A Phase Ia/Ib, Open-Label, Multicentre, Two-Part Study to Assess the Safety, Tolerability, Pharmacokinetics and Efficacy of AZD1208 Administered Daily in Adult Patients with Recurrent or Refractory Acute Myelogenous Leukemia (AML)
The goal of Part 1 of this clinical research study is to find the highest tolerable dose of AZD1208 that can be given to patients with AML. The goal of Part 2 of this study is to learn if AZD1208 can control AML. The safety of this drug will also be studied in both parts. AZD1208 is designed to stop the growth of abnormal white blood cells. This may help to control AML. This is the first study using AZD1208 in humans.
Disease Group: Leukemia
Treatment Agent: AZD1208
Treatment Location: Both at MD Anderson & Other Sites
Sponsor: AstraZeneca Pharmaceuticals LP
Primary Objective Part A • To identify a maximum tolerated dose (MTD) of AZD1208 on a daily schedule by assessment of incidence of dose limiting toxicities (DLTs) Part B • To assess the effect of AZD1208 on the rate of CR including CRi in FLT3 mutation positive and FLT3 wild-type (FLT3 mutation negative) patients with relapsed or refractory acute myelogenous leukemia (AML), with CR and CRi defined by bone marrow and blood myeloblast counts and recovery of normal hematopoiesis Secondary Objective(s) Part A • To evaluate the safety and tolerability of AZD1208 on a daily schedule by assessment of CTCAE grade and type of an AE, and changes in laboratory values and vital signs • To characterize the pharmacokinetics of AZD1208 in patients for a daily schedule • To seek preliminary evidence of the anti-leukemic activity of AZD1208 via the effect on rate of CR, CRi, PR, and overall response (MLF, CR, CRi, PR). Part B • To evaluate the safety and tolerability of AZD1208 on a daily schedule by assessment of CTCAE grade and type of an AE, and changes in laboratory values and vital signs • To characterize the pharmacokinetics of AZD1208 in patients for a daily schedule • To assess the effect of AZD1208 on rate of CR, CRi, PR, and overall response (MLF, CR, CRi, PR). • To assess the effect of AZD1208 on duration of CR or CRi based on time from first documentation of CR to relapse, as defined by reappearance of leukemic blasts in blood or bone marrow, the reappearance of new dysplastic changes, or the reappearance or development of extramedullary leukemia Exploratory Objective(s) Part A & B • To evaluate the extent of pharmacodynamic biomarker (such as pBAD, p-p70S6K, and p-4EBP1) inhibition in bone marrow and peripheral blasts following treatment with AZD1208 • To investigate the PK-PD relationship between AZD1208 exposure and pharmacodynamic biomarker inhibition over dose and time in both peripheral blood and bone marrow • To investigate possible relationships between PIM1 and other gene expression signatures and clinical response • To seek evidence of a relationship between the presence of FLT3, NPM1 and other mutations, FLT3 ligand levels, cytokine levels, cytogenetics, and clinical response • To collect and store deoxyribonucleic acid (DNA) for futer exploratory research into genes/genetic variation that may influence response (eg,pharmacokinetics, safety, tolerability, and efficacy) to AZD1208 treatment (Optional) • To store and/or analyze surplus blood or tissue including bone marrow, if available, for potential future exploratory research into factors that may influence development of AML and/or response to AZD1208 (where response is defined broadly to include efficacy, tolerability or safety)
IRB Review and Approval Date: 01/12/2012
Recruitment Status: Not Accepting
Projected Accrual: 52
1) Provision of signed and dated, written informed consent prior to any
study specific procedures, sampling and analyses
2) Aged at least 18 years
3) Patients with relapsed or refractory AML [including AML secondary to myelodysplastic syndromes (MDS), myeloproliferative neoplasm (MPN), or CML (chronic myelogenous leukemia)].
4) Eastern Cooperative Oncology Group (ECOG) performance status 0-2 and considered likely to complete at least 4 weeks of therapy
5) The interval from prior treatment to time of screening PD bone marrow and subsequent study drug administration should be at least 2 weeks for cytotoxic agents, or at least 5 half-lives for non-cytotoxic agents. If a patient is receiving high dose cytarabine, liposomal cytarabine, or standard-dose cytarabine (100-200 mg/m(2)/day), the patient must be off the drug for at least 2 weeks. However, if the patient is receiving low-dose cytarabine (10-30 mg/m(2)/day), considering the dose is low and the short half-life, the patient can initiate the study treatment after at least 48 hours off from cytarabine.
6) If the patient is receiving hydroxyurea to control peripheral blood leukemia cell counts, the patient must be off hydroxyurea for at least 48 hours prior to obtaining PD biomarker samples (screening, C1D1, C1D14) and on the day of sample collection itself (bone marrow aspirate and blood).
7) Patients with active central nervous system (CNS) disease are eligible to participate and may be treated concurrently with intrathecal (or intra-Ommaya) chemotherapy
8) Females should be using adequate contraceptive measures, should not be breast feeding and must have a negative pregnancy test prior to start of dosing if of child-bearing potential or must have evidence of non-child-bearing potential by fulfilling one of the following criteria at screening: Post-menopausal defined as aged more than 50 years and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments; documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation. Acceptable forms of birth control include intrauterine devices (IUD) and hormonal methods (such as birth control pills) during this study. Hormonal birth control should be combined with barrier method of birth control (such as condoms or diaphrams).
