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Adult Acute Minimally Differentiated Myeloid Leukemia (M0)Phase 1NCT02049801

MEK Inhibitor MEK162, Idarubicin, and Cytarabine in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia

A Phase 1 study testing MEK inhibitor MEK162, idarubicin and cytarabine in people with Adult Acute Minimally Differentiated Myeloid Leukemia (M0) and Adult Acute Monoblastic Leukemia (M5a), run by Bruno C. Medeiros at 1 site in United States.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial summary

This phase I trial studies the MEK inhibitor MEK162 to see if it is safe in patients when combined with idarubicin and cytarabine. MEK inhibitor MEK162 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Read more about this study

Who is it for?
Ages 18 to 75 years
What is being tested?
MEK inhibitor MEK162, idarubicin and cytarabine
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
1 participants
Where
1 siteUnited States
Study dates
Dec 2014to 1 Nov 2017
Phase
Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 75 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Prior morphological diagnosis of AML other than acute promyelocytic leukemia according to the 2001 World Health Organization (WHO) diagnostic criteria; patients with biphenotypic, RAS-mutated acute leukemia are also eligible
  • Requiring salvage chemotherapy for persistent/refractory or relapsed disease after at least one course of conventional chemotherapy, e.g. with "7+3", as defined by persistence of >= 20% myeloid blasts on bone marrow aspirate or peripheral blood smear; a bone marrow biopsy is not routinely required, but should be obtained if the aspirate is dilute, hypocellular, or inaspirable; outside bone marrow examinations performed within the stipulated time period are acceptable for screening as long as the slides are reviewed at the study institution; flow cytometric analysis of the bone marrow aspirate should be performed according to institutional practice guidelines
  • Confirmed RAS mutation (NRAS or KRAS) or confirmed PTPN11 mutation, measured on peripheral blood or bone marrow aspirate as part of screening prior to study enrollment; mutation status must be confirmed within 45 days of initiation of therapy
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 1
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 times upper limit of normal (ULN)
  • Serum bilirubin =< 2 times ULN
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  • Serum creatinine =< 1.5 mg/dl and/or creatinine clearance >= 50 mL/min
  • Ejection fraction >= 50% by echocardiogram
  • Corrected QT (QTc) interval =< 480 ms
  • Ability to take oral medications
  • Ability to understand and the willingness to sign a written informed consent document
  • Ability to undergo standard induction chemotherapy
  • Ability to adhere to the study visit schedule and other protocol requirements
  • Life expectancy of greater than 2 months
  • Negative serum beta-human chorionic gonadotropin (HCG) test (female patient of childbearing potential only) performed locally within 72 hrs prior to first dose

