To evaluate the maximum tolerated dose (MTD) of ruxolitinib in combination with venetoclax.
I. To assess the preliminary efficacy of the ruxolitinib and venetoclax combination.
II. To estimate overall and event-free survival.
I. To assess in vitro kinase inhibitor sensitivity using patients' bone marrow in response to
ruxolitinib and venetoclax combination.
II. Use molecular techniques (potentially including next-generation sequencing and/or BH3
profiling) to examine the mechanisms of response vs. no response
III. To correlate molecular features with the patient response and resistance to venetoclax
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 physician's discretion.
- Ability to understand and the willingness to sign a written informed consent document.
- Morphologically documented relapsed/refractory AML as defined by World Health
organization (WHO) criteria after at least 2 prior therapies for AML with the
exception of hydroxyurea.
- 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
- 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 ≤2× ULN unless thought to be due to leukemic involvement.
- Serum aspartate transaminase (AST) and/or alanine transaminase (ALT) ≤2.5× ULN unless
thought to be due to leukemic involvement.
- 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 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
- 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 HIV or active hepatitis C detectable by PCR, or chronic hepatitis B
(patients positive for hepatitis B core antibody who are receiving IVIG are eligible
if HepB 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
a. 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 on an alternative therapy
within 7 days prior to the first dose of study drug:
1. Steroid therapy for anti-neoplastic intent;
2. Strong and moderate CYP3A inhibitors
3. Strong and Moderate CYP3A inducers
- Patients with uncontrolled white blood cell count (defined as >50 K/mm3 not controlled