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

Phase 2

Recruiting

• Conditions: Acute Myeloid Leukemia
• Interventions: Drug: RVU120; Drug: Venetoclax

• Registration Number: NCT06191263
• Lead Sponsor: Ryvu Therapeutics SA

Brief 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

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 Timeline

• Study First Submitted: 2023-12-19
• Study First Submitted QC: 2023-12-19
• Study Start: 2024-01-05
• Study First Posted: 2024-01-05
• Status Verified: 2024-12
• Last Update Submitted: 2024-12-12
• Last Update Posted: 2024-12-17
• Primary Completion: 2026-02
• Study Completion: 2026-09

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 98

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

Read More

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

Read More

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
RVU120 + Venetoclax	RVU120	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
RVU120 + Venetoclax	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

Primary Outcome Measures

Name	Time	Method
(Part 1) recommended doses of RVU120 and venetoclax for further study	approx. 12 months	Incidence and severity of toxicities and number of dose limiting toxicities per dose cohort
(Parts 2 & 3) CR/CRh rate (Complete Remission/Complete Remission with incomplete Hematologic Recovery)	approx. 36 months	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

Secondary Outcome Measures

Name	Time	Method
Relapse-free survival	approx. 36 months	Number of participants alive without relapse
Duration of response	approx. 36 months	Time from randomization to disease progression or death in patients who achieve CR/CRh
Progression-free survival	approx. 36 months	Time from randomization until first evidence of disease progression or death
Incidence and severity of adverse events (safety and tolerability)	approx. 36 months	Number and grade of adverse events assessed by CTCAE v5.0
Post baseline transfusion independence rate	approx. 36 months	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
Overall survival	approx. 36 months	Time from randomization to death
Percentage of patients bridged to hematopoietic stem cell transplantation	approx. 36 months	Number of hematopoietic stem cell transplantations following response
(Parts 2 & 3) Impact of treatment on HM-PRO (hematologic malignancy specific patient reported outcome measure)	approx. 36 months	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).

Trial Locations

Locations (34)

Centre Hospitalier Universitaire Grenoble Alpes; 🇫🇷 Grenoble, France

Centre Hospitalier Le Mans; 🇫🇷 Le Mans, France

Centre Hospitalier Universitaire De Lille; 🇫🇷 Lille, France

Centre Hospitalier Universitaire De Nice; 🇫🇷 Nice, France

Centre Henri Becquerel; 🇫🇷 Rouen, France

Ospedale Vito Fazzi Lecce; 🇮🇹 Lecce, Italy

Azienda Ospedaliera Universitaria Citta Della Salute E Della Scienza Di Torino; 🇮🇹 Turin, Italy

Wojewodzki Szpital Specjalistyczny w Bialej Podlaskiej; 🇵🇱 Biała Podlaska, Poland

Uniwersyteckie Centrum Kliniczne; 🇵🇱 Gdańsk, Poland

Institut Paoli-Calmettes; 🇫🇷 Marseille, France

Centre Hospitalier Universitaire De Nimes; 🇫🇷 Nîmes, France

Assistance Publique Hopitaux De Paris; 🇫🇷 Paris, France

Azienda Ospedaliero Universitaria Delle Marche; 🇮🇹 Ancona, Italy

Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori; 🇮🇹 Meldola, Forlì-Cesena, Italy

Univerisity of Bologna Policlinico Sant'Orsola; 🇮🇹 Bologna, Italy

Wojskowy Instytut Medyczny Panstwowy Instytut Badawczy; 🇵🇱 Warsaw, Poland

Azienda Socio Sanitaria Territoriale Degli Spedali Civili Di Brescia; 🇮🇹 Brescia, Italy

Azienda Ospedaliera Policlinico Universitario Tor Vergata; 🇮🇹 Roma, Italy

MTZ Clinical Research; 🇵🇱 Warszawa, Mazowieckie województwo, Poland

Wojewodzki Szpital Zespolony Im.L.Rydygiera w Toruniu; 🇵🇱 Toruń, Poland

Dolnoslaskie Centrum Onkologii Pulmonologii i Hematologii; 🇵🇱 Wrocław, Poland

Hospital Del Mar; 🇪🇸 Barcelona, Spain

Hospital De La Santa Creu I Sant Pau; 🇪🇸 Barcelona, Spain

Instytut Hematologii i Transfuzjologii; 🇵🇱 Warsaw, Poland

Specjalistyczny Szpital Im. Dra Alfreda Sokolowskiego; 🇵🇱 Wałbrzych, Poland

Szpital Uniwersytecki Imienia Karola Marcinkowskiego w Zielonej Gorze Sp. z o. o.; 🇵🇱 Zielona Góra, Poland

Institut Catala D'oncologia; 🇪🇸 Barcelona, Spain

Hospital San Pedro De Alcantara; 🇪🇸 Cáceres, Spain

Hospital Universitario Regional De Malaga; 🇪🇸 Málaga, Spain

University Hospital Virgen Del Rocio S.L.; 🇪🇸 Sevilla, Spain

Hospital Universitario Y Politecnico La Fe; 🇪🇸 Valencia, Spain

MD Anderson Cancer Center; 🇪🇸 Madrid, Spain

Hospital Universitario La Paz; 🇪🇸 Madrid, Spain

Clinica Universidad De Navarra; 🇪🇸 Pamplona, Spain