Cytarabine and Daunorubicin in Combination With Ruxolitinib for the Treatment of Secondary Acute Myeloid Leukemia Transformed From Myeloproliferative Neoplasms.

PRIMARY OBJECTIVES:

I. Phase I: To evaluate the MTD of ruxolitinib in combination with CPX-351 for treatment of
post-MPN AML.

II. Phase II. To evaluate the rate of composite complete remission in patients with secondary
AML transformed from MPNs (PV, ET and MF) following treatment with the combination of
Ruxolitinib and CPX-351 (8 weeks at end of induction or re-induction). The composite complete
remission (CRc) includes complete remission (morphologic CR) and complete remission with
incomplete count recovery (CRi).

SECONDARY OBJECTIVES:

I. Phase I: To evaluate the safety and tolerability of ruxolitinib in combination with
CPX-351 for treatment of post-MPN AML II. Phase II: Assess survival outcomes and proportion
of patients receiving transplant associated with ruxolitinib in combination with CPX-351.

III. Phase II: Assess safety and incidence of adverse events as assessed by CTCAE v5.0.

EXPLORATORY OBJECTIVES:

I. Phase II: Assess the proportion of treated (completion of induction or re-induction)
participants with sub-clinical levels of AML (i.e., minimal residual disease, MRD) as
measured by flow cytometry and/or next generation sequencing of known mutations (e.g., JAK-2,
CALR and other disease-specific mutations) at the end of 6 months. Cytogenetic and molecular
remission will be measured.

OUTLINE:

Phase I. Eligible participants will first receive induction therapy consisting of intravenous
CPX-351 (65 u/m2) administered on day 1, 3, and 5, which will be followed by a 23 day course
of ruxolitinib (days 6 to 28) that will be given at a starting dose of 20 mg BID and will
increase according to the mTPI dose escalation/de-escalation rule (up to the maximum dose of
25 mg BID). A bone marrow aspirate/biopsy will be performed between D14-D22 to assess disease
status and possible need for re-induction. A recovery bone marrow aspirate/biopsy to assess
response to induction will be performed between D35-D42 or when ANC>500 and platelet count >
50,000 per microliter; depend on which events occurs first. An enrollment of up to 24
participants is planned for the phase I portion of this study.

Phase II. Once the MTD is established and phase I objectives completed, the study will open
for enrollment in the phase II portion of the trial. The phase II portion of the trial will
assess the efficacy of the ruxolitinib and CPX-351 combination by evaluating the rate of
composite complete remission in participants using a Simon's two-stage minimax design.
Enrollment in phase II is planned for a total of 26 participants. The combination treatment
regimen will be the same as described for phase I except that ruxolitinib dose will also be
fixed per the recommended phase 2 dose (RP2D)(i.e., established MTD).

Participants are eligible to proceed to allogeneic hematopoietic stem cell transplantation
(allo-HSCT) at any time after achieving complete remission (CR/CRi) if they have a suitable
donor. In this case, participants will come off treatment and be followed for disease status
and survival outcomes, including peri-transplant data

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. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2

4. Newly diagnosed secondary AML patients (including transformed AML).

1. Diagnosis of essential thrombocythemia, polycythemia vera, or myelofibrosis
(based on prior bone marrow biopsy or presence of known MPN-associated mutations
[e.g., JAK2, CALR and MPL]) that has transformed to AML after receiving
one/multiple of the treatments listed below :Hydroxyurea, HMA therapy,

2. JAK2 inhibitors including ruxolitinib , and/or

3. Anti-platelet therapies, including hydroxyurea and anagrelide are allowable.

5. Female patients of childbearing potential must agree to use adequate contraception (2
forms of contraception or abstinence) from the screening visit until 30 days following
the last dose of study treatment. Should a woman become pregnant or suspect she is
pregnant while she or her partner is participating in this study, she should inform
her treating physician immediately.

6. Male patients of childbearing potential having intercourse with females of
childbearing potential must agree to abstain from heterosexual intercourse or have
their partner use 2 forms of contraception from the screening visit until 90 days
until the last dose of study treatment. They must also refrain from sperm donation
from the screening visit until 90 days following the last dose of study treatment.

7. Left ventricular ejection fraction at >/= 50% above the lower limit of institutional
normal by echocardiogram (ECHO) or multigated acquisition (MUGA) scan (14 days prior).

8. Candidate for cytotoxic-intensive induction chemotherapy.

9. Must be able to take oral medication.

10. Adequate organ function as defined by the following:

1. Serum creatinine ≤2× the upper limit of normal (ULN), or glomerular filtration
rate >20ml/h as calculated by Cockgroft-Gault formula.

2. Serum potassium, magnesium, and calcium (corrected for albumin) within
institutional normal limits or can be corrected with supplementation.

3. Total serum bilirubin ≤2.5× ULN.

4. Serum aspartate transaminase (AST) and/or alanine transaminase (ALT) ≤2.5× ULN.

Exclusion Criteria:

1. Ongoing participation in another clinical trial.

2. Isolated myeloid sarcoma (i.e., participants must have blood or marrow involvement
with AML to enter the study).

3. Acute promyelocytic leukemia (FAB M3 Classification)

4. Active central nervous system (CNS) involvement by AML.

5. Any unresolved toxicity equal to or greater than Grade 2 from previous anticancer
therapy, except for stable chronic toxicities not expected to resolve, such as
peripheral neurotoxicity.

6. Incomplete recovery from any prior surgical procedures or had surgery within 4 weeks
prior to study entry, excluding the placement of vascular access.Disseminated
intravascular coagulopathy with active bleeding or signs of thrombosis.

7. Participants with rapidly progressive disease or organ dysfunction that would prevent
them from receiving these agents.

8. Participants with uncontrolled infection will not be enrolled until infection is
treated and symptoms controlled.

a. Participants with an infection receiving treatment (antibiotic, antifungal or
antiviral treatment) may be entered into the study but must be afebrile and
hemodynamically stable for ≥72 hrs.

9. Known hypersensitivity to ruxolitinib, cytarabine, daunorubicin, or liposomal
products.

10. History of Wilson's disease or other copper metabolism disorder.

11. Uncontrolled intercurrent illness or any concurrent condition that, in the
Investigator's opinion, would jeopardize the safety of the patient or compliance with
the protocol per investigator's discretion. Including, but not limited to, symptomatic
congestive heart failure, unstable angina pectoris, serious cardiac arrhythmia,
myocardial infarction within 6 months prior to enrollment, New York Heart Association
(NYHA) Class III or IV heart failure, severe uncontrolled ventricular arrhythmias.

12. Patients with prior cumulative anthracycline exposure of greater than 368 mg/m2
daunorubicin (or equivalent).

13. All patients must discontinue anti-platelet agents or anticoagulants prior to
initiation of study drug, including aspirin and clopidogrel.