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
Overview
- Phase
- Phase 2
- Intervention
- RVU120
- Conditions
- Acute Myeloid Leukemia
- Sponsor
- Ryvu Therapeutics SA
- Enrollment
- 98
- Locations
- 37
- Primary Endpoint
- (Part 1) recommended doses of RVU120 and venetoclax for further study
- Status
- Recruiting
- Last Updated
- last year
Overview
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.
Investigators
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:
- •WBC \< 25 x 10(9)/L on Day 1 prior to first dose of study drug
- •Platelet count \> 10,000/mcL on Day 1 prior to first dose of study drug
- •AST (aspartate transaminase) and ALT (alanine transaminase) ≤ 3 x ULN (upper limit of normal)
- •Total bilirubin ≤ 3 x ULN
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:
- •Active, Grade ≥2 acute GVHD (graft versus host disease) or requirement for systemic immunosuppressive medication for GVHD
- •Evidence of ongoing or uncontrolled systemic bacterial, fungal or viral infection and acute inflammatory conditions (including pancreatitis)
- •Ongoing significant liver disease such as cirrhosis, drug-induced liver injury, active hepatitis, or chronic persistent hepatitis B and/or hepatitis C
Arms & Interventions
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
Intervention: RVU120
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
Intervention: Venetoclax
Outcomes
Primary Outcomes
(Part 1) recommended doses of RVU120 and venetoclax for further study
Time Frame: 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)
Time Frame: 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 Outcomes
- Relapse-free survival(approx. 36 months)
- Duration of response(approx. 36 months)
- Progression-free survival(approx. 36 months)
- Incidence and severity of adverse events (safety and tolerability)(approx. 36 months)
- Post baseline transfusion independence rate(approx. 36 months)
- Overall survival(approx. 36 months)
- Percentage of patients bridged to hematopoietic stem cell transplantation(approx. 36 months)
- (Parts 2 & 3) Impact of treatment on HM-PRO (hematologic malignancy specific patient reported outcome measure)(approx. 36 months)