Clinical Trials /

Metformin+Cytarabine for the Treatment of Relapsed/Refractory AML

NCT01849276

Description:

The purpose of the study is to determine if metformin in combination with cytarabine is safe and effective. Participants in this research study have acute myeloid leukemia (AML) that has come back after initial treatment or has not gone away with initial therapy.There is evidence that metformin directly kills leukemia cells. Laboratory data have also shown that combinations of metformin with cytarabine are more efficient than each agent alone in killing leukemia cells in the laboratory.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Terminated

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Metformin+Cytarabine for the Treatment of Relapsed/Refractory AML
  • Official Title: A Phase I Study of Metformin and Cytarabine for the Treatment of Relapsed/Refractory Acute Myeloid Leukemia

Clinical Trial IDs

  • ORG STUDY ID: NU 11H03
  • SECONDARY ID: NCI-2011-01084
  • SECONDARY ID: STU00048047
  • NCT ID: NCT01849276

Conditions

  • 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)
  • Blastic Phase Chronic Myelogenous Leukemia
  • Recurrent Adult Acute Myeloid Leukemia
  • Untreated Adult Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
metformin hydrochlorideGlucophageTreatment (enzyme inhibitor and chemotherapy)
cytarabineARA-C, arabinofuranosylcytosine, arabinosylcytosine, Cytosar-U, cytosine arabinosideTreatment (enzyme inhibitor and chemotherapy)

Purpose

The purpose of the study is to determine if metformin in combination with cytarabine is safe and effective. Participants in this research study have acute myeloid leukemia (AML) that has come back after initial treatment or has not gone away with initial therapy.There is evidence that metformin directly kills leukemia cells. Laboratory data have also shown that combinations of metformin with cytarabine are more efficient than each agent alone in killing leukemia cells in the laboratory.

Detailed Description

      PRIMARY OBJECTIVES:

      I. Determine the maximum tolerated dose (MTD) of metformin (metformin hydrochloride) in
      combination with cytarabine in relapsed/refractory AML.

      II. Define the dose limiting toxicity (DLT) of metformin in combination with cytarabine in
      relapsed/refractory AML.

      SECONDARY OBJECTIVES:

      I. Remission rate. II. Overall survival (OS). III. Disease-free survival (DFS). IV. Length of
      remission.

      OUTLINE: This is a dose-escalation study of metformin hydrochloride in combination with
      Cytarabine.

      Patients receive metformin hydrochloride orally (PO) twice daily (BID) on days 1-15 and
      cytarabine intravenously (IV) over 3 hours BID on days 4-10.

      After completion of study treatment, patients are followed up every 3 months for 2 years and
      then every 6 months for 5 years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (enzyme inhibitor and chemotherapy)ExperimentalPatients receive metformin hydrochloride orally twice a day on days 1-15 and cytarabine IV over 3 hours twice on days 4-10.
  • metformin hydrochloride
  • cytarabine

Eligibility Criteria

        Inclusion Criteria:

          -  Patients with relapsed/refractory disease must have morphologic proof (from bone
             marrow aspirate, smears or touch preps of bone marrow biopsy) of AML with >= 10%
             blasts within two weeks (14 days) prior to initiation of therapy

               -  All immunophenotype and cytogenetic/molecular groups are eligible for
                  participation except for acute promyelocytic leukemia (APL) (as proven by the
                  presence of promyelocytic leukemia/retinoic acid receptor alpha [PML-RARα])

          -  Patients must demonstrate one of the following:

               -  Relapse after first complete remission

               -  Refractory to conventional induction chemotherapy (failure to respond to 1 or
                  more cycles of daunorubicin and cytarabine) or to re-induction

          -  Patients with previously untreated AML are candidates if they are unable to receive
             anthracyclines, and have documented AML with >= 20% blasts within one week prior to
             enrollment

          -  Patients with chronic myelogenous leukemia (CML) in myeloid blast crisis are eligible
             if their disease has failed to respond, and/or they are intolerant, to the available
             tyrosine kinase inhibitors (TKIs)

          -  Serum total and direct bilirubin =< upper limit of normal (ULN)

