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Metformin+Cytarabine for the Treatment of Relapsed/Refractory AML

Primary Purpose

Adult Acute Megakaryoblastic Leukemia (M7), Adult Acute Minimally Differentiated Myeloid Leukemia (M0), Adult Acute Monoblastic Leukemia (M5a)

Status

Terminated

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

metformin hydrochloride

cytarabine

laboratory biomarker analysis

About this trial

This is an interventional treatment trial for Adult Acute Megakaryoblastic Leukemia (M7)

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Northwestern University

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (enzyme inhibitor and chemotherapy)

Arm Description

Patients receive metformin hydrochloride orally twice a day on days 1-15 and cytarabine IV over 3 hours twice on days 4-10.

Outcomes

Primary Outcome Measures

Evaluate Toxicity by Assessing the Adverse Events of Metformin and Cytarabine

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.

Study Treatment Dose Toxicity Will be Evaluated by Measurement of Adverse Events Experienced While on Treatment

Determination of Dose Limiting Toxicity (DLT) as evidenced by adverse events due to toxicity from study treatment. If no DLT is observed, then 3 patients will be enrolled in the next dose escalated cohort. If one DLT is seen in the first 3 patients, then an additional 3 patients will be enrolled at the same dose cohort. If 0-1 in 6 patients experience a DLT this dose will be considered tolerable and the next dose escalated cohort with enroll 3 patients. If 2 or more in 6 patients experience a DLT, the maximum tolerated dose (MTD) will have been exceeded and the next cohort will enroll 3 patients at a reduced dose.

Secondary Outcome Measures

Remission Rate

Patients will be evaluated for remission status in response to therapy.

Overall Survival

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.

Disease-free Survival

Evaluation of Disease-Free Survival will defined as the time from the initiation of study treatment until the time of disease relapse.

Length of Remission

Patients will be followed-up with to determine Remission length which is defined as the time from attainment of remission to relapse of disease.

Full Information

NCT ID

NCT01849276

First Posted

May 6, 2013

Last Updated

January 8, 2019

Sponsor

Northwestern University

1. Study Identification

Unique Protocol Identification Number

NCT01849276

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

Study Type

Interventional

2. Study Status

Record Verification Date

January 2019

Overall Recruitment Status

Terminated

Why Stopped

Slow accrual

Study Start Date

March 11, 2015 (Actual)

Primary Completion Date

January 21, 2016 (Actual)

Study Completion Date

January 21, 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Northwestern University

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

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

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

2 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Treatment (enzyme inhibitor and chemotherapy)

Arm Type

Experimental

Arm Description

Patients receive metformin hydrochloride orally twice a day on days 1-15 and cytarabine IV over 3 hours twice on days 4-10.

Intervention Type

Drug

Intervention Name(s)

metformin hydrochloride

Other Intervention Name(s)

Glucophage

Intervention Description

Given orally

Intervention Type

Drug

Intervention Name(s)

cytarabine

Other Intervention Name(s)

ARA-C, arabinofuranosylcytosine, arabinosylcytosine, Cytosar-U, cytosine arabinoside

Intervention Description

Given IV

Intervention Type

Other

Intervention Name(s)

laboratory biomarker analysis

Intervention Description

Correlative studies

Primary Outcome Measure Information:

Title

Evaluate Toxicity by Assessing the Adverse Events of Metformin and Cytarabine

Description

Time Frame

Checked daily during administration of cytarabine and at least 2x weekly following therapy until desired blood counts acheived (maximum 15 days)

Title

Study Treatment Dose Toxicity Will be Evaluated by Measurement of Adverse Events Experienced While on Treatment

Description

Time Frame

Checked daily during administration of cytarabine and at least 2x weekly following therapy until desired blood counts acheived (maximum 15 days)

Secondary Outcome Measure Information:

Title

Remission Rate

Description

Patients will be evaluated for remission status in response to therapy.

Time Frame

Every 3 months for 2 years, and then every 6 months for 5 years post-treatment

Title

Overall Survival

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.

Time Frame

Every 3 months for 2 years, and then every 6 months for 5 years post-treatment

Title

Disease-free Survival

Description

Evaluation of Disease-Free Survival will defined as the time from the initiation of study treatment until the time of disease relapse.

Time Frame

Every 3 months for 2 years, and then every 6 months for 5 years post-treatment

Title

Length of Remission

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.

Time Frame

From date of remission of disease to date of relapse (maximum of 5 year follow-up)

Other Pre-specified Outcome Measures:

Title

Bone Marrow and Blood Samples Will be Taken Prior to Study Treatment to Determine Number of Leukemic Progenitor Cells

Time Frame

At baseline prior to study treatment

Title

Immunoblotting

Description

Bone marrow and/or blood samples taken prior to initiation of treatment will be used in Immunoblotting studies to observe enzyme and protein activity.

Time Frame

At baseline prior to study treatment

Title

Identical Immunoblotting

Description

Identical immunoblotting studies may also be performed using blood samples taken prior to start of treatment.

Time Frame

At baseline prior to study treatment

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Jessica Altman, MD

Organizational Affiliation

Northwestern University

Official's Role

Principal Investigator

Facility Information:

Facility Name

Northwestern University

City

Chicago

State/Province

Illinois

ZIP/Postal Code

60611

Country

United States

12. IPD Sharing Statement

Learn more about this trial

Metformin+Cytarabine for the Treatment of Relapsed/Refractory AML

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