Metformin+Cytarabine for the Treatment of Relapsed/Refractory AML

NCT01849276 | Terminated Phase 1 Results DMC

• 3 other identifiers: NU 11H03NCI-2011-01084STU00048047
• Study Type: interventional
• Target: 2
• Locations: 1 country
• Sites: 1

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.

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

Outcome Measures

Primary Outcomes (2)

• 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.

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

• 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.

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

Secondary Outcomes (4)

• Remission Rate

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

• Overall Survival

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

• Disease-free Survival

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

• Length of Remission

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

Other Outcomes (3)

• 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

• Immunoblotting

  At baseline prior to study treatment

• Identical Immunoblotting

  At baseline prior to study treatment

Study Arms (1)

Treatment (enzyme inhibitor and chemotherapy)

EXPERIMENTAL

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; Drug: cytarabine; Other: laboratory biomarker analysis

Interventions

metformin hydrochloride DRUG

Given orally

Also known as: Glucophage

Treatment (enzyme inhibitor and chemotherapy)

cytarabine DRUG

Given IV

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

Treatment (enzyme inhibitor and chemotherapy)

laboratory biomarker analysis OTHER

Correlative studies

Treatment (enzyme inhibitor and chemotherapy)

Eligibility Criteria

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

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Northwestern University: lead

Study Sites (1)

Northwestern University

Chicago, Illinois, 60611, United States

Location

MeSH Terms

Conditions

Leukemia, Megakaryoblastic, Acute; Leukemia, Monocytic, Acute; Leukemia, Myeloid, Acute; Congenital Abnormalities; Leukemia, Myelomonocytic, Acute; Leukemia, Erythroblastic, Acute; Blast Crisis

Interventions

Metformin; 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; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Cell Transformation, Neoplastic; Carcinogenesis; Neoplastic Processes; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides

Limitations and Caveats

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

Results Point of Contact

• Title: Dr. Jessica Altman
• Organization: Northwestern University

J-altman@northwestern.edu

312-503-1761

Study Officials

• Jessica Altman, MD

  Northwestern University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: May 6, 2013
• First Posted: May 8, 2013
• Study Start: March 11, 2015
• Primary Completion: January 21, 2016
• Study Completion: January 21, 2016
• Last Updated: January 31, 2019
• Results First Posted: November 13, 2018

Record last verified: 2019-01

Locations

US (1)