Metformin+Cytarabine for the Treatment of Relapsed/Refractory AML

• Sponsor: Northwestern University (Other)
• Overall Status: Terminated
• CT.gov ID: NCT01849276
• Collaborator: (none)
• Enrollment: 2
• Location: 1
• Arm: 1
• Actual Duration (Months): 10.4
• Patients Per Site Per Month: 0.2

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
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	Drug: metformin hydrochloride; Drug: cytarabine; Other: laboratory biomarker analysis	Phase 1

Detailed Description

PRIMARY OBJECTIVES:

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

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

SECONDARY OBJECTIVES:

1. 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 Design

• Study Type: Interventional
• Actual Enrollment: 2 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I Study of Metformin and Cytarabine for the Treatment of Relapsed/Refractory Acute Myeloid Leukemia
• Actual Study Start Date: Mar 11, 2015
• Actual Primary Completion Date: Jan 21, 2016
• Actual Study Completion Date: Jan 21, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (enzyme inhibitor and chemotherapy) Patients receive metformin hydrochloride orally twice a day on days 1-15 and cytarabine IV over 3 hours twice on days 4-10.	Drug: metformin hydrochloride; Given orally; Other Names: Glucophage ; Drug: cytarabine; Given IV; Other Names: ARA-C arabinofuranosylcytosine arabinosylcytosine Cytosar-U cytosine arabinoside ; Other: laboratory biomarker analysis; Correlative studies

Outcome Measures

Primary Outcome Measures

1. Evaluate Toxicity by Assessing the Adverse Events of Metformin and Cytarabine [Checked daily during administration of cytarabine and at least 2x weekly following therapy until desired blood counts acheived (maximum 15 days)]

   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.

2. Study Treatment Dose Toxicity Will be Evaluated by Measurement of Adverse Events Experienced While on Treatment [Checked daily during administration of cytarabine and at least 2x weekly following therapy until desired blood counts acheived (maximum 15 days)]

   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

1. Remission Rate [Every 3 months for 2 years, and then every 6 months for 5 years post-treatment]

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

2. Overall Survival [Every 3 months for 2 years, and then every 6 months for 5 years post-treatment]

   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.

3. Disease-free Survival [Every 3 months for 2 years, and then every 6 months for 5 years post-treatment]

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

4. Length of Remission [From date of remission of disease to date of relapse (maximum of 5 year follow-up)]

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

Other Outcome Measures

1. Bone Marrow and Blood Samples Will be Taken Prior to Study Treatment to Determine Number of Leukemic Progenitor Cells [At baseline prior to study treatment]

2. Immunoblotting [At baseline prior to study treatment]

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

3. Identical Immunoblotting [At baseline prior to study treatment]

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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Northwestern University	Chicago	Illinois	United States	60611

Sponsors and Collaborators

• Northwestern University

Investigators

• Principal Investigator: Jessica Altman, MD, Northwestern University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Jessica Altman, Principal Investigator, Northwestern University
• ClinicalTrials.gov Identifier: NCT01849276
• Other Study ID Numbers: NU 11H03; NCI-2011-01084; STU00048047
• First Posted: May 8, 2013
• Last Update Posted: Jan 31, 2019
• Last Verified: Jan 1, 2019

• Additional relevant MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Blast Crisis; Leukemia, Monocytic, Acute; Leukemia, Myelomonocytic, Acute; Leukemia, Megakaryoblastic, Acute; Leukemia, Erythroblastic, Acute; Metformin; Cytarabine

Study Results

Participant Flow

Recruitment Details	The study opened for accrual July 29, 2013 with an accrual goal of between 19 to 28 participants in a 3 + 3 dose escalation design to find the maximum tolerated dose of metformin in combination with cytarabine. The study was closed permanently on January 21 2016 due to slow accrual.

Arm/Group Title	Treatment (Enzyme Inhibitor and Chemotherapy)
Arm/Group Description	Patients receive metformin hydrochloride orally twice a day on days 1-15 and cytarabine IV over 3 hours twice on days 4-10. metformin hydrochloride: Given orally cytarabine: Given IV laboratory biomarker analysis: Correlative studies
Period Title: Registered to the Study
STARTED	2
COMPLETED	2
NOT COMPLETED	0
Period Title: Registered to the Study
STARTED	2
COMPLETED	2
NOT COMPLETED	0
Period Title: Registered to the Study
STARTED	2
COMPLETED	0
NOT COMPLETED	2

Baseline Characteristics

Arm/Group Title	Treatment (Enzyme Inhibitor and Chemotherapy)
Arm/Group Description	Patients receive metformin hydrochloride orally twice a day on days 1-15 and cytarabine IV over 3 hours twice on days 4-10. metformin hydrochloride: Given orally cytarabine: Given IV laboratory biomarker analysis: Correlative studies
Overall Participants	2
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	1 50%
>=65 years	1 50%
Sex: Female, Male (Count of Participants)
Female	1 50%
Male	1 50%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 50%
Not Hispanic or Latino	1 50%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	1 50%
White	1 50%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	2 100%

Outcome Measures

1. Primary Outcome

Title	Evaluate Toxicity by Assessing the Adverse Events of Metformin and Cytarabine
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.
Time Frame	Checked daily during administration of cytarabine and at least 2x weekly following therapy until desired blood counts acheived (maximum 15 days)

Outcome Measure Data

Analysis Population Description

Adverse events that were assessed to be either possibly or unlikely related to treatment on study (i.e. relationship between treatment and adverse event could not be ruled out)

Arm/Group Title	Treatment (Enzyme Inhibitor and Chemotherapy)
Arm/Group Description	Patients receive metformin hydrochloride orally twice a day on days 1-15 and cytarabine IV over 3 hours twice on days 4-10. metformin hydrochloride: Given orally cytarabine: Given IV laboratory biomarker analysis: Correlative studies
Measure Participants	2
Grade 1	4
Grade 2	6
Grade 3	2
Grade 4	0

2. Primary Outcome

Title	Study Treatment Dose Toxicity Will be Evaluated by Measurement of Adverse Events Experienced While on Treatment
Description	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.
Time Frame	Checked daily during administration of cytarabine and at least 2x weekly following therapy until desired blood counts acheived (maximum 15 days)

Outcome Measure Data

Analysis Population Description

The study was terminated early due to slow accrual, thus insufficient data was collected to be analysed.

Arm/Group Title	Treatment (Enzyme Inhibitor and Chemotherapy)
Arm/Group Description	Patients receive metformin hydrochloride orally twice a day on days 1-15 and cytarabine IV over 3 hours twice on days 4-10. metformin hydrochloride: Given orally cytarabine: Given IV laboratory biomarker analysis: Correlative studies
Measure Participants	0

3. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

The study was terminated early due to slow accrual. As a result no data was collected or analyzed for this outcome measure.

Arm/Group Title	Treatment (Enzyme Inhibitor and Chemotherapy)
Arm/Group Description	Patients receive metformin hydrochloride orally twice a day on days 1-15 and cytarabine IV over 3 hours twice on days 4-10. metformin hydrochloride: Given orally cytarabine: Given IV laboratory biomarker analysis: Correlative studies
Measure Participants	0

4. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

The study was terminated early due to slow accrual. As a result no data was collected or analyzed for this outcome measure.

Arm/Group Title	Treatment (Enzyme Inhibitor and Chemotherapy)
Arm/Group Description	Patients receive metformin hydrochloride orally twice a day on days 1-15 and cytarabine IV over 3 hours twice on days 4-10. metformin hydrochloride: Given orally cytarabine: Given IV laboratory biomarker analysis: Correlative studies
Measure Participants	0

5. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

The study was terminated early due to slow accrual. As a result no data was collected or analyzed for this outcome measure.

Arm/Group Title	Treatment (Enzyme Inhibitor and Chemotherapy)
Arm/Group Description	Patients receive metformin hydrochloride orally twice a day on days 1-15 and cytarabine IV over 3 hours twice on days 4-10. metformin hydrochloride: Given orally cytarabine: Given IV laboratory biomarker analysis: Correlative studies
Measure Participants	0

6. Secondary Outcome

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)

Outcome Measure Data

Analysis Population Description

The study was terminated early due to slow accrual. As a result no data was collected or analyzed for this outcome measure.

Arm/Group Title	Treatment (Enzyme Inhibitor and Chemotherapy)
Arm/Group Description	Patients receive metformin hydrochloride orally twice a day on days 1-15 and cytarabine IV over 3 hours twice on days 4-10. metformin hydrochloride: Given orally cytarabine: Given IV laboratory biomarker analysis: Correlative studies
Measure Participants	0

7. Other Pre-specified Outcome

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

Outcome Measure Data

Analysis Population Description

The study was terminated early due to slow accrual. As a result no data was collected or analyzed for this outcome measure.

