Working... Menu

Vincristine, Dexamethasone, Doxorubicin, and PEG-asparaginase (VPLD) and Metformin for Relapsed Childhood Acute Lymphoblastic Leukemia (ALL)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01324180
Recruitment Status : Completed
First Posted : March 28, 2011
Last Update Posted : August 7, 2017
Pediatric Cancer Foundation
Information provided by (Responsible Party):
H. Lee Moffitt Cancer Center and Research Institute

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.

Condition or disease Intervention/treatment Phase
Acute Lymphoblastic Leukemia Drug: Metformin Drug: Vincristine Drug: Dexamethasone Drug: PEG-asparaginase Drug: Doxorubicin Drug: Intrathecal chemotherapy Phase 1

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.

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 14 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
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)
Actual Study Start Date : July 18, 2011
Actual Primary Completion Date : November 16, 2016
Actual Study Completion Date : July 27, 2017

Arm Intervention/treatment
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.
Drug: Metformin
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:
  • Oncovin®
  • VCR
  • LCR
  • NSC #67574

Drug: Dexamethasone
  • 10 mg/m^2/day divided BID
  • Take dexamethasone by mouth days 2-15
Other Names:
  • Decadron®
  • Hexadrol®
  • Dexone®
  • Dexameth®
  • NSC #34521 (112004)

Drug: PEG-asparaginase
  • 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.
Other Names:
  • Oncaspar
  • NSC #644954
  • Pegaspargase
  • Oncaspar®
  • Polyethylene
  • Glycol Conjugated L-asparaginase-H

Drug: Doxorubicin
60 mg/m^2/day IV over 15 minutes on day 2
Other Names:
  • Adriamycin®
  • NSC #123127 (102004)

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.

  • 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.
Other Names:
  • Cytosine Arabinoside
  • Ara-C
  • Cytosar®
  • NSC #63878 (102004)

Primary Outcome Measures :
  1. 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.

Secondary Outcome Measures :
  1. 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

  2. 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.

  3. 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.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

Layout table for eligibility information
Ages Eligible for Study:   1 Year to 30 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01324180

Layout table for location information
United States, Florida
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
Sponsors and Collaborators
H. Lee Moffitt Cancer Center and Research Institute
Pediatric Cancer Foundation
Layout table for investigator information
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

Additional Information:
Layout table for additonal information
Responsible Party: H. Lee Moffitt Cancer Center and Research Institute Identifier: NCT01324180     History of Changes
Other Study ID Numbers: MCC-16601
Sunshine Project 001 ( Other Grant/Funding Number: Pediatric Cancer Foundation )
First Posted: March 28, 2011    Key Record Dates
Last Update Posted: August 7, 2017
Last Verified: August 2017

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by H. Lee Moffitt Cancer Center and Research Institute:

Additional relevant MeSH terms:
Layout table for MeSH terms
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Dexamethasone acetate
Liposomal doxorubicin
BB 1101
Anti-Inflammatory Agents
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Protease Inhibitors