Back to resultsVincristine, Dexamethasone, Doxorubicin, and PEG-asparaginase (VPLD) and Metformin for Relapsed Childhood Acute Lymphoblastic Leukemia (ALL)
Primary Purpose
Acute Lymphoblastic Leukemia
Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Metformin
Vincristine
Dexamethasone
PEG-asparaginase
Doxorubicin
Intrathecal chemotherapy
Sponsored by
About this trial
This is an interventional treatment trial for Acute Lymphoblastic Leukemia focused on measuring ALL, Relapsed, Refractory
Eligibility Criteria
Inclusion Criteria:
- ALL or lymphoblastic lymphoma patients in first or higher relapse.
- Male or Female age 1-30 years at initial diagnosis.
- Signed informed consent.
- Karnofsky / Lansky score above 50%.
- No known contraindications to intended therapies.
- Prior anthracycline exposure: Patients must have had less than 350 mg/m^2 lifetime exposure of anthracycline chemotherapy.
- It must be at least 6 months since the last treatment with a "VPLD" induction/re-induction type regimen (i.e. anthracycline, steroid, asparaginase and vincristine).
Patients must have adequate organ function.
- Adequate renal function defined as serum creatinine < 1.5 x upper limit of normal (ULN) for age.
- Total bilirubin < 1.5 X ULN for age.
- Alanine transaminase (ALT) < 5 X ULN for age, unless the elevation is disease-related.
- Adequate cardiac function as defined as shortening fraction of > 27% by echocardiogram or ejection fraction > 45% by gated radionuclide study.
Exclusion Criteria:
- Significant renal impairment as determined per investigator discretion.
- Patients planning on receiving other investigational agents while on this study.
- Patients planning on receiving other anti-cancer therapies while on this study.
- Patients with active infection defined as: positive blood culture within 48 hours of study registration; need for supplemental oxygen or vasopressors within 48 hours of study entry.
- Patient receiving corticosteroids, aside from dexamethasone treatment directed at leukemia.
- Known intolerance to doxorubicin, metformin, or vincristine.
- Patients who have started protocol therapy prior to enrollment. Patient may still enroll if IT therapy was given within 72 hours of study enrollment as part of the diagnostic lumbar procedure.
- Patients may be on hydroxurea until the first dose of metformin is to be given.
- Patients who have a need to continue hydroxurea while on study (Patients may continue on hydroxurea only until the first dose of metformin is to given).
- Patients with creatinine more than 1.5 x the ULN
Patients must have recovered from the acute side effects of all prior anticancer therapy.
- At least 1 week from prior cytotoxic chemotherapy.
- At least 4 weeks from craniospinal irradiation.
- At least 4 months since hematopoietic stem cell transplant (HSCT) with no evidence of active graft-versus-host disease (GVHD).
- Pregnant or lactating women.
Sites / Locations
- Holtz Children's Hospital University of Miami Miller School of Medicine
- Arnold Palmer Hospital for Children
- All Children's Hospital
- Montefiore Medical Center, The Children's Hospital at Montefiore
- Nationwide Children's Hospital
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
VLPD Regimen
Arm Description
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.
Outcomes
Primary Outcome Measures
Maximum Tolerated Dose (MTD)
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.
Secondary Outcome Measures
The Number of Participants with Complete Remission
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
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
To demonstrate the safety and feasibility of the addition of metformin to induction chemotherapy for recurrent ALL.
Full Information
NCT ID
NCT01324180
First Posted
March 24, 2011
Last Updated
August 4, 2017
Sponsor
H. Lee Moffitt Cancer Center and Research Institute
Collaborators
Pediatric Cancer Foundation
1. Study Identification
Unique Protocol Identification Number
NCT01324180
Brief Title
Vincristine, Dexamethasone, Doxorubicin, and PEG-asparaginase (VPLD) and Metformin for Relapsed Childhood Acute Lymphoblastic Leukemia (ALL)
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)
Study Type
Interventional
2. Study Status
Record Verification Date
August 2017
Overall Recruitment Status
Completed
Study Start Date
July 18, 2011 (Actual)
Primary Completion Date
November 16, 2016 (Actual)
Study Completion Date
July 27, 2017 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
H. Lee Moffitt Cancer Center and Research Institute
Collaborators
Pediatric Cancer Foundation
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
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.
Detailed Description
This will be a phase I protocol of Vincristine, Dexamethasone, Doxorubicin, and PEG-asparaginase (VPLD) and metformin conducted in the Sunshine Project sites for children with recurrent ALL. All sites will be eligible to open this study, provided they agree to adhere to all study procedures and make a good faith effort to obtain all pharmacodynamic and pharmacokinetic evaluations requested.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Lymphoblastic Leukemia
Keywords
ALL, Relapsed, Refractory
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
14 (Actual)
8. Arms, Groups, and Interventions
Arm Title
VLPD Regimen
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Metformin
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Vincristine
Other Intervention Name(s)
Oncovin®, VCR, LCR, NSC #67574
Intervention Description
1.5 mg/m^2/dose IV push (maximum single dose 2 mg) on days 2, 9, 16 and 23
Intervention Type
Drug
Intervention Name(s)
Dexamethasone
Other Intervention Name(s)
Decadron®, Hexadrol®, Dexone®, Dexameth®, NSC #34521 (112004)
Intervention Description
10 mg/m^2/day divided BID
Take dexamethasone by mouth days 2-15
Intervention Type
Drug
Intervention Name(s)
PEG-asparaginase
Other Intervention Name(s)
Oncaspar, NSC #644954, Pegaspargase, Oncaspar®, Polyethylene, Glycol Conjugated L-asparaginase-H
Intervention Description
2500 IU's/m^2/day
Intramuscular injection (IM) or intravenous infusion per institutional standard on days 3, 9, 16 and 23
If the patient develops an allergic reaction to PEG while being treated on this protocol, eliminate all future doses of PEG and substitute Erwinia if not intolerant of Erwinia and has no history of pancreatitis.