Arm/Group Title	Treatment (Enzyme Inhibitor and Chemotherapy)
Arm/Group Description	Patients receive metformin hydrochloride orally twice a day on days 1-15 and cytarabine IV over 3 hours twice on days 4-10. metformin hydrochloride: Given orally cytarabine: Given IV laboratory biomarker analysis: Correlative studies
Measure Participants	0

8. Other Pre-specified Outcome

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

Outcome Measure Data

Analysis Population Description

The study was terminated early due to slow accrual. As a result no data was collected or analyzed for this outcome measure.

Arm/Group Title	Treatment (Enzyme Inhibitor and Chemotherapy)
Arm/Group Description	Patients receive metformin hydrochloride orally twice a day on days 1-15 and cytarabine IV over 3 hours twice on days 4-10. metformin hydrochloride: Given orally cytarabine: Given IV laboratory biomarker analysis: Correlative studies
Measure Participants	0

9. Other Pre-specified Outcome

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

Outcome Measure Data

Analysis Population Description

The study was terminated early due to slow accrual. As a result no data was collected or analyzed for this outcome measure.

Arm/Group Title	Treatment (Enzyme Inhibitor and Chemotherapy)
Arm/Group Description	Patients receive metformin hydrochloride orally twice a day on days 1-15 and cytarabine IV over 3 hours twice on days 4-10. metformin hydrochloride: Given orally cytarabine: Given IV laboratory biomarker analysis: Correlative studies
Measure Participants	0

Adverse Events

Time Frame	Adverse events were collect cover a 7 month period before the study was terminated early due to slow accrual
Arm/Group Title	Treatment (Enzyme Inhibitor and Chemotherapy)
Arm/Group Description	Patients receive metformin hydrochloride orally twice a day on days 1-15 and cytarabine IV over 3 hours twice on days 4-10. metformin hydrochloride: Given orally cytarabine: Given IV laboratory biomarker analysis: Correlative studies
All Cause Mortality
	Treatment (Enzyme Inhibitor and Chemotherapy)
	Affected / at Risk (%)	# Events
Total	2/2 (100%)
Serious Adverse Events
	Treatment (Enzyme Inhibitor and Chemotherapy)
	Affected / at Risk (%)	# Events
Total	2/2 (100%)
Gastrointestinal disorders
Gastric perforation	1/2 (50%)	1
Hepatobiliary disorders
Other-Transminitis	1/2 (50%)	1
Infections and infestations
Sepsis	1/2 (50%)	1
Other (Not Including Serious) Adverse Events
	Treatment (Enzyme Inhibitor and Chemotherapy)
	Affected / at Risk (%)	# Events
Total	2/2 (100%)
Blood and lymphatic system disorders
Anemia	1/2 (50%)	1
Febrile neutropenia	1/2 (50%)	1
Thrombocytopenia	1/2 (50%)	1
Elevated D-Dimer	1/2 (50%)	1
Elevated INR	1/2 (50%)	1
Eye disorders
Blurred vision	1/2 (50%)	1
Gastrointestinal disorders
Diarrhea	1/2 (50%)	1
Lower gastrointestinal hemorrhage - Hematochezia	1/2 (50%)	1
General disorders
Fever	1/2 (50%)	5
Infections and infestations
Pleural infection	1/2 (50%)	1
Investigations
Alanine aminotransferase increased	1/2 (50%)	1
Aspartate aminotransferase increased	1/2 (50%)	1
Weight loss	1/2 (50%)	3
White blood cell decreased	1/2 (50%)	1
Metabolism and nutrition disorders
Hyperglycemia	1/2 (50%)	1
Hypoalbuminemia	1/2 (50%)	2
Hypoalbuminema	1/2 (50%)	7
Musculoskeletal and connective tissue disorders
Chest wall pain	1/2 (50%)	1
Renal and urinary disorders
Dysuria	1/2 (50%)	1
Urinary tract infection	1/2 (50%)	1
Reproductive system and breast disorders
Symptomatic Bartholin gland	1/2 (50%)	1
Respiratory, thoracic and mediastinal disorders
Epistaxis	1/2 (50%)	1
Cough	1/2 (50%)	1
Pneumonitis	1/2 (50%)	1
Dyspnea	1/2 (50%)	1
Vascular disorders
Thromboembolic event	1/2 (50%)	1

Limitations/Caveats

The study terminated early due to slow accrual and there was not sufficient data collected for statistical analysis.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.