Safety and Efficacy of RVU120 Combined With Venetoclax for Treatment of Relapsed/Refractory AML (RIVER-81)

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 Ventoclax and a Hypomethylating Agent

The goal of this study is to assess the safety, tolerability, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of RVU120 when administered in combination with venetoclax to adult patients with acute myeloid leukemia (AML) who are relapsed or refractory to prior therapy with venetoclax and a hypomethylating agent. The study consists of three parts. Part 1 aims to identify the doses of RVU120 and venetoclax that are considered to be safe and tolerated. Part 2 will assess the safety and efficacy of the doses selected. And Part 3 is a confirmatory cohort where patients will be treated at the same doses assessed in Part 2

Study Overview

• Status: Recruiting
• Conditions: Acute Myeloid Leukemia
• Intervention / Treatment: Drug: RVU120; Drug: Venetoclax

Detailed Description

In Part 1 dose-escalation participants will receive escalating oral doses of RVU120 starting at 125 mg administered every other day on days 1-13, and escalating oral doses of venetoclax starting with 200 mg administered daily on days 1-14 of each 21-day cycle of treatment. The recommended doses for further study will be based on the observed safety, tolerance, PK and PD.

In Part 2, it will be assessed whether the recommended dose level from Part 1 reaches the targetted response criteria, and if reached, Part 3 will be initiated to further evaluate the efficacy and safety of the recommended doses in a larger population.

• Study Type: Interventional
• Enrollment (Estimated): 98
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Head of Clinical Operations; Phone Number: +48-538-898-766; Email: clinicaltrials@ryvu.com

Study Locations

• France
  • Grenoble, France, 38043
    • Recruiting
    • Centre Hospitalier Universitaire Grenoble Alpes
    • Contact: Claude-Eric Bulabois, Dr
  • Le Mans, France, 72037
    • Recruiting
    • Centre Hospitalier Le Mans
    • Contact: Kamel Laribi, Dr
  • Lille, France, 59000
    • Recruiting
    • Centre Hospitalier Universitaire De Lille
    • Contact: Laure Goursaud, Dr
  • Marseille, France, 13009
    • Recruiting
    • Institut Paoli-Calmettes
    • Contact: Sylvian Garciaz, Dr
  • Nice, France, 06200
    • Recruiting
    • Centre Hospitalier Universitaire de Nice
    • Contact: Thomas Cluzeau, Dr
  • Nîmes, France, 30900
    • Recruiting
    • Centre Hospitalier Universitaire de Nīmes
    • Contact: Stefan Wickenhauser, Dr
  • Paris, France, 75010
    • Recruiting
    • Assistance Publique Hopitaux de Paris
    • Contact: Pierre Fenaux, Dr
  • Rouen, France, 76000
    • Recruiting
    • Centre Henri Becquerel
    • Contact: Emilie Lemasle-Hue, Dr
• Italy
  • Ancona, Italy, 60126
    • Recruiting
    • Azienda Ospedaliero Universitaria delle Marche
    • Contact: Debora Capelli, Dr
  • Bologna, Italy, 40138
    • Recruiting
    • Univerisity of Bologna Policlinico Sant'Orsola
    • Contact: Cristina Papayannidis, Prof.
  • Brescia, Italy, 25123
    • Recruiting
    • Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia
    • Contact: Erika Borlenghi, Dr
  • Lecce, Italy, 73100
    • Recruiting
    • Ospedale Vito Fazzi Lecce
    • Contact: Nicola Di Renzo, Dr
  • Ravenna, Italy
    • Recruiting
    • AUSL Romagna - Ospedale S.M. Delle Croci
    • Contact: Giovanni Marconi, Prof.
  • Roma, Italy, 00133
    • Recruiting
    • Azienda Ospedaliera Policlinico Universitario Tor Vergata
    • Contact: Adriano Venditti, Prof.
  • Rozzano, Italy
    • Recruiting
    • Istituto Clinico Humanitas
    • Contact: Matteo Della Porte, Prof.
  • Turin, Italy, 10126
    • Recruiting
    • Azienda Ospedaliera Universitaria Citta della Salute e della Scienza di Torino
    • Contact: Ernesta Audisio, Dr
  • Forlì-Cesena
    • Meldola, Forlì-Cesena, Italy, 47014
      • Recruiting
      • Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori
      • Contact: Maria Giannini, Dr; Phone Number: +39 0543 739100; Email: info@irst.emr.it
      • Contact: Maria Giannini, Dr
• Poland
  • Biała Podlaska, Poland, 21-500
    • Recruiting
    • Wojewodzki Szpital Specjalistyczny w Bialej Podlaskiej
    • Contact: Piotr Centkowski, Dr
  • Gdańsk, Poland, 80-214
    • Recruiting
    • Uniwersyteckie Centrum Kliniczne
    • Contact: Witold Prejzner, Dr
  • Katowice, Poland
    • Recruiting
    • Pratia Onkologia Katowice
    • Contact: Sebastian Grosicki, Prof.
  • Toruń, Poland, 87-100
    • Recruiting
    • Wojewodzki Szpital Zespolony Im.L.Rydygiera W Toruniu
    • Contact: Marcin Rymko, Dr
  • Warsaw, Poland, 02-776
    • Recruiting
    • Instytut Hematologii i Transfuzjologii
    • Contact: Ewa Lech-Marańda, Prof.
  • Warsaw, Poland, 04-141
    • Recruiting
    • Wojskowy Instytut Medyczny Państwowy Instytut Badawczy
    • Contact: Krzysztof Gawroński, Dr
  • Wałbrzych, Poland, 58-309
    • Recruiting
    • Specjalistyczny Szpital im. dra Alfreda Sokolowskiego
    • Contact: Aleksandra Butrym, Prof.
  • Wrocław, Poland, 53-439
    • Recruiting
    • Dolnoslaskie Centrum Onkologii Pulmonologii i Hematologii
    • Contact: Jarosław Dybko, Dr
  • Zielona Góra, Poland, 65-046
    • Recruiting
    • Szpital Uniwersytecki Imienia Karola Marcinkowskiego w Zielonej Gorze Sp. z o. o.
    • Contact: Emilian Snarski, Prof.
  • Mazowieckie województwo
    • Warszawa, Mazowieckie województwo, Poland, 02-172
      • Recruiting
      • MTZ Clinical Research
      • Contact: Krzysztof Mądry; Phone Number: +48 22 572 59 59; Email: info@pratia.com
      • Contact: Krzysztof Mądry
• Spain
  • Barcelona, Spain, 08003
    • Recruiting
    • Hospital del Mar
    • Contact: Sara Garcia Avila, Dr
  • Barcelona, Spain, 08041
    • Recruiting
    • Hospital De La Santa Creu I Sant Pau
    • Contact: Guadalupe Oñate, Dr
  • Barcelona, Spain, 08908
    • Not yet recruiting
    • Institut Catala d'Oncologia
    • Contact: Montserrat Arnan Sangerman, Dr
  • Cáceres, Spain, 10002
    • Recruiting
    • Hospital San Pedro de Alcántara
    • Contact: Juan Miguel Bergua Burgués, Dr
  • Madrid, Spain, 28046
    • Recruiting
    • Hospital Universitario La Paz
    • Contact: Irene Sanchez Vandillo, Dr
  • Madrid, Spain, 28033
    • Recruiting
    • MD Anderson Cancer Center
    • Contact: Adolfo De La Fuente, Dr
  • Málaga, Spain, 29010
    • Recruiting
    • Hospital Universitario Regional de Malaga
    • Contact: Alejandro Luis Contento Gonzalo, Dr
  • Pamplona, Spain, 31008
    • Recruiting
    • Clinica Universidad de Navarra
    • Contact: Ana Alfonso Pierola, Dr
  • Sevilla, Spain, 41013
    • Recruiting
    • University Hospital Virgen Del Rocio S.L.
    • Contact: Jose Antonio Perez Simón, Dr
  • Valencia, Spain, 46026
    • Recruiting
    • Hospital Universitario y Politecnico La Fe
    • Contact: Pau Montesinos Fernandez, Dr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients must have a diagnosis of AML (per 2022 WHO classification)
• Patients must have relapsed or refractory AML (per ELN 2022 criteria)
• Patients must have failed first-line treatment with venetoclax combined with a hypomethylating agent
• Patients must have no alternative therapeutic options likely to produce clinical benefit
• Patients must have ECOG performance status of 0 to 2

• Patients must have adequate end organ function defined as:

  1. WBC < 25 x 10(9)/L on Day 1 prior to first dose of study drug
  2. Platelet count > 10,000/mcL on Day 1 prior to first dose of study drug
  3. AST (aspartate transaminase) and ALT (alanine transaminase) ≤ 3 x ULN (upper limit of normal)
  4. Total bilirubin ≤ 3 x ULN
  5. Creatinine clearance (Cockcroft & Gault formula) ≥ 50 mL/min
  6. LVEF (left ventricular ejection fraction) ≥ 40% by electrocardiography
• Subjects must have the ability to understand and the willingness to sign a written informed consent document and complete study related procedures

Exclusion Criteria:

• APL (acute promyelocytic leukemia), the M3 subtype of AML
• Active CNS (central nervous system) leukemia
• Previous treatment with CDK8 and/or CDK19-targeted therapy
• Major surgery within 28 days prior to the first dose of study drug
• Hematopoietic stem cell transplant within 120 days prior to the first dose of study drug
• Currently pregnant or breast-feeding. Females of child bearing potential must have a negative serum pregnancy test within 72 hours prior to the first dose of study drug

