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

NCT02049801 | Terminated Phase 1 DMC FDA Drug

• 3 other identifiers: IRB-29150NCI-2014-00169HEMAML0030
• Study Type: interventional
• Target: 1
• Locations: 1 country
• Sites: 1

Brief 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. 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.

Conditions

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(15;17)(q22;q12); 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

Outcome Measures

Primary Outcomes (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.

  28 days

Secondary Outcomes (4)

• Pharmacodynamic analysis of downstream inhibition of RAS signaling following therapy with single-agent MEK inhibitor MEK162

  Day -4, -1, and 18

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

  Up to day 19

• Overall survival

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

• Duration of response

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

Study Arms (1)

Treatment (MEK inhibitor, MEK162, idarubicin, cytarabine)

EXPERIMENTAL

INDUCTION 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.

Drug: MEK inhibitor MEK162; Drug: idarubicin; Drug: cytarabine; Other: pharmacological study; Other: laboratory biomarker analysis

Interventions

MEK inhibitor MEK162 DRUG

Given PO

Also known as: ARRY-162, ARRY-438162

Treatment (MEK inhibitor, MEK162, idarubicin, cytarabine)

idarubicin DRUG

Given IV

Also known as: 4-demethoxydaunorubicin, 4-DMDR, DMDR, IDA

Treatment (MEK inhibitor, MEK162, idarubicin, cytarabine)

cytarabine DRUG

Given IV

Also known as: ARA-C, arabinofuranosylcytosine, arabinosylcytosine, Cytosar-U, cytosine arabinoside

Treatment (MEK inhibitor, MEK162, idarubicin, cytarabine)

pharmacological study OTHER

Correlative studies

Also known as: pharmacological studies

Treatment (MEK inhibitor, MEK162, idarubicin, cytarabine)

laboratory biomarker analysis OTHER

Correlative studies

Treatment (MEK inhibitor, MEK162, idarubicin, cytarabine)

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• 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

You may not qualify if:

• 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
• 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

Sponsors & Collaborators

• Bruno C. Medeiros: lead
• National Cancer Institute (NCI): collaborator

Study Sites (1)

Stanford University, School of Medicine

Stanford, California, 94305, United States

Location

MeSH Terms

Conditions

Leukemia, Monocytic, Acute; Leukemia, Myeloid, Acute; Congenital Abnormalities; Leukemia, Myelomonocytic, Acute; Leukemia, Erythroblastic, Acute

Interventions

Idarubicin; Cytarabine

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Myeloproliferative Disorders; Bone Marrow Diseases

Intervention Hierarchy (Ancestors)

Daunorubicin; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Aminoglycosides; Glycosides; Carbohydrates; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides

Study Officials

• Bruno de Medeiros

  Stanford University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Assistant Professor of Medicine

Study Record Dates

• First Submitted: January 28, 2014
• First Posted: January 30, 2014
• Study Start: December 1, 2014
• Primary Completion: February 4, 2015
• Study Completion: November 1, 2017
• Last Updated: December 6, 2017

Record last verified: 2017-12

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)