Ruxolitinib in Combination With Venetoclax for the Treatment of Relapsed/Refractory Acute Myeloid Leukemia

PRIMARY OBJECTIVES:

To evaluate the maximum tolerated dose (MTD) 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.

TERTIARY OBJECTIVES:

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
combination therapies.

OUTLINE:

The study will start at dose level 0 and the dose is escalated/de-escalated according to the
Bayesian Optimal Interval Design (BOIN) rule in a cohort of 3 participants until the total of
30 participants are evaluated or the maximum of 15 patients at one dose level. The rule is
based on a target dose limiting toxicity (DLT) of 0.30. Participants, on Day 1, will receive
a starting dose (i.e., dose level 0) of ruxolitinib (20 mg PO, b.i.d) and venetoclax (200 mg,
PO, qd). Per BOIN, a cohort of 3 participants will be treated at the same dose level, or
higher or lower dose level, depending on the cumulative number of participants experiencing
DLT and number of individuals treated at that dose level.

Participants will be followed in subsequent cycles for safety and will be assessed for status
of their disease in every second cycle or as otherwise specified. Treatment cycles will be
repeated until intolerability or disease progression.

Inclusion Criteria:

1. Ability to understand and the willingness to sign a written informed consent document.

2. Age ≥18 years at time of informed consent. Both men and women and members of all races
and ethnic groups will be included.

3. Morphologically documented relapsed/refractory AML as defined by World Health
organization (WHO) criteria after at least 1 prior therapy for AML with the exception
of hydroxyurea.

4. ECOG performance status 0 to 2

5. 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.

6. Participants must agree to use an adequate method of contraception.

7. Must be able to take oral medications.

8. Adequate organ function as defined by the following:

1. Creatinine clearance ≥ 30 mL/min; calculated by the Cockcroft Gault formula or
measured by 24 hours urine collection.

2. Total serum bilirubin ≤2× ULN unless thought to be due to leukemic involvement.

3. Serum aspartate transaminase (AST) and/or alanine transaminase (ALT) ≤2.5× ULN
unless thought to be due to leukemic involvement.

Exclusion Criteria:

1. Diagnosis of acute promyelocytic leukemia (APL, or AML M3 subtype)

2. Active central nervous system involvement with AML

3. 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.

4. Clinically significant graft versus host disease (GVHD) or active GVHD requiring
initiation or escalation of treatment within 28 day screening period

5. Participants with rapidly progressive disease (defined by blast count doubles within
48 hours) or organ dysfunction.

6. Clinically significant coagulation abnormality, such as disseminated intravascular
coagulation.

7. Participants who are currently receiving any other investigational agents.

8. 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.

9. 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).

10. Known history of cerebrovascular accident, myocardial infarction, or intracranial
hemorrhage within 2 months of enrollment.

11. Clinically significant surgery within 2 weeks of enrollment.

12. Per PI discretion, active infection that is not well controlled by antibacterial or
antiviral therapy.

13. Cancer-directed therapy within 1 week prior to starting treatment, with the exception
of hydroxyurea, which is allowed to control white blood cell count.

14. Unwillingness to receive infusion of blood products.

15. 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

16. Patients with uncontrolled white blood cell count (defined as >50 K/mm3 not controlled
with hydroxyurea).