Metformin+Cytarabine for the Treatment of Relapsed/Refractory AML

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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

Brief Summary

      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.
    

Study Phase

Phase 1

Study Type

Interventional


Primary Outcome

Evaluate Toxicity by Assessing the Adverse Events of Metformin and Cytarabine

Secondary Outcome

 Remission Rate

Condition

Adult Acute Megakaryoblastic Leukemia (M7)

Intervention

metformin hydrochloride

Study Arms / Comparison Groups

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

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

2

Start Date

March 11, 2015

Completion Date

January 21, 2016

Primary Completion Date

January 21, 2016

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
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Jessica Altman, MD, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT01849276

Organization ID

NU 11H03

Secondary IDs

NCI-2011-01084

Responsible Party

Principal Investigator

Study Sponsor

Northwestern University


Study Sponsor

Jessica Altman, MD, Principal Investigator, Northwestern University


Verification Date

January 2019