9) Male patients should be willing to use barrier contraception (ie, condoms)
10) Ability to swallow and retain oral medication
1) Treatment with any of the following: Any investigational agents or
study drugs from a previous clinical study less than the longer of 1
week or 5 half lives before the first dose of study treatment; Prior
exposure to AZD1208; Major surgery (excluding placement of vascular
access) within 4 weeks of the first dose of study treatment;
Radiotherapy with a wide field of radiation within 4 weeks or
radiotherapy with a limited field of radiation for palliation within 2
weeks of the first dose of study treatment; Patients who received CNS
irradiation for meningeal leukemia, except if radiotherapy occurred >
3 months previously
2) With the exception of alopecia, any unresolved toxicities from prior therapy greater than Common Terminology Criteria for Adverse Events (CTCAE) grade 1 at the time of starting study treatment
3) As judged by the investigator, any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension, active bleeding diatheses, or active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV). Screening for chronic conditions is not required
4) Any of the following cardiac criteria: Mean resting corrected QT interval (QTc) >/= 470msec (using Fridericia's correction) obtained from 3 digital electrocardiograms (dECGs); Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG eg, complete left bundle branch block, third degree heart block; Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age or any concomitant medication known to prolong the QT interval
5) Active heart disease including myocardial infarction within the last 3 months, symptomatic coronary artery disease, clinically significant arrhythmias not controlled by medication or uncontrolled congestive heart failure
6) Inadequate organ function as demonstrated by any of the following laboratory values: Alanine aminotransferase > 2.5 times the upper limit of normal (ULN) if no demonstrable leukemic organ involvement or > 5 times ULN in the presence of leukemic organ involvement; Aspartate aminotransferase > 2.5 times ULN if no demonstrable leukemic organ involvement or > 5 times ULN in the presence of leukemic organ involvement; Total bilirubin > 1.5 times ULN if no leukemic organ involvement or > 3 times ULN in the presence of leukemic organ involvement; Creatinine >1.5 times ULN concurrent with creatinine clearance < 50 ml/min (measured or calculated by Cockcroft and Gault equation) (confirmation of creatinine clearance is only required when creatinine is > 1.5 times ULN)
7) White blood cell count >/= 100,000/mm(3) [100x10(9)/L] in screening. Patients with WBC>/= 100,000/mm(3) [100 x 10(9)/L] on Cycle 1, Day 1 of dosing due to cessation of hydroxyurea remain eligible unless symptoms of leukostasis are present.
8) Uric acid > ULN to 10 mg/dL (594.8 umol/L), with physiologic consequences (grade 3), or > 10 mg/dL (594.8 umol/L) (grade 4). [Patients with uric acid >ULN to 10 mg/dl (594.8 umol/L) without physiological consequences are eligible but should receive treatment with allopurinol].
9) Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of AZD1208
10) History of hypersensitivity to active or inactive excipients of AZD1208
11) Prior allogeneic transplant requiring immunosuppressive therapy (Patients with prior allogeneic transplants who remain clinically stable for >/= 2 weeks or more off immunosuppressive therapy, are eligible)
12) Clinically significant uncontrolled active fungal, bacterial or viral infection
13) Pregnancy or breast-feeding. Women of childbearing potential must have a negative pregnancy test prior to starting first dose of study treatment.
14) Involvement in the planning and conduct of the study (applies to both AstraZeneca staff or staff at the study site)
15) Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements
16) Type 1 Diabetes or uncontrolled Type II Diabetes
17) HbA1C >/= 8% or fasting blood glucose >/= 160 mg/dL (>/= 8.9 mmol/L)
18) Baseline fasting total cholesterol > 300 mg/dL (> 7.75 mmol/L)
19) Prior treatment with mitomycin C within 6 weeks of starting AZD1208.
20) Any prior treatment with nitrosurea (BCNU), busulfan or bleomycin.
21) For monoclonal antibodies, 4 weeks must have elapsed from treatment to the first dose of investigational product. All toxicity from prior therapy should be resolved to Grade 1 or less.
22) Previous radiation therapy to chest wall with pulmonary tissue exposure.
23) Evidence of established Interstitial Lung Disease (ILD) on baseline high resolution computerized tomography (HRCT).
24) Patients requiring oxygen supplementation.
25) Persistent asthma - patients receiving no more than "rescue" short acting bronchodilators and/or inhaled low dose corticosteroids are permitted to enter the trial as long as the symptoms are intermittent, defined as occurring less than once per week with only brief exacerbations and with nocturnal symptoms occurring not more than twice per month.
26) History of pulmonary fibrosis either idiopathic or due to occupational/environmental exposure, drugs/radiation, vasculitides, collagen vascular disorders, sarcoidosis, hypersensitivity pneumonitis or immunosuppression/transplantation.
27) Chest infection requiring antibiotics within the 7 days prior to the first dose of investigational product.
28) History of or currently present interstitial lung disease, or radiation pneumonitis.
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