Safety and Efficacy of RVU120 Combined With Venetoclax for Treatment of Relapsed/Refractory AML

Acute Myeloid Leukemia Clinical Trial

— RIVER-81  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06191263
• Other study ID #: RIVER-81
• Status: Recruiting
• Phase: Phase 2
• Start date: January 5, 2024
• Est. completion date: September 2026

Study information

• Verified date: June 2024
• Source: Ryvu Therapeutics SA
• Contact: Head of Clinical Operations
• Phone: +48-538-898-766
• Email: clinicaltrials[@]ryvu.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 98
• Est. completion date: September 2026
• Est. primary completion date: February 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Acute Myeloid Leukemia
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute

Intervention

Drug:
• RVU120
RVU120 is a potent, selective inhibitor of CDK8 and its paralog CDK19
• Venetoclax
Venetoclax specifically binds to BCL-2, displacing proapoptotic proteins and triggering events that lead to apoptosis

Locations

Country	Name	City	State
France	Centre Hospitalier Universitaire Grenoble Alpes	Grenoble
France	Centre Hospitalier Le Mans	Le Mans
France	Centre Hospitalier Universitaire De Lille	Lille
France	Institut Paoli-Calmettes	Marseille
France	Centre Hospitalier Universitaire De Nice	Nice
France	Centre Hospitalier Universitaire De Nimes	Nîmes
France	Assistance Publique Hopitaux De Paris	Paris
France	Centre Henri Becquerel	Rouen
Italy	Azienda Ospedaliero Universitaria Delle Marche	Ancona
Italy	Univerisity of Bologna Policlinico Sant'Orsola	Bologna
Italy	Azienda Socio Sanitaria Territoriale Degli Spedali Civili Di Brescia	Brescia
Italy	Ospedale Vito Fazzi Lecce	Lecce
Italy	Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori	Meldola	Forlì-Cesena
Italy	Azienda Ospedaliera Policlinico Universitario Tor Vergata	Roma
Italy	Azienda Ospedaliera Universitaria Citta Della Salute E Della Scienza Di Torino	Turin
Poland	Wojewodzki Szpital Specjalistyczny w Bialej Podlaskiej	Biala Podlaska
Poland	Uniwersyteckie Centrum Kliniczne	Gdansk
Poland	Swietokrzyskie Centrum Onkologii Samodzielny Publiczny Zaklad Opieki Zdrowotnej w Kielcach	Kielce
Poland	Wojewodzki Szpital Zespolony Im.L.Rydygiera w Toruniu	Torun
Poland	Specjalistyczny Szpital Im. Dra Alfreda Sokolowskiego	Walbrzych
Poland	Instytut Hematologii i Transfuzjologii	Warsaw
Poland	Wojskowy Instytut Medyczny Panstwowy Instytut Badawczy	Warsaw
Poland	MTZ Clinical Research	Warszawa	Mazowieckie Województwo
Poland	Dolnoslaskie Centrum Onkologii Pulmonologii i Hematologii	Wroclaw
Poland	Uniwersytecki Szpital Kliniczny Im. Jana Mikulicza-Radeckiego we Wroclawiu	Wroclaw
Poland	Szpital Uniwersytecki Imienia Karola Marcinkowskiego w Zielonej Gorze Sp. z o. o.	Zielona Góra
Spain	Hospital De La Santa Creu I Sant Pau	Barcelona
Spain	Hospital Del Mar	Barcelona
Spain	Institut Catala D'oncologia	Barcelona
Spain	Hospital San Pedro De Alcantara	Cáceres
Spain	Hospital Universitario La Paz	Madrid
Spain	MD Anderson Cancer Center	Madrid
Spain	Hospital Universitario Regional De Malaga	Málaga
Spain	Clinica Universidad De Navarra	Pamplona
Spain	University Hospital Virgen Del Rocio S.L.	Sevilla
Spain	Hospital Universitario Y Politecnico La Fe	Valencia

Sponsors (1)

Lead Sponsor	Collaborator
Ryvu Therapeutics SA

Countries where clinical trial is conducted

France,  Italy,  Poland,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	(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
Primary	(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	Incidence and severity of adverse events (safety and tolerability)	Number and grade of adverse events assessed by CTCAE v5.0	approx. 36 months
Secondary	Duration of response	Time from randomization to disease progression or death in patients who achieve CR/CRh	approx. 36 months
Secondary	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
Secondary	Progression-free survival	Time from randomization until first evidence of disease progression or death	approx. 36 months
Secondary	Relapse-free survival	Number of participants alive without relapse	approx. 36 months
Secondary	Overall survival	Time from randomization to death	approx. 36 months
Secondary	Percentage of patients bridged to hematopoietic stem cell transplantation	Number of hematopoietic stem cell transplantations following response	approx. 36 months
Secondary	(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