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.
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.
Inclusion Criteria:
- Ability to understand and the willingness to sign a written informed consent document
- 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
