Clinical Trials

The James Cancer Center Columbus, OH

open for enrollment

Pacritinib and Chemotherapy in Treating Patients with Acute Myeloid Leukemia and FLT3 Mutations

Protocol: OSU-14169

Full Title

Phase I Study of Pacritinib and Chemotherapy in Patients with Acute Myeloid Leukemia and FLT3 mutations

Purpose

This phase I trial studies the side effects and best dose of pacritinib when given together with chemotherapy in treating patients with acute myeloid leukemia that have an abnormal change (mutation) in the fms-related tyrosine kinase 3 (FLT3) gene. Pacritinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as cytarabine, daunorubicin hydrochloride, and decitabine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving pacritinib and chemotherapy may be a better treatment for acute myeloid leukemia with FLT3 mutations.

Study Objective

PRIMARY OBJECTIVES:

I. To evaluate the safety and tolerability of pacritinib in combination with 7+3 or decitabine (respective cohorts are independent of each other) in patients with newly diagnosed or relapsed/refractory acute myeloid leukemia (AML) with FLT3 mutations.

II. To define the specific toxicities, maximum tolerated dose (MTD) and the dose limiting toxicities (DLT) of these combinations.

III. To determine the recommended phase 2 dose (RP2D) of these combinations.

SECONDARY OBJECTIVES:

I. To determine the rate and duration of complete remission (CR) +/- hematologic recovery of pacritinib and 7+3 or decitabine in AML.

II. To determine the overall response rate (ORR) and disease free survival at 1 year.

TERTIARY OBJECTIVES:

I. To conduct pharmacokinetic studies of pacritinib in combination with chemotherapy.

II. To determine the impact of pacritinib on the inhibition of Janus kinase 2 (JAK2), FLT3, AXL receptor tyrosine kinase (AXL), signal transducer and activator of transcription 5A (STAT5), spleen tyrosine kinase (Syk).

III. To examine the exosome, cytokine, and chemokine changes of FLT3 down-stream inhibition by pacritinib.

IV. To examine resistance patterns associated with treatment with pacritinib.

V. To examine baseline cytogenetic, GTP binding protein overexpressed in skeletal muscle (GEM) signature, and long non-coding (Lnc) ribonucleic acid (RNA) signature and mutational status of the AML tumor cells to better identify subsets of patients with highest likelihood of responding to therapy.

OUTLINE: This is a dose-escalation study of pacritinib. Patients are assigned to 1 of 2 treatment arms.

COHORT A:

INDUCTION: Patients receive pacritinib orally (PO) on days 1-21, cytarabine intravenously (IV) every 24 hours on days 5-11, and daunorubicin hydrochloride IV every 24 hours on days 5-7. Treatment repeats every 28 days for 1-2 courses in the absence of disease progression or unacceptable toxicity.

COHORT B:

INDUCTION: Patients receive pacritinib PO on days 1-21 and decitabine IV every 24 hours on days 5-14. Treatment repeats every 28 days for 2-4 courses in the absence of disease progression or unacceptable toxicity.

MAINTENANCE: Patients achieving CR will proceed with transplant evaluation (if appropriate). Transplant-ineligible patients will receive maintenance courses of pacritinib PO on days 1-21 and decitabine IV over 1 hour daily on days 1-5. Maintenance courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for at least 30 days.

Are you eligible?

Inclusion Criteria:

Patients with AML and the presence of FLT3 mutation

Patients with secondary AML or therapy related disease (t-AML) are eligible

If the patient has co-morbid medical illness, life expectancy attributed to this must be greater than 6 months

Eastern Cooperative Oncology Group (ECOG) performance status =< 2

Total bilirubin < 2.0mg/dL unless due to Gilbert’s disease

Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) < 2.5 X institutional upper limit of normal

Creatinine (Cr) clearance > 50 mL/min by Cockcroft-Gault calculation

New York Heart Association (NYHA) congestive heart failure (CHF) class II or better

Cardiac ejection fraction (left ventricular ejection fraction [LVEF]) >= 50%

Female patients of child-bearing potential must agree to use dual methods of contraception and have a negative serum pregnancy test at screening, and male patients must use an effective barrier method of contraception if sexually active with a female of child-bearing potential; acceptable methods of contraception are condoms with contraceptive foam, oral, implantable or injectable contraceptives, contraceptive patch, intrauterine device, diaphragm with spermicidal gel, or a sexual partner who is surgically sterilized or post-menopausal; for both male and female patients, effective methods of contraception must be used throughout the study and for three months following the last dose

Ability to understand and willingness to sign the written informed consent document

Exclusion Criteria:

Patients with core-binding factor AML (inv[16], t[8;21]) or t(15;17)

Patients who have had chemotherapy or radiotherapy within 2 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study; treatment with hydroxyurea is permitted during cycle 1 to maintain white blood cell (WBC) < 40,000/uL

Patients receiving any other investigational agents or patients that have received other investigational agents within 14 days of enrollment

Patients with active central nervous system (CNS) malignancy

Major surgery within 2 weeks before day 1

Uncontrolled active infection; patients with infection requiring parenteral antibiotics are eligible if the infection is controlled

Patients with significantly diseased or obstructed gastrointestinal tract

Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure (New York Heart Association [NYHA] class III or IV), unstable angina pectoris, myocardial infarction within 6 months prior to enrollment, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities; prior to study entry, any electrocardiogram (ECG) abnormality at screening has to be documented by the investigator as not medically relevant

Patients with serious medical or psychiatric illness likely to interfere with participation in this clinical study

Pregnant women or women who are breastfeeding are excluded from this study; confirmation that the subject is not pregnant must be established by a negative serum beta-human chorionic gonadotropin (beta-hCG) pregnancy test result obtained during screening; pregnancy testing is not required for post-menopausal or surgically sterilized women

Patients with advanced malignant solid tumors

Patients who are not able to swallow capsules or tablets

Patients with baseline corrected QT (QTc) > 450 ms or patients who are taking medications that prolong the QTc interval

Known active human immunodeficiency virus (HIV) or hepatitis A, B, or C virus infection

Less than 1 week since prior treatment (most recent dose) with a potent cytochrome P450 family 3, subtype A, polypeptide 4 (3A4) (CYP3A4) inhibitor

Concomitant use of potent P450 3A4 (CYP3A4) inducers

Patients with a history of platelet alloimmunization

Acute Myeloid Leukemia Leukemia