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

This study is currently recruiting participants. (see Contacts and Locations)
Verified March 2016 by H. Lee Moffitt Cancer Center and Research Institute
Sponsor:
Collaborator:
Pediatric Cancer Foundation
Information provided by (Responsible Party):
H. Lee Moffitt Cancer Center and Research Institute
ClinicalTrials.gov Identifier:
NCT01324180
First received: March 24, 2011
Last updated: March 25, 2016
Last verified: March 2016
  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.


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

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: 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)

Resource links provided by NLM:


Further study details as provided by H. Lee Moffitt Cancer Center and Research Institute:

Primary Outcome Measures:
  • Maximum 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.


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.


Estimated Enrollment: 18
Study Start Date: March 2011
Estimated Study Completion Date: November 2016
Estimated Primary Completion Date: November 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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)

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.
  Eligibility

Ages Eligible for Study:   1 Year to 30 Years   (Child, Adult)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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 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.
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01324180

Contacts
Contact: Tiffany Smith 813-745-6250 tiffany.smith@moffitt.org
Contact: Damon Reed, M.D. 813-745-2297 damon.reed@moffitt.org

Locations
United States, Connecticut
Connecticut Children's Medical Center Recruiting
Hartford, Connecticut, United States, 06106
Contact: Robin Arens    860-545-9637    Rarens@ccmckids.org   
Principal Investigator: Michael Isakoff, M.D.         
United States, Delaware
Nemours/Alfred I. duPont Hospital for Children Recruiting
Wilmington, Delaware, United States, 19803
Contact: Debra J. Bertz    302-651-5757    debra.bertz@nemours.org   
Principal Investigator: Christopher Frantz, M.D.         
Sub-Investigator: Lisa Sray, M.D.         
Sub-Investigator: Robin E. Miller, M.D.         
Sub-Investigator: Edward A. Kolb, M.D.         
Sub-Investigator: Emi H. Caywood, M.D.         
Sub-Investigator: Andrew W. Walter, M.D.         
Sub-Investigator: Jonathan Powell, M.D.         
Sub-Investigator: Gregory C. Griffin, M.D.         
United States, Florida
University of Florida Shands Cancer Center Recruiting
Gainesville, Florida, United States, 32610
Contact: Giselle Moore-Higs    352-271-8154    moorgi@ufl.edu   
Principal Investigator: William Slayton, M.D.         
Sub-Investigator: Levette Dunbar, M.D.         
Sub-Investigator: Joanne Lagmay, M.D.         
Sub-Investigator: Lamis Eldjerou, M.D.         
Sub-Investigator: Burak Gumuscu, M.D.         
Sub-Investigator: Tung Wynn, M.D.         
Sub-Investigator: Elias Sayour, M.D.         
Sub-Investigator: John Fort, M.D.         
Nemours Children's Clinic Recruiting
Jacksonville, Florida, United States, 32207
Contact: Mary Lawlor-Barry    904-697-3817    mbarry@nemours.org   
Principal Investigator: Scott Bradfield, M.D.         
Sub-Investigator: Eric Sandler, M.D.         
Sub-Investigator: Michael Joyce, M.D.         
Sub-Investigator: Paul Pitel, M.D.         
Sub-Investigator: Manisha Bansal, M.D.         
Sub-Investigator: Cynthia Gauger, M.D.         
Holtz Children's Hospital University of Miami Miller School of Medicine Recruiting
Miami, Florida, United States, 33136
Contact: Myriam Zayas    305-243-7846    MZayas2@med.miami.edu   
Principal Investigator: John M. Goldberg, M.D.         
Sub-Investigator: Julio Barredo, M.D.         
Sub-Investigator: Ofelia Alvarez, M.D.         
Sub-Investigator: Cristina Fernandes, M.D.         
Sub-Investigator: Joanna Davis, M.D.         
Sub-Investigator: Antonello Podda, M.D.         
Sub-Investigator: Martin Andreansky, M.d.         
Arnold Palmer Hospital for Children Recruiting
Orlando, Florida, United States, 32806
Contact: Stacey O'Brien    321-841-7957    obrien@orlandohealth.com   
Principal Investigator: Robert M. Sutphin, M.D.         
Sub-Investigator: Alejandro Levy, M.D.         
Sub-Investigator: Susan Kelly, M.D.         
Sub-Investigator: Amy A. Smith, M.D.         
Sub-Investigator: Don E. Eslin, M.D.         
Sub-Investigator: Vincent F. Giusti, M.D.         
All Children's Hospital Recruiting
St. Petersburg, Florida, United States, 33701
Contact: Ashley J. Repp, RN    727-767-4784    Ashley.Repp@allkids.org   
Principal Investigator: Gregory Hale, M.D.         
Sub-Investigator: Irmel Ayala, M.D.         
Sub-Investigator: Jennifer Mayer, M.D.         
Sub-Investigator: Nanette Grana, M.D.         
Sub-Investigator: Stacie Stapleton, M.D.         
Sub-Investigator: Michael Nieder, M.D.         
Sub-Investigator: Jessica Wishnew, M.D.         
Sub-Investigator: Benjamin Oshrine, M.D.         
Sub-Investigator: Calvin Lee, M.D.         
Sub-Investigator: Alesksandra Petrovic, M.D.         
Sub-Investigator: David Shyr, M.D.         
Sub-Investigator: Colin Moore, M.D.         
Principal Investigator: Damon Reed, M.D.         
Tampa General Hospital Recruiting
Tampa, Florida, United States, 33606
Contact: Katherine Seib    813-844-7829    katherinenseib@tgh.org   
Principal Investigator: Cameron Tebbi, M.D.         
United States, New York
Montefiore Medical Center, The Children's Hospital at Montefiore Recruiting
Bronx, New York, United States, 10467
Contact: Brian J. Sunwoo    718-741-2356    cstanfor@montefiore.org   
Contact: Noam Zeffren    718-741-2356    bsunwoo@montefiore.org   
Principal Investigator: Jonathan Gill, M.D.         
Sub-Investigator: Richard Gorlick, M.D.         
Sub-Investigator: Rosanna Ricafort, M.D.         
Sub-Investigator: Peter Cole, M.D.         
Sub-Investigator: Deepa Manwani, M.D.         
Sub-Investigator: Catherine Driscoll, M.D.         
Sub-Investigator: Karen Moody, M.D.         
Sub-Investigator: Adam Levy, M.D.         
United States, Ohio
Nationwide Children's Hospital Recruiting
Columbus, Ohio, United States, 43205
Contact: Amy Yekisa    614-722-6570    Amy.Yekisa@nationwidechildrens.org   
Principal Investigator: Bhuvana Setty, M.D.         
Sub-Investigator: Robyn Dennis, M.D.         
Sponsors and Collaborators
H. Lee Moffitt Cancer Center and Research Institute
Pediatric Cancer Foundation
Investigators
Study Chair: John M. Goldberg, 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
  More Information

Additional Information:
Responsible Party: H. Lee Moffitt Cancer Center and Research Institute
ClinicalTrials.gov Identifier: NCT01324180     History of Changes
Other Study ID Numbers: MCC-16601  Sunshine Project 001 
Study First Received: March 24, 2011
Last Updated: March 25, 2016
Health Authority: United States: Food and Drug Administration

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

Additional relevant MeSH terms:
Leukemia
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Metformin
Dexamethasone acetate
Dexamethasone
Dexamethasone 21-phosphate
Liposomal doxorubicin
Pegaspargase
Doxorubicin
Vincristine
Asparaginase
Cytarabine
BB 1101
Hypoglycemic Agents
Physiological Effects of Drugs
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists

ClinicalTrials.gov processed this record on July 24, 2016