Metformin in Children With Relapsed or Refractory Solid Tumors

This study is currently recruiting participants.
Verified April 2014 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:
NCT01528046
First received: February 3, 2012
Last updated: April 4, 2014
Last verified: April 2014
  Purpose

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 Intervention Phase
Solid Tumors
Primary Brain Tumors
Drug: Vincristine sulfate
Drug: Irinotecan
Drug: Temozolomide
Drug: Metformin
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 Trial of Dose Escalation of Metformin in Combination With Vincristine, Irinotecan, and Temozolomide in Children With Relapsed or Refractory Solid Tumors

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: Average of 3 Months ] [ Designated as safety issue: Yes ]
    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:
  • Number of Participants with Antitumor Activity [ Time Frame: Average of 3 Months ] [ Designated as safety issue: No ]
    To evaluate the antitumor activity of the addition of metformin to VIT.

  • Pharmacokinetics [ Time Frame: Average of 3 Months ] [ Designated as safety issue: No ]
    To describe the pharmacokinetics of metformin in children with relapsed malignancies receiving VIT combination chemotherapy.

  • Pharmacodynamics [ Time Frame: Average of 3 Months ] [ Designated as safety issue: No ]
    To define the pharmacodynamics of metformin.

  • Metformin Concentrations [ Time Frame: Average of 3 Months ] [ Designated as safety issue: No ]
    To determine tissue and tumor metformin concentrations in patients undergoing resection.


Estimated Enrollment: 25
Study Start Date: September 2012
Estimated Study Completion Date: April 2015
Estimated Primary Completion Date: April 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Metformin in Combination with VIT

All patients will receive VIT only for their initial cycle of protocol treatment.

All patients who have no significant bone marrow suppression (hematologic parameters recovered by Day 21, meeting eligibility criteria to proceed to next cycle) will proceed with metformin as per dose escalation with the second and all subsequent cycles.

For patients with bone marrow suppression not recovered by Day 21:

  • Dose modification as per protocol
  • Second cycle with VIT only, to validate that dose modification has resolved the bone marrow suppression.

    • Patients who tolerate dose modification with their second cycle will receive metformin with their subsequent cycles as per dose escalation stratum.
    • Patients who had dose modification and do not recover by Day 21 to meet eligibility criteria will be removed from study prior to receiving metformin and will be considered unevaluable.
Drug: Vincristine sulfate
Vincristine (VCR) = 1.5 mg/m^2/day (maximum dose 2 mg), days 1 and 8, administered as IV bolus over 1-5 minutes
Other Names:
  • VCR
  • Oncovin
  • NSC #067574
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) = 100 mg/m^2/day PO Days 1-5
Other Names:
  • Temodar™
  • NSC #362856
  • TEM
Drug: Metformin
Metformin (MET) = dose as per dose escalation, divided BID, PO continuously Metformin will only be started after the completion of first cycle, in patients who have demonstrated no significant bone marrow suppression with VIT only.
Other Names:
  • Glucophage ®
  • MET

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.

  Eligibility

Ages Eligible for Study:   1 Year to 18 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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 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 10 years old, and Lansky ≥ 50 for patients ≤ 10 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 patients' 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.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01528046

Contacts
Contact: Kathleen Manning 813-745-7412 kathleen.manning@moffitt.org
Contact: Damon Reed, M.D. 813-745-2297 damon.reed@moffitt.org

Locations
United States, Delaware
Nemours/Alfred I. duPont Hospital for Children, Delaware Recruiting
Wilmington, Delaware, United States, 19803
Contact: Debra J. Bertz    302-651-5757    debra.bertz@nemours.org   
Principal Investigator: Edward A. Kolb, M.D.         
United States, Florida
University of Florida Recruiting
Gainesville, Florida, United States, 32611
Contact: Heather Rogers    352-265-0027    heatherrogers@ufl.edu   
Principal Investigator: Joanne Lagmay, M.D.         
Sub-Investigator: Tung Wynn, M.D.         
Sub-Investigator: William Slayton, M.D.         
Sub-Investigator: Lamis Eldjerou, M.D.         
Sub-Investigator: John Fort, M.D.         
Sub-Investigator: Levette Dunbar, M.D.         
Nemours Children's Clinic Recruiting
Jacksonville, Florida, United States, 32207
Contact: Ingrid Ingram    904-697-3985    iingram@nemours.org   
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.         
University of Miami Recruiting
Miami, Florida, United States, 33124
Contact: Myriam Zayas    305-243-7846    MZayas2@med.miami.edu   
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: Andreansky Martin, M.D.         
Sub-Investigator: Julio Barredo, M.D.         
Sub-Investigator: Ofelia Alvarez, M.D.         
All Children's Hospital Recruiting
St. Petersburg, Florida, United States, 33701
Contact: Ashley Repp, RN    727-767-4784    Ashley.Repp@allkids.org   
Contact: Frances Hamblin    727-767-2423    frances.hamblin@allkids.org   
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.         
United States, New York
The Children's Hospital at Montefiore Recruiting
Bronx, New York, United States, 10467
Contact: Noam Zeffren    718-741-2356    nzeffren@montefiore.org   
Principal Investigator: Jonathan Gill, 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    melissa.bolton@hsc.utah.edu   
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
Investigators
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
  More Information

Additional Information:
No publications provided

Responsible Party: H. Lee Moffitt Cancer Center and Research Institute
ClinicalTrials.gov Identifier: NCT01528046     History of Changes
Other Study ID Numbers: MCC-16962, SP003
Study First Received: February 3, 2012
Last Updated: April 4, 2014
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by H. Lee Moffitt Cancer Center and Research Institute:
central nervous system (CNS)
malignancy
relapsed
refractory
pediatric
recurrent

Additional relevant MeSH terms:
Brain Neoplasms
Neoplasms
Central Nervous System Neoplasms
Nervous System Neoplasms
Neoplasms by Site
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Camptothecin
Irinotecan
Vincristine
Temozolomide
Metformin
Topoisomerase I Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Antineoplastic Agents, Phytogenic
Hypoglycemic Agents
Physiological Effects of Drugs
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Antineoplastic Agents, Alkylating
Alkylating Agents
Radiation-Sensitizing Agents

ClinicalTrials.gov processed this record on April 17, 2014