• Uncontrolled intercurrent illness that could limit life expectancy or ability to complete study correlates. This includes but is not limited to:

  1. Active, Grade ≥2 acute GVHD (graft versus host disease) or requirement for systemic immunosuppressive medication for GVHD
  2. Evidence of ongoing or uncontrolled systemic bacterial, fungal or viral infection and acute inflammatory conditions (including pancreatitis)
  3. Ongoing significant liver disease such as cirrhosis, drug-induced liver injury, active hepatitis, or chronic persistent hepatitis B and/or hepatitis C
  4. Ongoing drug-induced pneumonitis
  5. Significant cardiac dysfunction, defined as myocardial infarction within 12 months prior to the first dose of study drug, NYHA (New York Heart Association) Class III or IV heart failure, uncontrolled dysrhythmias, poorly controlled angina
  6. History of ventricular arrhythmia or QTc ≥ 470 ms (Bazett's formula)
  7. Prior history of malignancies other than AML, unless disease-free for 5 years or more or prior basal cell carcinoma of the skin, non-metastatic squamous cell carcinoma of the skin, carcinoma in situ of cervix, breast or bladder, and incidental histological finding of prostate cancer (TMN stage T1a or T1b)
• Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of RVU120 and/or venetoclax
• 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
• Taking any medications, over-the-counter medications, foods or herbal supplements that are known to be strong or moderate inhibitors of CYP3A4 or P-gp (P-glycoprotein)
• Known allergy or hypersensitivity to any component of RVU120 or venetoclax formulations

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: RVU120 + Venetoclax; RVU120 oral capsule, 125 or 250 mg administered every other day on Days 1-13 of each 21-day cycle of treatment, combined with venetoclax oral tablet, 200 or 400 mg administered once daily on Days 1-14 of each 21-day cycle of treatment	Drug: RVU120; RVU120 is a potent, selective inhibitor of CDK8 and its paralog CDK19; Other Names: SEL120; Drug: Venetoclax; Venetoclax specifically binds to BCL-2, displacing proapoptotic proteins and triggering events that lead to apoptosis

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
(Part 1) recommended doses of RVU120 and venetoclax for further study	Incidence and severity of toxicities and number of dose limiting toxicities per dose cohort	approx. 12 months
(Parts 2 & 3) CR/CRh rate (Complete Remission/Complete Remission with incomplete Hematologic Recovery)	Preliminary efficacy of RVU120 combined with venetoclax to recommended doses from Part 1. A response of CRh is defined as bone marrow with <5% blasts, peripheral blood neutrophil count >0.5 x 10(3)/mcL, and peripheral blood platelet count of >0.5 x 10(5)/mcL	approx. 36 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence and severity of adverse events (safety and tolerability)	Number and grade of adverse events assessed by CTCAE v5.0	approx. 36 months
Duration of response	Time from randomization to disease progression or death in patients who achieve CR/CRh	approx. 36 months
Post baseline transfusion independence rate	Transfusion independence is defined as a period of 56 days with no transfusion between the first dose of study drug and the last dose of study drug + 30 days. The rate of conversion of red blood cells (RBC) and platelets is defined as percentage of participants being post-baseline transfusion independent from baseline transfusion dependent	approx. 36 months
Progression-free survival	Time from randomization until first evidence of disease progression or death	approx. 36 months
Relapse-free survival	Number of participants alive without relapse	approx. 36 months
Overall survival	Time from randomization to death	approx. 36 months
Percentage of patients bridged to hematopoietic stem cell transplantation	Number of hematopoietic stem cell transplantations following response	approx. 36 months
(Parts 2 & 3) Impact of treatment on HM-PRO (hematologic malignancy specific patient reported outcome measure)	The HM-PRO consists of two scales, Part A (Impact) that measures treatment impact on patient's health-related quality of life using a three-point Likert scale (Not at all, A little, A lot) and Part B (Signs and Symptoms) that captures the severity of disease or treatment related signs and symptoms on a three-point Likert scale (Not at all, Mild, Severe).	approx. 36 months

Collaborators and Investigators

• Sponsor: Ryvu Therapeutics SA

Study record dates

Study Major Dates

• Study Start (Actual): January 5, 2024
• Primary Completion (Estimated): February 1, 2026
• Study Completion (Estimated): September 1, 2026

Study Registration Dates

• First Submitted: December 19, 2023
• First Submitted That Met QC Criteria: December 19, 2023
• First Posted (Actual): January 5, 2024

Study Record Updates

• Last Update Posted (Actual): April 13, 2025
• Last Update Submitted That Met QC Criteria: April 9, 2025
• Last Verified: December 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Hematologic Diseases; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Antineoplastic Agents; Venetoclax
• Other Study ID Numbers: RIVER-81

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No