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

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

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