specify any particular dietary or physical activity requirements.

Plans and Procedures

The clinical trial is designed to evaluate the safety, pharmacokinetics, pharmacodynamics, and clinical efficacy of RVU120 in combination with venetoclax in participants with acute myeloid leukemia (AML) who have failed prior therapy with venetoclax and a hypomethylating agent. This is a multicenter, open-label, dose-finding study. The trial is structured in multiple parts, with Part 1 focusing on determining the recommended dose (RD) of RVU120 plus venetoclax, while Parts 2 and 3 aim to evaluate the anti-leukemic activity of the combination, including measurable residual disease (MRD) response where applicable. The trial is expected to conclude by February 2026, with recruitment starting in December 2023. Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on specific criteria, such as recovery from previous treatment toxicities, adequate cardiac function, and laboratory parameters. The trial includes follow-up visits to monitor safety and efficacy, with assessments of adverse events (AEs), complete response (CR) rates, and other clinical outcomes. The end-of-study visit will conclude the participant's involvement, which is anticipated to last up to 15 weeks, depending on individual response and treatment tolerability. Participants may be withdrawn from the study early if they experience unacceptable toxicity, fail to comply with study procedures, or if the investigator deems it in their best interest. The trial employs a rigorous methodology to ensure the reliability of results, with primary endpoints including the incidence and severity of AEs and CR rates. Secondary endpoints encompass transfusion independence, duration of response (DoR), progression-free survival (PFS), and overall survival, among others. The study is not classified as low intervention and is categorized as a Phase II trial, reflecting its exploratory nature in assessing the combination therapy's potential benefits in a specific patient population.

Treatment

The clinical trial involves the administration of VENETOCLAX, a BCL-2 inhibitor, as part of the experimental treatment regimen. VENETOCLAX is provided in the form of a film-coated tablet and is administered orally. The maximum daily dose is 400 mg, with a total maximum dose of 84,000 mg over a treatment period of 15 days. The tablets are repackaged and relabeled specifically for use in this clinical trial. Participant compliance with the dosing schedule is monitored to ensure adherence to the treatment protocol. Another experimental medication used in the trial is SEL120 monohydrochloride, which is provided in capsule form. 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. The capsules are administered orally, with a maximum daily dose of 250 mg and a total maximum dose of 26,250 mg over a 15-day treatment period. The medication is produced by RYVU THERAPEUTICS S.A. and is also repackaged for clinical trial use. Compliance with the dosing regimen is closely monitored to ensure accurate data collection and participant safety.

Efficacy

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints for Part 1 include the incidence and severity of adverse events (AEs), including events qualifying as dose-limiting toxicities (DLTs). For Parts 2 and 3, the primary endpoint is the complete composite response (CCR) rate, which includes complete remission (CR), CR with partial hematologic recovery (CRh), and CR with incomplete hematologic recovery (CRi), with and without measurable residual disease (MRD), according to the European LeukemiaNet (ELN) 2022 guidelines. Secondary endpoints across all parts of the trial include the incidence and severity of AEs, transfusion independence, duration of response (DoR), progression-free survival (PFS), relapse-free survival (RFS), event-free survival (EFS), overall survival, and the percentage of participants bridged to hematopoietic stem cell transplantation (HSCT). In Part 1, pharmacokinetics (PK) of RVU120 will be evaluated, including maximum concentration (Cmax), time to reach maximum concentration (tmax), area under the curve over the dosing interval (AUCtau), area under the curve from time zero to infinity (AUCinf), and half-life (t½). For Parts 2 and 3, changes in patient-reported outcomes will be assessed by changes in summary scores of the HM-PRO.

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.
  • 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).
  • 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.
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Exclusion Criteria

  • 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.
  • 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.
  • 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.
  • 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) 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • Systemic corticosteroids exceeding prednisone 10 mg/day (or equivalent) used as physiologic replacement are prohibited.

Trial Status by Country

Country Status Start of Recruitment Planned Patients
France FranceRecruiting12 Dec 202331
Italy ItalyRecruiting12 Dec 202345
Poland PolandRecruiting12 Dec 202360
Spain SpainRecruiting12 Dec 202355

Sites & Investigators

Investigational Products

Details about the medicinal products being studied in this clinical trial.

Product Name Role in Trial Formulation Administration Max Daily Dose Treatment Duration EU MP Number
SEL120 monohydrochloride
TestCAPSULEORAL20015PRD8279115
VENETOCLAX
Test—ORAL40015SUB176260
SEL120 monohydrochloride
TestCAPSULEORAL20015PRD8279114
VENETOCLAX
Test—ORAL40015SUB176260
VENETOCLAX
Test—ORAL40015SUB176260

Conditions Studied in This Trial

Interventions Studied in This Trial

vaccines
7,8-Dibromo-5,6-Dihydro-9-Methyl-2-(1-Piperazinyl)-4H-Imidazo[4,5,1-Ij]Quinoline Hydrochloride
7 trials

Also investigated for

Acute myeloid leukaemia 3Myelodysplastic syndrome 3Myelofibrosis 2Neoplasm 2
vaccines
Venetoclax
119 trials

Also investigated for

Acute myeloid leukaemia 48Chronic lymphocytic leukaemia 31Myelodysplastic syndrome 9B-cell small lymphocytic lymphoma 8