Who cannot join

  • Concomitant treatment with other anti-neoplastic agents, with the exception of hydroxyurea
  • Anti-neoplastic treatment less than 14 days prior to enrollment, with the exceptions of hydroxyurea or, in the case of a patient with primary refractory AML, prior induction chemotherapy
  • Prior therapy with a MEK inhibitor
  • Uncontrolled opportunistic infection or treatment for opportunistic infection within 4 weeks of first day of study drug dosing
  • Other medical or psychiatric illness or organ dysfunction or laboratory abnormality which in the opinion of the investigator would compromise the patient's safety or interfere with data interpretation, e.g., infection/inflammation, intestinal obstruction, unable to swallow medication, social/ psychological issues, etc.
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to MEK162, anthracycline, or cytarabine
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  • Known impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of MEK162 (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection)
  • Previous or concurrent malignancy with the following exceptions:
  • Carcinoma in situ
  • Adequately treated skin basal cell or squamous cell carcinoma (adequate wound healing is required prior to study entry)
  • In situ carcinoma of the cervix, treated curatively and without evidence of recurrence for at least 3 years prior to the study
  • A primary malignancy which has been completely resected and in complete remission for >= 5 years
  • Impaired cardiovascular function or clinically significant cardiovascular diseases, including any of the following:
  • History of acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass grafting [CABG], coronary angioplasty, or stenting) < 6 months prior to screening
  • Symptomatic chronic heart failure
  • Evidence of clinically significant cardiac arrhythmias and/or conduction abnormalities < 6 months prior to screening except atrial fibrillation and paroxysmal supraventricular tachycardia
  • Uncontrolled arterial hypertension despite appropriate medical therapy
  • Patients who have neuromuscular disorders that are associated with elevated creatine kinase (CK) (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy)
  • Known confirmed diagnosis of human immunodeficiency virus (HIV) infection or active viral hepatitis (hepatitis B or hepatitis C)
  • Any surgical procedure, excluding central venous catheter placement, bone marrow biopsy, lumbar puncture, or other minor procedures (e.g., skin biopsy) within 14 days of day 1; patients who have undergone major surgery =< 21 days prior to starting study drug or who have not recovered from side effects of such procedure are ineligible for the study
  • Pregnant or nursing (lactating) women confirmed by a positive hCG laboratory test
  • Women of child-bearing potential unless they are using highly effective methods of contraception throughout the study and for 30 days after study drug discontinuation
  • Sexually active males unless they use a condom during intercourse while taking the drug and for 30 days after stopping treatment and should not father a child in this period; a condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid
  • Unwillingness or inability to comply with the protocol
  • Known active leukemia of the central nervous system
  • Known history of Gilbert's syndrome
  • History or current evidence of retinal pigment epithelial detachment (RPED), retinal vein occlusion (RVO), or predisposing factors to RPED or RVO (e.g. uncontrolled glaucoma or ocular hypertension, uncontrolled diabetes mellitus, hyperviscosity or hypercoagulability syndromes)
  • History of retinal degenerative disease

Trial locations and contacts

1 site in 1 country.

United States1 site
  • Stanford University, School of Medicine

    Stanford, California, 94305

Other trials in United States

About this study

Official title: A Phase I Study of MEK Inhibitor MEK162 Combined With Idarubicin and Cytarabine Induction in Patients With Relapsed/Refractory RAS-Mutated Acute Myeloid Leukemia

This phase I trial studies the MEK inhibitor MEK162 to see if it is safe in patients when combined with idarubicin and cytarabine. MEK inhibitor MEK162 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as idarubicin and cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving MEK inhibitor MEK162, cytarabine, and idarubicin may be an effective treatment for acute myeloid leukemia.

Read the detailed description

PRIMARY OBJECTIVES:

  1. Determine maximum tolerated dose (MTD) of MEK162 (MEK inhibitor MEK162) in patients with RAS-mutated acute myeloid leukemia (AML) when combined with sequential induction chemotherapy (3+4) as measured by development of grade 3-4 dose-limiting toxicities (DLT).

SECONDARY OBJECTIVES:

  1. Analyze downstream inhibition of RAS signaling following therapy with single-agent MEK162 with exploratory pharmacodynamics (PD) studies.

II. Perform preliminary efficacy analysis of combination of MEK162 and induction chemotherapy (3+4) in patients with RAS-mutated AML by measuring complete remission rate, 2-year overall survival, and duration of response.

OUTLINE:

INDUCTION THERAPY: Patients receive MEK inhibitor MEK162 orally (PO) twice daily (BID) on days -4 to -1 and days 5-18, cytarabine intravenously (IV) continuously over 24 hours on days 1-4, and idarubicin IV over 1 hour on days 1-3. Patients may receive a second course of induction at the discretion of the principal investigator.

POST-REMISSION THERAPY: Patients receive cytarabine IV continuously over 24 hours on days 1-3, idarubicin IV over 1 hour on days 1 and 2, and MEK inhibitor MEK 162 PO BID on days 4-17. Treatment repeats every 28 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.

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

Being tested
MEK inhibitor MEK162, idarubicin, cytarabine, pharmacological study, laboratory biomarker analysis
Medical subject headings
Leukemia, Monocytic, Acute, Leukemia, Myeloid, Acute, Congenital Abnormalities, Leukemia, Myelomonocytic, Acute, Leukemia, Erythroblastic, Acute

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • MEK inhibitor MEK162Drug

    Also called ARRY-162, ARRY-438162

    Given PO

  • idarubicinDrug

    Also called 4-demethoxydaunorubicin, 4-DMDR, DMDR, IDA

    Given IV

  • cytarabineDrug

    Also called ARA-C, arabinofuranosylcytosine, arabinosylcytosine, Cytosar-U

    Given IV

  • pharmacological studyOther

    Also called pharmacological studies

    Correlative studies

  • laboratory biomarker analysisOther

    Correlative studies

Study groups in NCT02049801
Study groupRoleWhat they receive
Treatment (MEK inhibitor, MEK162, idarubicin, cytarabine)ExperimentalINDUCTION THERAPY: Patients receive MEK inhibitor MEK162 PO BID on days -4 to -1 and days 5-18, cytarabine IV continuously over 24 hours on days 1-4, and idarubicin IV over 1 hour on days 1-3. Patients may receive a second course of induction at the discretion of the principal investigator. POST-REMISSION THERAPY: Patients receive cytarabine IV continuously over 24 hours on days 1-3, idarubicin IV over 1 hour on days 1 and 2, and MEK inhibitor MEK 162 PO BID on days 4-17. Treatment repeats every 28 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.
Receives: Drug: MEK inhibitor MEK162; Drug: idarubicin; Drug: cytarabine; Other: pharmacological study; Other: laboratory biomarker analysis

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. MTD of MEK inhibitor MEK162 in combination with chemotherapy, defined as the dose associated with a dose-limiting toxicity rate of 35% assessed by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03

    Dose limiting toxicities will be tabulated by dose, severity and major organ system.

    Measured: 28 days

Secondary outcomes (4)
  1. Pharmacodynamic analysis of downstream inhibition of RAS signaling following therapy with single-agent MEK inhibitor MEK162

    Pharmacodynamic correlative data will be summarized with medians and ranges for each dose group. If there are a sufficient number of patients assigned to both doses, the medians will be compared with a Wilcoxon Rank Sum test.

    Measured: Day -4, -1, and 18

  2. Complete remission rate, defined as bone marrow biopsy demonstrating < 5% blasts and recovery of peripheral blood counts after induction chemotherapy

    The proportion of patients who achieve complete remission will be estimated overall with an exact 95% confidence interval; for descriptive purpose the same proportion at each dose will similarly described.

    Measured: Up to day 19

  3. Overall survival

    The proportion of patients who achieve 2-year overall survival will be estimated overall with an exact 95% confidence interval; for descriptive purpose the same proportion at each dose will similarly described.

    Measured: Time of study entry to the time of death from any cause, assessed at 2 years

  4. Duration of response

    Measured: Time of complete response to biopsy-documented recurrence of disease, assessed up to 4 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted30 Jan 2014 (estimated)
  2. Study startDec 2014
  3. Primary completion4 Feb 2015
  4. Study completion1 Nov 2017

Why it stopped: logistics

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
1 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02049801
Sponsor's protocol ID
IRB-29150
Other IDs
NCI-2014-00169, HEMAML0030
Status last verified
Dec 2017
First submitted
28 Jan 2014
Last updated
6 Dec 2017
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing MEK inhibitor MEK162, idarubicin and cytarabine in people with Adult Acute Minimally Differentiated Myeloid Leukemia (M0) and Adult Acute Monoblastic Leukemia (M5a), run by Bruno C. Medeiros at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 15 inclusion and 28 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 6 Dec 2017. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was stopped early (reason given: logistics). Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

MTD of MEK inhibitor MEK162 in combination with chemotherapy, defined as the dose associated with a dose-limiting toxicity rate of 35% assessed by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 (time frame: 28 days). It is what the study was designed to measure, not a finding.

Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 Dec 2017.

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