          -  Serum creatinine < 1.4 mg/dl in females and < 1.5 mg/dl in males, and creatinine
             clearance > 60 mL/min

          -  Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase
             [AST])/serum glutamic pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =<
             ULN

          -  Bicarbonate within the normal range of the hospital lab (24-32 mmol/L)

          -  Patients must exhibit an Eastern Cooperative Oncology Group (ECOG) performance status
             of 0, 1, or 2

          -  Females of childbearing potential and sexually active males must agree to use an
             accepted and effective method of contraception while on study

          -  Childbearing potential is defined as any woman (regardless of sexual orientation,
             having undergone a tubal ligation, or remaining celibate by choice) who meets the
             following criteria:

               -  Has NOT undergone a hysterectomy or bilateral oophorectomy; OR

               -  Has NOT been naturally postmenopausal for at least 12 consecutive months (i.e.
                  has had menses at any time in the preceding 12 consecutive months)

          -  Patients with a history of central nervous system (CNS) leukemia are eligible if they
             are not symptomatic from current CNS involvement

               -  If there is CNS involvement that is known prior to enrollment or identified
                  subsequently, it will be treated accordingly

          -  Patients may have received therapy for other malignancies, as long as they have
             completed therapy at least 6 months prior to study entry and be deemed to have a life
             expectancy of at least 2 years with regard to that malignancy

          -  All patients must have given signed, informed consent prior to registration on study

        Exclusion Criteria:

          -  Patients who have received chemotherapy or radiotherapy within 4 weeks prior to
             enrollment are NOT eligible for participation

               -  The exception to this is patients who are refractory to conventional initial
                  induction chemotherapy (=< 2 courses) or to first radiation (1 course); patients
                  must have morphologic proof (from bone marrow aspirate, smears, or touch preps of
                  marrow biopsy) of AML with > 10% blasts within 2 weeks prior to initiation of
                  study therapy; the last dose of cytotoxic therapy (NOT including hydrea, which is
                  allowed) must have been given >= 14 days prior to initiation of study therapy

          -  Patients with a history of diabetes mellitus (DM) treated with metformin are NOT
             eligible for participation

          -  Patients who are pregnant or breast feeding are NOT eligible for participation due to
             the lack of knowledge regarding the effects of the drugs on the fetus and during
             breast feeding

          -  Patients with any intercurrent organ damage or medical problems that would prohibit
             therapy are NOT eligible for participation

          -  Patients with any active, uncontrolled infection are NOT eligible for participation

          -  Patients who are receiving therapy for another active malignancy are NOT eligible for
             participation

               -  The exception to this is squamous cell carcinoma or basal cell carcinoma of the
                  skin
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Evaluate Toxicity by Assessing the Adverse Events of Metformin and Cytarabine
Time Frame:Checked daily during administration of cytarabine and at least 2x weekly following therapy until desired blood counts acheived (maximum 15 days)
Safety Issue:
Description:To determine the maximum tolerated dose (MTD) by assessing the adverse events of metformin in combination with cytarabine in evaluating toxicity. Assessments will occur daily during cytarabine administration and at least twice weekly following treatment until blood count recovery.

Secondary Outcome Measures

Measure:Remission Rate
Time Frame:Every 3 months for 2 years, and then every 6 months for 5 years post-treatment
Safety Issue:
Description:Patients will be evaluated for remission status in response to therapy.
Measure:Overall Survival
Time Frame:Every 3 months for 2 years, and then every 6 months for 5 years post-treatment
Safety Issue:
Description:Patients will be followed-up with from the initiation of study treatment until progression of disease or for up to 5 years, whichever comes first.
Measure:Disease-free Survival
Time Frame:Every 3 months for 2 years, and then every 6 months for 5 years post-treatment
Safety Issue:
Description:Evaluation of Disease-Free Survival will defined as the time from the initiation of study treatment until the time of disease relapse.
Measure:Length of Remission
Time Frame:From date of remission of disease to date of relapse (maximum of 5 year follow-up)
Safety Issue:
Description:Patients will be followed-up with to determine Remission length which is defined as the time from attainment of remission to relapse of disease.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Terminated
Lead Sponsor:Northwestern University

Last Updated