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

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ClinicalTrials.gov Identifier: NCT02323607
Recruitment Status : Completed
First Posted : December 23, 2014
Last Update Posted : January 25, 2019
Sponsor:
Collaborator:
CTI BioPharma
Information provided by (Responsible Party):
Bhavana Bhatnagar, Ohio State University Comprehensive Cancer Center

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Recurrent Adult Acute Myeloid Leukemia Secondary Acute Myeloid Leukemia Therapy-Related Acute Myeloid Leukemia Untreated Adult Acute Myeloid Leukemia Drug: Pacritinib Drug: Cytarabine Drug: Daunorubicin Hydrochloride Drug: Decitabine Other: Laboratory Biomarker Analysis Other: Pharmacological Study Phase 1

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 13 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I Study of Pacritinib and Chemotherapy in Patients With Acute Myeloid Leukemia and FLT3 Mutations
Actual Study Start Date : January 12, 2016
Actual Primary Completion Date : July 12, 2018
Actual Study Completion Date : July 12, 2018


Arm Intervention/treatment
Experimental: Cohort A (pacritinib, cytarabine, daunorubicin hydrochloride)
INDUCTION: Patients receive pacritinib PO on days 1-21, cytarabine 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.
Drug: Pacritinib
Given PO
Other Names:
  • Oral JAK2 Inhibitor SB1518
  • SB1518

Drug: Cytarabine
Given IV
Other Names:
  • CHX-3311
  • U-19920

Drug: Daunorubicin Hydrochloride
Given IV
Other Names:
  • DNM
  • DNR
  • DRB

Other: Laboratory Biomarker Analysis
Correlative studies

Other: Pharmacological Study
Correlative studies
Other Name: pharmacological studies

Experimental: Cohort B (pacritinib, decitabine)

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.

Drug: Pacritinib
Given PO
Other Names:
  • Oral JAK2 Inhibitor SB1518
  • SB1518

Drug: Decitabine
Given IV
Other Names:
  • 5AZA
  • DAC

Other: Laboratory Biomarker Analysis
Correlative studies

Other: Pharmacological Study
Correlative studies
Other Name: pharmacological studies




Primary Outcome Measures :
  1. MTD of pacritinib defined as the highest safely tolerated dose where, at most, one patient experiences DLT in 6 evaluable patients, with the next higher dose having at least 2 patients who experience DLT [ Time Frame: 28 days ]
    Assessed using National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03. Toxicities will be tabulated by type and grade and displayed in summary form. Further, all adverse event data that are graded as 3, 4, or 5 and classified as either unrelated or unlikely to be related to study treatment will be reviewed for completeness.


Secondary Outcome Measures :
  1. Clinical response according to International Working Group criteria [ Time Frame: Up to at least 30 days post-treatment ]
    The degree of response will be summarized within each stratum and at each dose level. ORR will also be presented for those patients treated at the MTD with an exact 95% confidence interval.

  2. Duration of response [ Time Frame: Up to at least 30 days post-treatment ]
    For patients who achieve complete remission, duration of response will be reported.


Other Outcome Measures:
  1. Change in FLT3 and JAK2 expression [ Time Frame: Baseline to up to at least 30 days post-treatment ]
    Expression prior to administration of pacritinib and following treatment with pacritinib will be described graphically using boxplots or summary measures (e.g. mean and standard errors). Trends of dose response will be explored within each stratum, as well as whether targets are being "hit" between the strata. Due to data limitations in early clinical trials, analyses will be descriptive in nature.

  2. Change in various genes/microRNA [ Time Frame: Baseline to up to at least 30 days post-treatment ]
    Expression prior to administration of pacritinib and following treatment with pacritinib will be described graphically using boxplots or summary measures (e.g. mean and standard errors). Trends of dose response will be explored within each stratum, as well as whether targets are being "hit" between the strata. Due to data limitations in early clinical trials, analyses will be descriptive in nature.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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 >= 50% for Arm A, >= 40% for Arm B
  • 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
  • Human immunodeficiency virus (HIV) infection without history of acquired immune deficiency syndrome (AIDS) and sufficiently high cluster of differentiation (CD)4 cells (> 400/mm^3) and low HIV viral loads (< 30,000 copies/ml plasma) not requiring anti-HIV therapy are eligible

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) > 500 ms

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02323607


Locations
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United States, Ohio
Arthur G. James Cancer Hospital and Solove Research Institute at Ohio State University Medical Center
Columbus, Ohio, United States, 43210
Sponsors and Collaborators
Bhavana Bhatnagar
CTI BioPharma
Investigators
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Principal Investigator: Bhavana Bhatnagar, DO Arthur G. James Cancer Hospital and Solove Research Institute at Wexner Medical Center

Additional Information:
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Responsible Party: Bhavana Bhatnagar, Principal Investigator, Ohio State University Comprehensive Cancer Center
ClinicalTrials.gov Identifier: NCT02323607     History of Changes
Other Study ID Numbers: OSU-14169
NCI-2014-02436 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
First Posted: December 23, 2014    Key Record Dates
Last Update Posted: January 25, 2019
Last Verified: January 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Cytarabine
Daunorubicin
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Neoplasms
Decitabine
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Enzyme Inhibitors
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors