Vincristine, Dexamethasone, Doxorubicin, and PEG-asparaginase (VPLD) and Metformin for Relapsed Childhood Acute Lymphoblastic Leukemia (ALL)
H. Lee Moffitt Cancer Center and Research Institute will be the Sunshine Project Coordinator, but will not be recruiting locally.
The purpose of the trial is to study the clinical and biological effects of metformin in combination with standard systemic chemotherapy in a disease (relapsed ALL) that has a dismal outcome, as well as to do a dose escalation study to find the Maximum Tolerated Dose (MTD) of metformin in conjunction with ALL therapy. There have also been analysis of patients enrolled on trials who were diabetics on metformin and their outcome was better than patients on the same trial that were not on metformin as their antihyperglycemic.
Acute Lymphoblastic Leukemia
Drug: Intrathecal chemotherapy
|Study Design:||Intervention Model: Single Group Assignment
Masking: No masking
Primary Purpose: Treatment
|Official Title:||A Phase I Window, Dose Escalating and Safety Trial of Metformin in Combination With Induction Chemotherapy in Relapsed Refractory Acute Lymphoblastic Leukemia: Metformin With Induction Chemotherapy of Vincristine, Dexamethasone, Doxorubicin, and PEG-asparaginase (VPLD)|
- Maximum Tolerated Dose (MTD) [ Time Frame: 45 days ]MTD determined by Dose Limiting Toxicity (DLT), any time during the first course of therapy. Dose Limiting Toxicities: Any Grade 3 or 4 non-hematological toxicity by Common Toxicity Criteria for Adverse Effects (CTCAE) version 4.0 felt to be probably or definitely related to the study agent, persistent marrow aplasia at day 44, lactic acidosis for grade 3 or 4, grade 3 and 4 hypoglycemia.
- The Number of Participants with Complete Remission [ Time Frame: 45 days ]
Patients who have:
- No evidence of circulating blasts or extramedullary disease;
- A bone marrow with <5% blasts (M1 marrow); and
Recovery of peripheral counts (platelets ≥75,000 and absolute neutrophil count (ANC) ≥750)
- Qualifying marrow and peripheral counts should be performed within 1 week of each other
- The Number of Participants with Biological Response to Treatment [ Time Frame: 45 days ]To evaluate the biological response of ALL blasts from children receiving metformin in a window fashion and in later time points.
- The Number of Participants with Adverse Events as a Measure of Safety and Feasibility [ Time Frame: 45 Days ]To demonstrate the safety and feasibility of the addition of metformin to induction chemotherapy for recurrent ALL.
|Actual Study Start Date:||July 18, 2011|
|Estimated Study Completion Date:||January 2018|
|Primary Completion Date:||November 2016 (Final data collection date for primary outcome measure)|
Experimental: VLPD Regimen
Induction will consist of vincristine, dexamethasone, doxorubicin and PEG asparaginase (so called VPLD - dexamethasone is substituted for prednisone and PEG asparaginase is substituted for L-asparaginase) in combination with metformin. Eligible patients will receive 24 hours of metformin followed by induction. Intrathecal chemotherapy with standard dose cytarabine will be administered at the start of each cycle, with central nervous system (CNS) therapy afterwards determined by findings on staging lumbar puncture.
Will be dosed orally BID as per dose level of subject as defined in dose escalation schema. Both liquid and tablet forms are allowed and can be chosen based on convenience. Metformin will be continued throughout the cycle until Day 28 or until the patient is removed from study (e.g. to pursue new lines of therapy such as transplant), whichever occurs sooner.Drug: Vincristine
1.5 mg/m^2/dose IV push (maximum single dose 2 mg) on days 2, 9, 16 and 23
Other Names:Drug: Dexamethasone
Other Names:Drug: PEG-asparaginase
Other Names:Drug: Doxorubicin
60 mg/m^2/day IV over 15 minutes on day 2
Other Names:Drug: Intrathecal chemotherapy
IT cytarabine given intrathecally to all patients on day 1 of each cycle. Dose defined by age. May be given with staging lumbar puncture before enrollment, but must be within 72 hours of starting therapy. If not done at study entry or before, may be done on Day 2 prior to doxorubicin administration.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01324180
|United States, Connecticut|
|Connecticut Children's Medical Center|
|Hartford, Connecticut, United States, 06106|
|United States, Delaware|
|Nemours/Alfred I. duPont Hospital for Children|
|Wilmington, Delaware, United States, 19803|
|United States, Florida|
|University of Florida Shands Cancer Center|
|Gainesville, Florida, United States, 32610|
|Nemours Children's Clinic|
|Jacksonville, Florida, United States, 32207|
|Holtz Children's Hospital University of Miami Miller School of Medicine|
|Miami, Florida, United States, 33136|
|Arnold Palmer Hospital for Children|
|Orlando, Florida, United States, 32806|
|All Children's Hospital|
|Saint Petersburg, Florida, United States, 33701|
|United States, New York|
|Montefiore Medical Center, The Children's Hospital at Montefiore|
|The Bronx, New York, United States, 10467|
|United States, Ohio|
|Nationwide Children's Hospital|
|Columbus, Ohio, United States, 43205|
|Study Chair:||Julio M. Barredo, M.D.||Holtz Children's Hospital University of Miami Miller School of Medicine|
|Principal Investigator:||Damon Reed, M.D.||H. Lee Moffitt Cancer Center and Research Institute|