Clinical trial NCT04021368: RVU120 in Patients With Acute Myeloid Leukemia or High-risk Myelodysplastic Syndrome
Official title: A Phase Ib Study of RVU120 (SEL120) in Patients With Acute Myeloid Leukemia or High-risk Myelodysplastic Syndrome
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
Conditions: Acute Myeloid Leukemia
High-risk Myelodysplastic Syndrome
Keywords: Acute Myeloid Leukemia
Myelodysplastic Syndrome
CDK8/19 Inhibitor
RVU120 (SEL120)
Clinical Trial, Phase Ib
Lead sponsor: Ryvu Therapeutics SA
Sponsor class: INDUSTRY
First posted: 2019-07-16
Enrollment: 112
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Dose escalating Cohorts with a safety expansion Cohort
Primary purpose: TREATMENT

Brief summary: This first-in-human study will evaluate RVU120 (SEL120), a novel small molecule CDK8/19 inhibitor, in patients with Acute Myeloid Leukemia (AML) or High-risk Myelodysplastic Syndrome (HR-MDS), in terms of selection of the recommended dose for further clinical development and assessment of safety, tolerability, preliminary anti-leukemic activity, as well as pharmacokinetic and pharmacodynamic profiles.

Detailed description: The study will determine the recommended phase II dose (RP2D) and safety of RVU120 (SEL120) given as monotherapy over a range of dose-levels, following a closely controlled dose escalation study design.

Eligibility criteria: Inclusion Criteria:

All the following criteria must be met for a patient to be eligible for the study:

1. Written informed consent provided prior to any study-related procedure.
2. Age ≥18 years.
3. AML diagnosis according to the 2016 World Health Organisation (WHO) classification (Arber et al. 2016) with relapsed or refractory disease with no available therapy who have exhausted the applicable standard of care; or Myelodysplastic Syndrome (MDS) diagnosis according to the 2016 WHO classification (Arber et al. 2016) with high-risk disease per the Revised International Prognostic Scoring System (IPSS-R \>4.5) and with relapsed or refractory disease with no available therapy who have exhausted the applicable standard of care.
4. Eastern Cooperative Oncology Group (ECOG) performance score of 0-2.
5. Patients must have been off anti-cancer treatment prior to study.
6. Patients must have recovered from the toxic effects of previous treatments.
7. Peripheral white blood cell (WBC) count \<10x10\^9/L; Platelet count \>10,000/μL; Serum albumin ≥ 30g/L (3.0g/dL); Normal coagulation (elevated INR, prothrombin time or APTT \<1.3 x ULN acceptable); AST and ALT ≤3x ULN; Total bilirubin ≤1.5 x ULN; Creatinine clearance ≥60 mL/min (Cockcroft-Gault formula);
8. Adequate cardiac function
9. Life expectancy of at least 12 weeks.
10. For females of childbearing potential (FCBP), a negative pregnancy test must be confirmed before enrolment. FCBP must commit to use a highly effective method of contraception during study participation and until 6 months after the last dose of study drug. Females must also refrain from donating blood or egg (ovum) during the same time period.
11. For males, an effective barrier method of contraception must be used during study participation until 6 months after the last dose of study drug, if the patient is sexually active with a FCBP. Males must also refrain from donating blood or sperm during the same time-period.
12. Investigator considers the patient to be suitable for participation in the clinical study

Exclusion Criteria:

1. Active central nervous system (CNS) leukemia.
2. Previous treatment with CDK8-targeted therapy.
3. Patients who have undergone major surgery within 28 days prior to first dose of study drug.
4. Hematopoietic stem cell transplant within 120 days prior to first dose of study drug.
5. Active acute graft versus host disease (GVHD)
6. Infections and acute inflammatory conditions
7. Known seropositivity or history of HIV
8. Known positive test of / or known active diagnosis of COVID-19 viral infection
9. Ongoing significant liver disease
10. Impairment of gastrointestinal function or gastrointestinal disease
11. Ongoing drug-induced pneumonitis.
12. Concurrent participation in another investigational clinical trial.
13. Taking any medications, herbal supplements or other substances (including smoking) that are known to be strong inhibitors or inducers of CYP1A2 or that can prolong Q wave to T wave (QT) interval and/or cause torsade de pointes within less than 5 half-lives, prior to first dose of study drug.
14. Significant cardiac dysfunction or poorly controlled angina.
15. Currently taking drugs that are documented, in the drug package insert, to have a risk of causing prolonged QTc or torsades de pointes (TdP) within 5 half-lives prior to first dose of study drug.
16. Personal or family history of serious ventricular arrhythmia, or QT interval corrected for heart rate (QTc) ≥470 ms (Bazett's formula).
17. Any other prior or current medical condition or extenuating circumstance that, in the Investigator's opinion, could jeopardize patient safety or interfere with the objectives of the study.
18. Prior history of malignancies other than AML or MDS, unless the patient has been free of the disease for 5 years or more prior to Screening.
19. Pregnant or breast-feeding females.

Primary outcomes:
measure: Recommended dose (RD)
timeFrame: Up to 2 years
measure: Incidence of Adverse Events (Safety and Tolerability)
timeFrame: Up to 2 years
Secondary outcomes:
measure: The Maximum Observed Concentration (C[max])
timeFrame: Up to 2 years
measure: The Terminal Half-life (t[1/2])
timeFrame: Up to 2 years
measure: The Area Under the Curve (AUC)
timeFrame: Up to 2 years
measure: The Volume of Distribution at Steady State (Vss)
timeFrame: Up to 2 years
measure: Anti-leukemic activity
timeFrame: Up to 2 years
Other outcomes:
measure: AML surface markers
timeFrame: Up to 2 years
measure: Phosphorylated protein levels in AML blasts
timeFrame: Up to 2 years
measure: Transcriptomic profile changes in AML blasts
timeFrame: Up to 2 years
measure: Genetic profile changes in AML blasts
timeFrame: Up to 2 years
Locations:
city: Miami
country: United States
facility: Sylvester Comprehensive Cancer Center, University of Miami Hospital and Clinics
state: Florida
city: Atlanta
country: United States
facility: Northside Hospital
state: Georgia
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Nashville
country: United States
facility: Tennessee Oncology
state: Tennessee
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Gdańsk
country: Poland
facility: Uniwersyteckie Centrum Kliniczne
city: Toruń
country: Poland
facility: MICS Centrum Medyczne Toruń
city: Warsaw
country: Poland
facility: Instytut Hematologii i Transfuzjologii
city: Wrocław
country: Poland
facility: Dolnośląskie Centrum Onkologii, Pulmonologii i Hematologii
city: Kielce
country: Poland
facility: Świętokrzyskie Centrum Onkologii, Klinika Hematologii i Transplantacji Szpiku
state: Świętokrzyskie
Study officials:
References: