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Phase I Dose-Finding Study of Eltrombopag Following High Dose Cytarabine and Mitoxantrone in Relapsed/Refractory Patients With Acute Myeloid Leukemia


Phase 1
18 Years
N/A
Open (Enrolling)
Both
Adult Acute Basophilic Leukemia, Adult Acute Eosinophilic Leukemia, Adult Acute Megakaryoblastic Leukemia (M7), Adult Acute Minimally Differentiated Myeloid Leukemia (M0), Adult Acute Monoblastic Leukemia (M5a), Adult Acute Monocytic Leukemia (M5b), Adult Acute Myeloblastic Leukemia With Maturation (M2), Adult Acute Myeloblastic Leukemia Without Maturation (M1), Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities, Adult Acute Myeloid Leukemia With Del(5q), Adult Acute Myeloid Leukemia With Inv(16)(p13;q22), Adult Acute Myeloid Leukemia With t(16;16)(p13;q22), Adult Acute Myeloid Leukemia With t(8;21)(q22;q22), Adult Acute Myelomonocytic Leukemia (M4), Adult Erythroleukemia (M6a), Adult Pure Erythroid Leukemia (M6b), Recurrent Adult Acute Myeloid Leukemia

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Trial Information

Phase I Dose-Finding Study of Eltrombopag Following High Dose Cytarabine and Mitoxantrone in Relapsed/Refractory Patients With Acute Myeloid Leukemia


PRIMARY OBJECTIVES:

I. To estimate the maximum tolerated dose (MTD) and examine the tolerability of daily oral
eltrombopag (eltrombopag olamine) (14 days +/- 2 days after initiation of cytarabine) in
patients receiving high dose cytarabine and mitoxantrone for the treatment of acute myeloid
leukemia patients with hypoplastic bone marrow 14 days +/- 2 days from initiation of
cytarabine.

II. To examine platelet count recovery to >= 100 x 10^9/L when eltrombopag is administered
following high dose cytarabine and mitoxantrone for the treatment of acute myeloid leukemic
patients.

OUTLINE: This is a dose-escalation study.

Patients receive eltrombopag olamine orally (PO) once daily (QD) from day 1 up to day 62.
Treatment continues for up to 9 weeks in the absence of disease progression or unacceptable
toxicity.

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


Inclusion Criteria:



- Relapsed/refractory AML patients who received standard of care cytarabine and
mitoxantrone as their chemotherapy regimen

- Patients must either have Grade 4 thrombocytopenia (platelet counts < 25 x 10^9/L)
due to chemotherapy unless transfusion within 24-72 hours

- Current systemic treatment for AML, with the exception of granulocyte
colony-stimulating factor (G-CSF) must have been discontinued at least 7 days prior
to entry into the study; in addition:

- At least 4 weeks before Day 1 for interleukin (IL)-11 (oprelvekin)

- At least 8 weeks before Day 1 for antithymocyte/antilymphocyte globulin

- Patients with a prior stem cell transplant (SCT) must have failed the SCT

- Patients must have documented hypoplasia from the bone marrow aspiration and biopsy
14 days +/- 2 days from the initiation of cytarabine treatment schedule (defined as <
5% blasts and < 20% cellularity)

- Have an Eastern Cooperative Oncology Group (ECOG) Performance Status of =< 2

- Patient is able to understand and comply with protocol requirements and instructions

- Total bilirubin =< 1.5 x upper limit of normal (ULN) except for Gilbert syndrome or
cases clearly not indicative of inadequate organ function, i.e., elevation of
indirect (hemolytic) bilirubin in the absence of alanine aminotransferase (ALT)
and/or aspartate aminotransferase (AST) abnormality

- ALT and AST =< 3 x ULN

- Creatinine =< 1.5 x ULN

- Patient is practicing an acceptable method of contraception (documented in chart);
female patients (or female partners of male patients) must either be non-childbearing
potential (hysterectomy, bilateral oophorectomy, bilateral tubal ligation or
post-menopausal > 1 year), or of childbearing potential and use 1 of the following
highly effective methods of contraception (i.e., Pearl Index < 1.0%) from 2 weeks
prior to administration of study medication, throughout the study, and 28 days after
completion or premature discontinuation from the study:

- Complete abstinence from intercourse

- Intrauterine device (IUD)

- Two forms of barrier contraception (diaphragm plus spermicide, and for males
condom plus spermicide)

- Male partner is sterile prior to entry into the study and is the only partner of
the female

- Systemic contraceptives (combined or progesterone only)

- Demonstrate the ability to swallow and retain oral medication

- Patient or legal representative must understand the investigational nature of this
study and sign an Independent Ethics Committee/Institutional Review Board approved
written informed consent form prior to receiving any study related procedure

Exclusion Criteria:

- Patients with a diagnosis of acute promyelocytic leukemia

- Patients with a QTcF > 450 msec (QTcF > 480 msec for patients with Bundle Branch
Block)

- AML patients with persistent disease from the recent treatment defined as > 5% blast
and/or > 20% cellularity and reported as persistent residual disease by a
pathological report of the patient's bone marrow biopsy 14 days +/- 2 days from the
initiation of cytarabine

- Patients with known thrombophilic risk factors; exception: patients for whom the
potential benefits of participating in the study outweigh the potential risks of
thromboembolic events, as determined by the investigator

- Current alcohol or drug abuse

- Treatment with an investigational drug within 30 days or 5 half-lives (whichever is
longer) preceding the first dose of study medication

- Active and uncontrolled infections

- Patients with known active hepatitis B, hepatitis C, or seropositive human
immunodeficiency virus (HIV); testing is not required in the absence of clinical
suspicion

- Patients with liver cirrhosis (as determined by the investigator)

- Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
chemically related to eltrombopag or excipient that contraindicates the patients'
participation

- Patients of East Asian ancestry (i.e., Chinese, Japanese, Taiwanese, or Korean)

- Patients with pre-existing cardiovascular disease (including congestive heart
failure, New York Heart Association [NYHA] Grade III-IV), or arrhythmia known to
increase the risk or thromboembolic events (e.g., atrial fibrillation)

- Unwilling or unable to follow protocol requirements

- Any condition which, in the Investigator's opinion, deems the patient an unsuitable
candidate to receive study drug

- No aspirin (ASA) or nonsteroidal antiinflammatory drugs (NSAIDS) administration

Type of Study:

Interventional

Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

MTD and tolerability of eltrombopag olamine in patients with AML, determined according to incidence of dose-limiting toxicity (DLT) graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4

Outcome Time Frame:

Up to day 15

Safety Issue:

Yes

Principal Investigator

Wetzler Meir

Investigator Role:

Principal Investigator

Investigator Affiliation:

Roswell Park Cancer Institute

Authority:

United States: Food and Drug Administration

Study ID:

I 206111

NCT ID:

NCT01550185

Start Date:

May 2012

Completion Date:

Related Keywords:

  • Adult Acute Basophilic Leukemia
  • Adult Acute Eosinophilic Leukemia
  • Adult Acute Megakaryoblastic Leukemia (M7)
  • Adult Acute Minimally Differentiated Myeloid Leukemia (M0)
  • Adult Acute Monoblastic Leukemia (M5a)
  • Adult Acute Monocytic Leukemia (M5b)
  • Adult Acute Myeloblastic Leukemia With Maturation (M2)
  • Adult Acute Myeloblastic Leukemia Without Maturation (M1)
  • Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities
  • Adult Acute Myeloid Leukemia With Del(5q)
  • Adult Acute Myeloid Leukemia With Inv(16)(p13;q22)
  • Adult Acute Myeloid Leukemia With t(16;16)(p13;q22)
  • Adult Acute Myeloid Leukemia With t(8;21)(q22;q22)
  • Adult Acute Myelomonocytic Leukemia (M4)
  • Adult Erythroleukemia (M6a)
  • Adult Pure Erythroid Leukemia (M6b)
  • Recurrent Adult Acute Myeloid Leukemia
  • Congenital Abnormalities
  • Leukemia
  • Leukemia, Basophilic, Acute
  • Leukemia, Eosinophilic, Acute
  • Leukemia, Erythroblastic, Acute
  • Leukemia, Megakaryoblastic, Acute
  • Leukemia, Monocytic, Acute
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid
  • Leukemia, Myelomonocytic, Acute
  • Leukemia, Myelomonocytic, Chronic
  • Hypereosinophilic Syndrome

Name

Location

Roswell Park Cancer InstituteBuffalo, New York  14263