Clinical trial NCT06191263: Safety and Efficacy of RVU120 Combined With Venetoclax for Treatment of Relapsed/Refractory AML
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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Acute Myeloid Leukemia
Lead sponsor: Ryvu Therapeutics SA
Sponsor class: INDUSTRY
First posted: 2024-01-05
Enrollment: 98
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: (Part 1) recommended doses of RVU120 and venetoclax for further study
timeFrame: approx. 12 months
measure: (Parts 2 & 3) CR/CRh rate (Complete Remission/Complete Remission with incomplete Hematologic Recovery)
timeFrame: approx. 36 months
Secondary outcomes:
measure: Incidence and severity of adverse events (safety and tolerability)
timeFrame: approx. 36 months
measure: Duration of response
timeFrame: approx. 36 months
measure: Post baseline transfusion independence rate
timeFrame: approx. 36 months
measure: Progression-free survival
timeFrame: approx. 36 months
measure: Relapse-free survival
timeFrame: approx. 36 months
measure: Overall survival
timeFrame: approx. 36 months
measure: Percentage of patients bridged to hematopoietic stem cell transplantation
timeFrame: approx. 36 months
measure: (Parts 2 & 3) Impact of treatment on HM-PRO (hematologic malignancy specific patient reported outcome measure)
timeFrame: approx. 36 months
Other outcomes:
Locations:
city: Grenoble
country: France
facility: Centre Hospitalier Universitaire Grenoble Alpes
city: Le Mans
country: France
facility: Centre Hospitalier Le Mans
city: Lille
country: France
facility: Centre Hospitalier Universitaire De Lille
city: Marseille
country: France
facility: Institut Paoli-Calmettes
city: Nice
country: France
facility: Centre Hospitalier Universitaire De Nice
city: Nîmes
country: France
facility: Centre Hospitalier Universitaire De Nimes
city: Paris
country: France
facility: Assistance Publique Hopitaux De Paris
city: Rouen
country: France
facility: Centre Henri Becquerel
city: Meldola
country: Italy
facility: Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori
state: Forlì-Cesena
city: Ancona
country: Italy
facility: Azienda Ospedaliero Universitaria Delle Marche
city: Bologna
country: Italy
facility: Univerisity of Bologna Policlinico Sant'Orsola
city: Brescia
country: Italy
facility: Azienda Socio Sanitaria Territoriale Degli Spedali Civili Di Brescia
city: Lecce
country: Italy
facility: Ospedale Vito Fazzi Lecce
city: Ravenna
country: Italy
facility: AUSL Romagna - Ospedale S.M. Delle Croci
city: Roma
country: Italy
facility: Azienda Ospedaliera Policlinico Universitario Tor Vergata
city: Rozzano
country: Italy
facility: Istituto Clinico Humanitas
city: Turin
country: Italy
facility: Azienda Ospedaliera Universitaria Citta Della Salute E Della Scienza Di Torino
city: Warszawa
country: Poland
facility: MTZ Clinical Research
state: Mazowieckie województwo
city: Biała Podlaska
country: Poland
facility: Wojewodzki Szpital Specjalistyczny w Bialej Podlaskiej
city: Gdańsk
country: Poland
facility: Uniwersyteckie Centrum Kliniczne
city: Katowice
country: Poland
facility: PRATIA Onkologia Katowice
city: Toruń
country: Poland
facility: Wojewodzki Szpital Zespolony Im.L.Rydygiera w Toruniu
city: Warsaw
country: Poland
facility: Instytut Hematologii i Transfuzjologii
city: Warsaw
country: Poland
facility: Wojskowy Instytut Medyczny Panstwowy Instytut Badawczy
city: Wałbrzych
country: Poland
facility: Specjalistyczny Szpital Im. Dra Alfreda Sokolowskiego
city: Wrocław
country: Poland
facility: Dolnoslaskie Centrum Onkologii Pulmonologii i Hematologii
city: Zielona Góra
country: Poland
facility: Szpital Uniwersytecki Imienia Karola Marcinkowskiego w Zielonej Gorze Sp. z o. o.
city: Barcelona
country: Spain
facility: Hospital Del Mar
city: Barcelona
country: Spain
facility: Hospital De La Santa Creu I Sant Pau
city: Barcelona
country: Spain
facility: Institut Catala D'oncologia
city: Cáceres
country: Spain
facility: Hospital San Pedro De Alcantara
city: Madrid
country: Spain
facility: MD Anderson Cancer Center
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Málaga
country: Spain
facility: Hospital Universitario Regional De Malaga
city: Pamplona
country: Spain
facility: Clinica Universidad De Navarra
city: Sevilla
country: Spain
facility: University Hospital Virgen Del Rocio S.L.
city: Valencia
country: Spain
facility: Hospital Universitario Y Politecnico La Fe
Study officials:
References: