Pacritinib Combined With Decitabine or Cytarabine in Older Patients With AML

The purpose of this study is to see if a medicine called pacritinib is both safe and effective as a study intervention for patients with AML in combination with either decitabine or cytarabine. Pacritinib is an experimental drug that is being studied to treat acute myeloid leukemia (AML). Decitabine and cytarabine are both FDA approved drugs that are used in treatment of AML. Pacritinib is being tested in clinical trials and has not been submitted to the U.S. Food and Drug Administration (FDA) for approval for any indications. Pacritinib is a drug that is designed to slow down the growth of leukemic cells.

This is a single-center, open label, two-arm phase II study of clinical activity of pacritinib in older patients newly diagnosed with AML combined with either decitabine or cytarabine. In this study, approximately 61 patients will be enrolled at the Weill Cornell Medical College. Arm A consists of pacritinib and decitabine and will enroll 31 subjects, and Arm B consists of pacritinib and cytarabine and will enroll 30 subjects. Arm A and B will enroll sequentially. The dose of pacritinib will be 200mg twice a day continuously.

Arm A: Each cycle: Decitabine 20mg/m2 intravenous daily for 10 days combined with ongoing pacritinib 200 mg twice daily.

Arm B: Each cycle: Cytarabine 20mg subcutaneous twice daily for 10 days combined with ongoing pacritinib 200mg twice daily.

Treatment may be given on an outpatient basis if hospitalization is not otherwise required. Every effort should be made to give decitabine or cytarabine consecutively for 10 days; however if interruption is needed, discussion will be held with the medical monitor and the investigator.

The first day of a cycle will be defined as the day on which decitabine or cytarabine is started. First treatment will take place on Cycle 1, day 1. Hydroxyurea may be used at the investigator's discretion for the first 28 days on Cycle 1 to maintain white blood cell count (WBC) \<30,000/µl. Bone marrow biopsy and aspiration will be performed between days 22-56 of each cycle and the subsequent treatment cycle will be started between days 22-56, at the investigator's discretion. Ideally, cycles will be administered at 28-day intervals, but treatment delays of decitabine or cytarabine up to 56 days will be permitted to allow resolution of non-hematologic and non-disease-related hematologic toxicities. Granulocyte-stimulating cytokine support will be permitted at the investigator's discretion in the event of neutropenic fever/sepsis as per American Society of Clinical Oncology (ASCO) guidelines.16 Bone marrow aspiration and biopsy will be performed within 5 days of peripheral blood count recovery to an absolute neutrophil count (ANC) ≥ 1000/µL and platelets ≥ 100,000/µL without transfusions, or day 28 whichever comes first. If the peripheral blood absolute blast count is ≥ 5000/µL on day 21 of the first cycle, the second cycle may be administered immediately after bone marrow aspiration and biopsy.

Each arm will enroll in a Simon's two-stage design as described in Section 8. In Arm A, 16 subjects will initially be entered into the study, and if 6 or fewer respond, then Arm A will be terminated early and study will proceed to Arm B. In Arm B, 15 subjects will initially be entered into the study, and if 2 or fewer respond, the study will be terminated early.

Duration of study therapy Patients will receive a minimum of 4 cycles of treatment unless there is evidence of unacceptable regimen-related toxicity or unequivocal disease progression for which the investigator is specifically recommending alternative therapy. Pacritinib will continue throughout the study.

Arm A:

Patients who achieve Complete Remission (CR), Complete Remission with incomplete platelet recovery (CRp), or complete remission with incomplete blood count recovery (CRi) will receive subsequent cycles of decitabine on a monthly basis with decitabine 20mg/m2 IV daily for 5 days with pacritinib. Patients who do not achieve complete remission, but who are responding to treatment (partial response, hematologic response, or clinical benefit as determined by the investigator) will receive four 10-day cycles of decitabine with pacritinib as indicated in the study design, followed by monthly maintenance cycles of decitabine 20mg/m2 IV daily for 5 days + daily pacritinib. The maintenance cycles will continue indefinitely until relapse or toxicity. Patients may be taken off study for allogeneic stem cell transplantation at the discretion of the investigator.

Arm B:

Patients will continue cytarabine 20mg subcutaneous twice daily for 10 days combined with pacritinib for up to 4 cycles to achieve CR, CRp, or CRi. Those patients who achieve CR, CRp, or CRi after 4 cycles may continue to receive monthly maintenance of cytarabine 20mg subcutaneous twice daily for 10 days with pacritinib. The maintenance cycles will continue indefinitely until relapse or toxicity. Patients may be taken off study for allogeneic stem cell transplantation at the discretion of the investigator.

Screening (Study Day -14 to Day 1) Initiate and complete screening activities within 14 days before Cycle 1, Day 1 treatment.

Treatment (Cycle 1, Day 1 through End-of-Treatment Visit) This period begins on the day the patient first receives treatment and ends at the End-of-Treatment Visit.

Follow-up After completion of the End-of-Treatment Visit, all patients are followed up for 30 days and followed every three months for survival and disease status.

Clinical Study Endpoints The Primary objective of the study is to evaluate the safety and efficacy of pacritinib combined with decitabine or cytarabine in newly diagnosed older (≥65 years old) patients with AML. The primary endpoint of this study will be complete remission according to the International Working Group (IWG) criteria.

The following secondary endpoints will be evaluated:

* Overall Survival (OS)
* Overall remission (OS) rate, defined as CR + CRp + Cri + Partial Remission (PR) based on IWG response criteria
* Relapse-free Survival (RFS)
* Event-free Survival (EFS)
* Time to Complete Response (TTCR)
* Remission Duration

DISCUSSION OF STUDY DESIGN

Prognosis for older patients with AML is poor, with median survival of only 9-12 months. Older patients are often not candidates for intensive chemotherapy or allogeneic stem cell transplantation. Decitabine and low-dose cytarabine are frequently used for upfront treatment of older AML patients, however CR rates are 40-50% with decitabine and 18% with cytarabine. Pacritinib is a potent tyrosine kinase inhibitor of FLT3 and Janus Kinase 3 (JAK3) tyrosine kinases. The objective of the proposed clinical trial is to evaluate the efficacy, safety, and feasibility of pacritinib combined with decitabine or cytarabine in newly diagnosed older AML patients. The primary endpoint will be increase in complete remission.

Eligibility Criteria:
Inclusion Criteria:

1. Patient has unequivocal pathologic diagnosis of AML (≥ 20% blasts in the bone marrow based on World Health Organization (WHO) criteria), excluding acute promyelocytic leukemia t(15;17)(q22;q12); Promyelocytic leukemia gene (PML)- retinoic acid receptor alpha (RARA)
2. Age ≥ 65 years old
3. No prior treatment for AML except:

   * Emergency leukapheresis
   * Emergency treatment for hyperleukocytosis with hydroxyurea
   * Cranial radiotherapy (RT) for Central Nervous System (CNS) leukostasis (one dose only)
   * Growth factor/cytokine support
4. AML patients with therapy-related myeloid neoplasms are eligible if they have not received radiation therapy or chemotherapy (not including hormonal therapy) for their primary malignancy or disorder for ≥ 6 months. Hydroxyurea may be used at the investigator's discretion up to the first 28 days on Cycle 1 to maintain WBC \<30,000/µl.
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
6. Subjects must have adequate hepatic and renal function
7. Female subject of child-bearing potential and male subjects with female partners of reproductive potential must use acceptable contraceptive methods
8. Able to understand and to provide written informed consent
9. Able to comply with all study procedures during the study including all visits and tests
10. Willing to adhere to the prohibitions and restrictions specified in this protocol
11. Patient must sign an informed consent form (ICF)

Exclusion Criteria:

1. Prior treatment with decitabine
2. Prior treatment with cytarabine
3. Prior treatment with pacritinib
4. Presence of serious illness, medical condition, or other medical history, involving the heart, kidney, liver, or other organ system, including abnormal laboratory parameters, which, in the opinion of the Investigator, would be likely to interfere with a subject's participation in the study or with the interpretation of the results.
5. Active, uncontrolled, clinically significant infection(s)
6. Have other active malignancies (excluding other myeloid hematologic malignancies) or other malignancies within 12 months before enrollment, except curatively treated non-melanoma skin cancer, cervical intraepithelial neoplasia, organ-confined or treated non-metastatic prostate cancer with negative prostate-specific antigen, in situ breast carcinoma after complete surgical resection, or superficial transitional cell bladder carcinoma
7. Are receiving any other investigational therapy or protocol-prohibited therapy
8. Any prior or co-existing medical condition that in the Investigator's judgment will substantially increase the risk associated with the subject's participation in the study
9. Psychiatric disorders or altered mental status precluding understanding of the informed consent process and/or completion of the necessary study procedures
10. Any gastrointestinal (GI) or metabolic condition that could interfere with absorption of oral medication
11. Inflammatory or chronic functional bowel disorder, such as Crohn's disease, inflammatory bowel disease, chronic diarrhea
12. Clinically symptomatic and uncontrolled cardiovascular disease
13. History of any of the following within 6 months: myocardial infarction, severe/unstable angina, or symptomatic congestive heart failure
14. New York Heart Association Class III or IV congestive heart failure
15. Patients with National Cancer Institute (NCI) Common Terminology for Adverse Events (CTCAE) grade 2 cardiac arrhythmias may be considered for inclusion with the approval of the investigator if the arrhythmias are stable, asymptomatic and unlikely to affect patient safety. Patients will be excluded if they have ongoing cardiac dysrhythmias of CTCAE grade 3, corrected QT interval (QTc) prolongation \>450 ms by Fridericia method, or other factors that increase the risk for QT prolongation (eg, heart failure, hypokalemia \[defined as serum potassium \< 3.0 milliequivalent (mEq/L) that is persistent and refractory to correction\], or family history of long QT interval syndrome).