Patients will receive Erwinase® 25,000 IU/m^2 x 6 doses intramuscularly (IM) on a Monday/Wednesday/Friday schedule as a replacement for each scheduled dose of PEG-asparaginase on the original protocol.
Intervention Type
Drug
Intervention Name(s)
Doxorubicin
Other Intervention Name(s)
Adriamycin®, NSC #123127 (102004)
Intervention Description
60 mg/m^2/day IV over 15 minutes on day 2
Intervention Type
Drug
Intervention Name(s)
Intrathecal chemotherapy
Other Intervention Name(s)
Cytosine Arabinoside, Ara-C, Cytosar®, NSC #63878 (102004)
Intervention Description
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.
30 mg for patients age 1-1.99
50 mg for patients age 2-2.99
70 mg for patients greater than 3 years of age IT methotrexate given Intrathecally to all patients who are CNS negative at study entry on day 16 at the dose defined by age.
Primary Outcome Measure Information:
Title
Maximum Tolerated Dose (MTD)
Description
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.
Time Frame
45 days
Secondary Outcome Measure Information:
Title
The Number of Participants with Complete Remission
Description
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
Time Frame
45 days
Title
The Number of Participants with Biological Response to Treatment
Description
To evaluate the biological response of ALL blasts from children receiving metformin in a window fashion and in later time points.
Time Frame
45 days
Title
The Number of Participants with Adverse Events as a Measure of Safety and Feasibility
Description
To demonstrate the safety and feasibility of the addition of metformin to induction chemotherapy for recurrent ALL.
Time Frame
45 Days
10. Eligibility
Sex
All
Minimum Age & Unit of Time
1 Year
Maximum Age & Unit of Time
30 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
ALL or lymphoblastic lymphoma patients in first or higher relapse.
Male or Female age 1-30 years at initial diagnosis.
Signed informed consent.
Karnofsky / Lansky score above 50%.
No known contraindications to intended therapies.
Prior anthracycline exposure: Patients must have had less than 350 mg/m^2 lifetime exposure of anthracycline chemotherapy.
It must be at least 6 months since the last treatment with a "VPLD" induction/re-induction type regimen (i.e. anthracycline, steroid, asparaginase and vincristine).
Patients must have adequate organ function.
Adequate renal function defined as serum creatinine < 1.5 x upper limit of normal (ULN) for age.
Total bilirubin < 1.5 X ULN for age.
Alanine transaminase (ALT) < 5 X ULN for age, unless the elevation is disease-related.
Adequate cardiac function as defined as shortening fraction of > 27% by echocardiogram or ejection fraction > 45% by gated radionuclide study.
Exclusion Criteria:
Significant renal impairment as determined per investigator discretion.
Patients planning on receiving other investigational agents while on this study.
Patients planning on receiving other anti-cancer therapies while on this study.
Patients with active infection defined as: positive blood culture within 48 hours of study registration; need for supplemental oxygen or vasopressors within 48 hours of study entry.
Patient receiving corticosteroids, aside from dexamethasone treatment directed at leukemia.
Known intolerance to doxorubicin, metformin, or vincristine.
Patients who have started protocol therapy prior to enrollment. Patient may still enroll if IT therapy was given within 72 hours of study enrollment as part of the diagnostic lumbar procedure.
Patients may be on hydroxurea until the first dose of metformin is to be given.
Patients who have a need to continue hydroxurea while on study (Patients may continue on hydroxurea only until the first dose of metformin is to given).
Patients with creatinine more than 1.5 x the ULN
Patients must have recovered from the acute side effects of all prior anticancer therapy.
At least 1 week from prior cytotoxic chemotherapy.
At least 4 weeks from craniospinal irradiation.
At least 4 months since hematopoietic stem cell transplant (HSCT) with no evidence of active graft-versus-host disease (GVHD).
Pregnant or lactating women.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Julio M. Barredo, M.D.
Organizational Affiliation
Holtz Children's Hospital University of Miami Miller School of Medicine
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Damon Reed, M.D.
Organizational Affiliation
H. Lee Moffitt Cancer Center and Research Institute
Official's Role
Principal Investigator
Facility Information:
Facility Name
Holtz Children's Hospital University of Miami Miller School of Medicine
City
Miami
State/Province
Florida
ZIP/Postal Code
33136
Country
United States
Facility Name
Arnold Palmer Hospital for Children
City
Orlando
State/Province
Florida
ZIP/Postal Code
32806
Country
United States
Facility Name
All Children's Hospital
City
Saint Petersburg
State/Province
Florida
ZIP/Postal Code
33701
Country
United States
Facility Name
Montefiore Medical Center, The Children's Hospital at Montefiore
City
The Bronx
State/Province
New York
ZIP/Postal Code
10467
Country
United States
Facility Name
Nationwide Children's Hospital
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43205
Country
United States
12. IPD Sharing Statement
Learn more about this trial
Vincristine, Dexamethasone, Doxorubicin, and PEG-asparaginase (VPLD) and Metformin for Relapsed Childhood Acute Lymphoblastic Leukemia (ALL)
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