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

Overview[ - collapse ][ - ]

Purpose 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.
ConditionAcute Lymphoblastic Leukemia
InterventionDrug: Metformin
Drug: Vincristine
Drug: Dexamethasone
Drug: PEG-asparaginase
Drug: Doxorubicin
Drug: Intrathecal chemotherapy
PhasePhase 1
SponsorH. Lee Moffitt Cancer Center and Research Institute
Responsible PartyH. Lee Moffitt Cancer Center and Research Institute
ClinicalTrials.gov IdentifierNCT01324180
First ReceivedMarch 24, 2011
Last UpdatedDecember 3, 2013
Last verifiedDecember 2013

Tracking Information[ + expand ][ + ]

First Received DateMarch 24, 2011
Last Updated DateDecember 3, 2013
Start DateMarch 2011
Estimated Primary Completion DateJuly 2014
Current Primary Outcome MeasuresMaximum Tolerated Dose (MTD) [Time Frame: 45 days] [Designated as safety issue: No]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.
Current Secondary Outcome Measures
  • The Number of Participants with Complete Remission [Time Frame: 45 days] [Designated as safety issue: No]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] [Designated as safety issue: No]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] [Designated as safety issue: Yes]To demonstrate the safety and feasibility of the addition of metformin to induction chemotherapy for recurrent ALL.

Descriptive Information[ + expand ][ + ]

Brief TitleVincristine, Dexamethasone, Doxorubicin, and PEG-asparaginase (VPLD) and Metformin for Relapsed Childhood Acute Lymphoblastic Leukemia (ALL)
Official TitleA 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)
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.
Study TypeInterventional
Study PhasePhase 1
Study DesignEndpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
ConditionAcute Lymphoblastic Leukemia
InterventionDrug: 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)
Study Arm (s)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.

Recruitment Information[ + expand ][ + ]

Recruitment StatusRecruiting
Estimated Enrollment18
Estimated Completion DateJuly 2014
Estimated Primary Completion DateJuly 2014
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.

- 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.

- No corticosteroids allowed aside from dexamethasone treatment directed at leukemia.

- Patients who are allergic to PEG-asparaginase or who cannot tolerate any
asparaginase, either because of history of pancreatitis or allergy, will go on study
without asparaginase.

- 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 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.
GenderBoth
Ages1 Year
Accepts Healthy VolunteersNo
ContactsContact: Kathleen Manning
813-745-7412
kathleen.manning@moffitt.org
Location CountriesUnited States

Administrative Information[ + expand ][ + ]

NCT Number NCT01324180
Other Study ID NumbersMCC-16601
Has Data Monitoring CommitteeYes
Information Provided ByH. Lee Moffitt Cancer Center and Research Institute
Study SponsorH. Lee Moffitt Cancer Center and Research Institute
CollaboratorsPediatric Cancer Foundation
Investigators Study Chair: John M. Goldberg, M.D. Holtz Children's Hospital University of Miami Miller School of MedicinePrincipal Investigator: Damon Reed, M.D. H. Lee Moffitt Cancer Center and Research Institute
Verification DateDecember 2013

Locations[ + expand ][ + ]

University of Florida Shands Cancer Center
Gainesville, Florida, United States, 32610
Contact: Heather Rogers | 352-265-0027 | heatherrogers@ufl.edu
Principal Investigator: William Slayton, M.D.
Recruiting
Nemours Children's Clinic
Jacksonville, Florida, United States, 32207
Contact: Mary Lawlor-Barry | 904-697-3817 | mbarry@nemours.org
Principal Investigator: Scott Bradfield, M.D.
Recruiting
Holtz Children's Hospital University of Miami Miller School of Medicine
Miami, Florida, United States, 33136
Contact: Myriam Zayas | 305-243-7846 | MZayas2@med.miami.edu
Principal Investigator: John M. Goldberg, M.D.
Recruiting
M.D. Anderson of Orlando
Orlando, Florida, United States, 32806
Contact: Stephanie Garber, R.N. | 321-841-3837 | stephanie.garber@orlandohealth.com
Principal Investigator: Robert Sutphin, M.D.
Recruiting
All Children's Hospital
St. Petersburg, Florida, United States, 33701
Contact: Frances Hamblin | 727-767-2423 | frances.hamblin@allkids.org
Principal Investigator: Gregory Hale, M.D.
Recruiting
Montefiore Medical Center, The Children's Hospital at Montefiore
Bronx, New York, United States, 10467
Contact: Catherine Stanford | 718-741-2356 | cstanfor@montefiore.org
Principal Investigator: Jonathan Gill, M.D.
Recruiting