Metformin in Children With Relapsed or Refractory Solid Tumors

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. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT01528046
Recruitment Status : Recruiting
First Posted : February 7, 2012
Last Update Posted : January 11, 2018
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 this study is to evaluate the tolerability and safety of escalating doses of metformin on a backbone of vincristine, irinotecan and temozolomide (VIT) in children with recurrent and refractory solid tumors.

Condition or disease Intervention/treatment Phase
Solid Tumors Primary Brain Tumors Drug: Vincristine Drug: Irinotecan Drug: Temozolomide Drug: Metformin Phase 1

Detailed Description:
Metformin is an oral anti-diabetes medication that activates AMP-activated protein kinase (AMPK). Recent data from in vitro and in vivo experiments, as well as epidemiologic retrospective analyses, suggest that metformin has anti-cancer activity. Vincristine, irinotecan, and temozolomide (VIT) is a combination of chemotherapeutic agents that have different mechanisms of action as well as disparate side effect profiles. Two recent phase 1 trials have demonstrated that this regimen is safe and well-tolerated in children with relapsed and refractory solid tumors.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 25 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I Trial of Dose Escalation of Metformin in Combination With Vincristine, Irinotecan, and Temozolomide in Children With Relapsed or Refractory Solid Tumors
Actual Study Start Date : April 25, 2012
Estimated Primary Completion Date : December 2018
Estimated Study Completion Date : December 2019

Resource links provided by the National Library of Medicine

U.S. FDA Resources

Arm Intervention/treatment
Experimental: Metformin in Combination with VIT
Participants will receive metformin in combination with vincristine, irinotecan and temozolomide (VIT).
Drug: Vincristine
Vincristine (VCR) = 1.5 mg/m^2/day (maximum dose 2 mg), days 1 and 8, administered as intravenous (IV) bolus over 1-5 minutes
Other Names:
  • VCR
  • Oncovin
  • NSC #067574
  • Vincristine sulfate
Drug: Irinotecan
Irinotecan (IRN) = 50 mg/m^2/day, days 1-5, IV over 60 minutes
Other Names:
  • CPT-11
  • Camptothecin-11
  • Camptosar ®
  • NSC#616348
  • IRN
Drug: Temozolomide
Temozolomide (TEM) = 50 mg/m^2/day by mouth (PO) Days 1-5
Other Names:
  • Temodar™
  • NSC #362856
  • TEM
Drug: Metformin
Metformin (MET) = dose as per dose escalation, divided twice a day (BID), PO continuously for the 21 day cycle.
Other Names:
  • Glucophage ®
  • MET

Primary Outcome Measures :
  1. Maximum Tolerated Dose (MTD) [ Time Frame: Average of 3 Months ]
    To determine the maximum tolerated dose (MTD) of metformin when given in conjunction with VIT in children with refractory and relapsed solid tumors.

Secondary Outcome Measures :
  1. Number of Participants with Antitumor Activity [ Time Frame: Average of 3 Months ]
    To evaluate the antitumor activity of the addition of metformin to VIT.

  2. Pharmacokinetics [ Time Frame: Average of 3 Months ]
    To describe the pharmacokinetics of metformin in children with relapsed malignancies receiving VIT combination chemotherapy.

  3. Pharmacodynamics [ Time Frame: Average of 3 Months ]
    To define the pharmacodynamics of metformin.

  4. Metformin Concentrations [ Time Frame: Average of 3 Months ]
    To determine tissue and tumor metformin concentrations in patients undergoing resection.

Information from the National Library of Medicine

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Ages Eligible for Study:   1 Year to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Age: Patients must be > 1 year of age and ≤ 18 years of age at time of initiation of protocol therapy.
  • Diagnosis: Patients have a histologically or radiographically confirmed relapsed or refractory solid tumor or primary central nervous system (CNS) malignancy.
  • Disease Status: Patients must have radiographically measurable disease.
  • Therapeutic Options: Patients must have relapsed or refractory cancers for which there is no known curative option or other available therapy proven to prolong survival with an acceptable quality of life.
  • Performance Level: Karnofsky ≥ 50% for patients older than 16 years old, and Lansky ≥ 50 for patients 1-16 years old.
  • Prior Therapy: Patients may have received prior therapy including vincristine, irinotecan, or temozolomide. Patients may not have previously been treated with combination therapy of irinotecan and temozolomide.
  • Patients must be fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study.

