Ruxolitinib and Venetoclax in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia

This phase I trial studies the side effects and best dose of ruxolitinib when given together with venetoclax in treating patients with acute myeloid leukemia that has come back (relapsed) or has not responded to treatment (refractory). Ruxolitinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. This study is being done to see if the combination of ruxolitinib and venetoclax works better in treating patients with acute myeloid leukemia compared to standard of care chemotherapy.

PRIMARY OBJECTIVE:

I. To evaluate the maximum-tolerated dose (MTD) and assess the safety of ruxolitinib in combination with venetoclax.

SECONDARY OBJECTIVES:

I. To assess the preliminary efficacy of the ruxolitinib and venetoclax combination.

II. To estimate overall and event-free survival.

EXPLORATORY OBJECTIVES:

I. To assess in vitro kinase inhibitor sensitivity using patient bone marrow (or peripheral blood) before and after treatment with the ruxolitinib and venetoclax combination.

II. To use molecular techniques (potentially including next-generation sequencing and/or BH3 profiling) to examine the mechanisms of response versus (vs.) no response.

III. To correlate molecular features with the patient response and resistance to venetoclax combination therapies.

IV. To determine the pharmacokinetic/pharmacodynamic (PK/PD) concentrations in vivo of the dual drug combination therapy.

OUTLINE: This is a dose-escalation study of ruxolitinib.

Patients receive ruxolitinib orally (PO) twice daily (BID) and venetoclax PO once daily (QD) on days 1-28. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients may receive additional cycles of ruxolitinib and venetoclax at the discretion of the sponsor-investigator.

After completion of study treatment, patients are followed up every 6 months.

Eligibility Criteria:
Inclusion Criteria:

* Ability to understand and the willingness to sign a written informed consent document
* Age \>= 18 years at time of informed consent. Both men and women and members of all races and ethnic groups will be included
* Morphologically documented relapsed/refractory acute myeloid leukemia (AML) as defined by World Health Organization (WHO) criteria after at least 1 prior therapy for AML with the exception of hydroxyurea. Patients with myelodysplastic syndrome (MDS) transformed to AML that have been treated with hypomethylating agents may be considered if they fulfill one or more of the following criteria: 1) patient has a left ventricular ejection fraction of 45% or less; 2) patient has a serum creatinine of \>= 1.4 gm/dl; 3) patient is age 75 or older
* Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2
* Women must not be pregnant or breastfeeding. Women of childbearing potential must have a negative serum or urine pregnancy test within 14 days prior to start of study drug administration
* Participants must agree to use an adequate method of contraception
* Must be able to take oral medications
* Creatinine clearance \>= 30 mL/min; calculated by the Cockcroft Gault formula or measured by 24 hours urine collection
* Total serum bilirubin =\< 1.5 x upper limit of normal (ULN) unless thought to be due to leukemic involvement
* Serum aspartate transaminase (AST) and/or alanine transaminase (ALT) =\< 3.0 x ULN unless thought to be due to leukemic involvement

Exclusion Criteria:

* Diagnosis of acute promyelocytic leukemia (APL, or AML M3 subtype)
* Active central nervous system involvement with AML
* Concurrent active malignancy with expected survival of less than 1 year. For example, candidates with treated skin cancers, prostate cancer, breast cancer, etc. without metastatic disease are candidates for therapy since their expected survival exceeds that of relapsed or refractory AML. All subjects with concurrent malignancies will be reviewed by the principal investigator (PI) prior to enrollment
* Clinically significant graft versus host disease (GVHD) or active GVHD requiring initiation or escalation of treatment within 28 day screening period
* Participants with rapidly progressive disease (defined by blast count doubles within 48 hours) or organ dysfunction
* Clinically significant coagulation abnormality, such as disseminated intravascular coagulation
* Participants who are currently receiving any other investigational agents
* Known clinically significant liver disease defined as ongoing drug-induced liver injury, chronic active hepatitis C (HCV), chronic active hepatitis B (HBV), alcoholic liver disease, non-alcoholic steatohepatitis, primary biliary cirrhosis, extrahepatic obstruction caused by cholelithiasis, cirrhosis of the liver, portal hypertension, or history of autoimmune hepatitis
* Untreated human immunodeficiency virus (HIV) or active hepatitis C detectable by polymerase chain reaction (PCR), or chronic hepatitis B (patients positive for hepatitis B core antibody who are receiving intravenous immunoglobulin \[IVIG\] are eligible if hepatitis \[Hep\]B PCR is negative)
* Known history of cerebrovascular accident, myocardial infarction, or intracranial hemorrhage within 2 months of enrollment
* Clinically significant surgery within 2 weeks of enrollment
* Per PI discretion, active infection that is not well controlled by antibacterial or antiviral therapy

  * Participants with known history of tuberculosis (TB; Mycobacterium tuberculosis) are not eligible for participation. At investigator discretion, latent TB test should be performed for individuals considered to be at high-risk (e.g., immune compromised, persons that have traveled to, or emigrated from, regions with high rates of TB)
* Cancer-directed therapy within 1 week prior to starting treatment, with the exception of hydroxyurea, which is allowed to control white blood cell count
* Unwillingness to receive infusion of blood products
* Participant on any of the following therapies need to be discussed with the sponsor investigator:

  * Strong and moderate CYP3A inhibitors
  * Strong and moderate CYP3A inducers
* Patients with uncontrolled white blood cell count (defined as \> 50 K/mm\^3 not controlled with hydroxyurea)
* Patients with known sensitivity to ruxolitinib or venetoclax