    • Myelosuppressive chemotherapy: Patients must not have received myelosuppressive chemotherapy within 3 weeks of starting protocol therapy, or a minimum of six weeks must have elapsed since prior nitrosurea chemotherapy.
    • Hematopoietic growth factor: At least 7 days must have elapsed since the last administration of filgrastim, or 14 days since administration of pegfilgrastim.
    • Biologic (anti-neoplastic agent): At least 7 must have elapsed since the last administration of any biologic agent.
    • Radiation therapy (XRT): At least 14 days since the last dose of local palliative radiation therapy. Greater than 6 months must have elapsed since the last day of treatment if given total body irradiation, craniospinal irradiation.
    • Autologous or Allogenic Stem Cell Transplant: Complete resolution of graft versus host disease and no current need for immunosuppressive medication. Greater than 3 months must have elapsed since engraftment and no longer requiring transfusion of platelets or injection of colony stimulating factors.
  • Organ Function Requirements

    • Bone Marrow Function: Peripheral absolute neutrophil count (ANC) ≥ 1000/μL; Platelet count ≥ 100,000/μL (no platelet transfusion within 7 days prior to obtaining laboratory result); Hemoglobin ≥ 8.0 gm/dL
    • Adequate Renal Function: Creatinine clearance or glomerular filtration rate ≥ 70ml/min/1.73m^2
    • Adequate Liver Function: Total bilirubin ≤ 1.5x upper limit of normal (ULN) for age; alanine transaminase (ALT) ≤ 5x ULN; Serum albumin ≥ 2gm/dL
  • Informed Consent: All patients ≥ 18 years of age must sign a written informed consent. For patients < 18 years old, the patient's parents or legal guardians must sign a written informed consent, unless the patient is an emancipated minor. Childhood Assent, when age appropriate as per institutional guidelines, should be signed by the participating patient.

Exclusion Criteria:

  • Significant organ dysfunction, not meeting inclusion criteria.
  • Pregnancy or Breast-Feeding woman will not be entered on this study due to risks of fetal and teratogenic adverse events as seen in animal/human studies.
  • Concomitant Medications:

    • Growth factor: Growth factors that support platelet or white cell number of function must not have been administered within the past 7 days.
    • Steroids: Patients with CNS tumors who have not been on a stable or decreasing dose of dexamethasone for the past 7 days.
    • Investigational Drugs: Patients who are currently receiving another investigational drug.
    • Anti-cancer Agents: Patients who are currently receiving other anti-cancer agents.
    • Medication Allergy: Allergy or intolerance to agents on this protocol: vincristine, irinotecan, temozolomide, or metformin; Allergy to cephalosporins.
    • Infection: Patients who have uncontrolled infection, positive blood cultures within the past 48 hours, or receiving treatment for Clostridium difficile infection.

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): NCT01528046

Contact: Tiffany Smith 813-745-6250
Contact: Damon Reed, M.D. 813-745-2297

United States, Connecticut
Connecticut Children's Medical Center Recruiting
Hartford, Connecticut, United States, 06106
Contact: Robin Arens    860-545-9637   
Principal Investigator: Michael Isakoff, M.D.         
Sub-Investigator: Donna Boruchov, M.D.         
Sub-Investigator: Kerry Moss, M.D.         
Sub-Investigator: Andrea Orsey, M.D.         
Sub-Investigator: Nehal Parikh, M.D.         
Sub-Investigator: Arnold Altman, M.D.         
United States, Delaware
Nemours/Alfred I. duPont Hospital for Children, Delaware Recruiting
Wilmington, Delaware, United States, 19803
Contact: Debra J. Bertz    302-651-5757   
Principal Investigator: Edward A. Kolb, M.D.         
Sub-Investigator: Andrew Walter, M.D.         
Sub-Investigator: Jonathan Powell, M.D.         
Sub-Investigator: Emi Caywood, M.D.         
Sub-Investigator: Robin Miller, M.D.         
Sub-Investigator: Gregory Griffin, M.D.         
United States, Florida
University of Florida Terminated
Gainesville, Florida, United States, 32611
Nemours Children's Clinic Recruiting
Jacksonville, Florida, United States, 32207
Contact: Ingrid Ingram    904-697-3985   
Principal Investigator: Scott Bradfield, M.D.         
Sub-Investigator: Eric Sandler, M.D.         
Sub-Investigator: Michael Joyce, M.D.         
Sub-Investigator: Cynthia Gauger, M.D.         
Sub-Investigator: Manisha Bansal, M.D.         
Sub-Investigator: Paul Pitel, M.D.         
Holtz Children's Hospital at the University of Miami Recruiting
Miami, Florida, United States, 33124
Contact: Myriam Zayas    305-243-7846   
Principal Investigator: John Goldberg, 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.         
Sub-Investigator: Julio Barredo, M.D.         
Sub-Investigator: Ofelia Alvarez, M.D.         
Johns Hopkins All Children's Hospital Recruiting
Saint Petersburg, Florida, United States, 33701
Contact: Ashley Repp, RN    727-767-4784   
Contact: Frances Hamblin    727-767-2423   
Principal Investigator: Damon Reed, M.D.         
Sub-Investigator: Irmel Ayala, M.D.         
Sub-Investigator: Gregory Hale, M.D.         
Sub-Investigator: Nanette Grana, M.D.         
Sub-Investigator: Stacie Stapleton, M.D.         
Sub-Investigator: Kelly Sawczyn, M.D.         
Sub-Investigator: Jennifer Mayer, M.D.         
Sub-Investigator: Jody Kerr, M.D.         
Tampa General Hospital Recruiting
Tampa, Florida, United States, 33606
Contact: Denise Fife    813-844-7829   
Principal Investigator: Cameron Tebbi, M.D.         
United States, Kentucky
University of Kentucky Recruiting
Lexington, Kentucky, United States, 40536
Contact: Tammy Taylor    859-323-6975   
Principal Investigator: Lars Wagner, M.D.         
United States, Maryland
Johns Hopkins Sidney Kimmel Comprehensive Cancer Center Recruiting
Baltimore, Maryland, United States, 21231
Contact: David Loeb, M.D.    410-502-7247   
Principal Investigator: David Loeb, M.D.         
United States, New York
The Children's Hospital at Montefiore Recruiting
Bronx, New York, United States, 10467
Contact: Noam Zeffren    718-741-2356   
Principal Investigator: Jonathan Gill, M.D.         
United States, North Carolina
University of North Carolina at Chapel Hill Recruiting
Chapel Hill, North Carolina, United States, 27599
Contact: Sharon Guerry    919-966-1178      
Contact: Patrick Thompson, M.D    919-966-1178   
Principal Investigator: Patrick Thompson, M.D.         
United States, Ohio
Nationwide Children's Hospital Recruiting
Columbus, Ohio, United States, 43205
Contact: Amy Yekisa    614-722-6570   
Principal Investigator: Bhuvana Setty, M.D.         
United States, Utah
Primary Children's Medical Center/Utah Recruiting
Salt Lake City, Utah, United States, 84113
Contact: Melissa Bolton    801-213-3909   
Principal Investigator: Holly Spraker-Perlman, M.D.         
Sub-Investigator: Richard Lemons, M.D., Ph.D.         
Sub-Investigator: Jennifer Wright, M.D.         
Sponsors and Collaborators
H. Lee Moffitt Cancer Center and Research Institute
Pediatric Cancer Foundation
Study Chair: Jonathan Gill, M.D. The Children's Hospital at Montefiore, Pediatric Cancer Foundation, Sunshine Project
Principal Investigator: Damon Reed, M.D. H. Lee Moffitt Cancer Center and Research Institute

Additional Information:
Responsible Party: H. Lee Moffitt Cancer Center and Research Institute Identifier: NCT01528046     History of Changes
Other Study ID Numbers: MCC-16962
SP003 ( Other Grant/Funding Number: Pediatric Cancer Foundation )
First Posted: February 7, 2012    Key Record Dates
Last Update Posted: January 11, 2018
Last Verified: January 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Keywords provided by H. Lee Moffitt Cancer Center and Research Institute:
central nervous system (CNS)

Additional relevant MeSH terms:
Brain Neoplasms
Central Nervous System Neoplasms
Nervous System Neoplasms
Neoplasms by Site
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Hypoglycemic Agents
Physiological Effects of Drugs
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Topoisomerase I Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Alkylating
Alkylating Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators