Metformin in Children With Relapsed or Refractory Solid Tumors

NCT ID: NCT01528046

Last Updated: 2023-01-13

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE1

Total Enrollment

26 participants

Study Classification

INTERVENTIONAL

Study Start Date

2012-09-24

Study Completion Date

2020-02-03

Brief Summary

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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.

Detailed Description

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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.

Conditions

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Solid Tumors Primary Brain Tumors

Study Design

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Allocation Method

NA

Intervention Model

SINGLE_GROUP

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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Metformin in Combination with VIT

Participants will receive metformin in combination with vincristine, irinotecan and temozolomide (VIT).

Group Type EXPERIMENTAL

Vincristine

Intervention Type DRUG

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

Irinotecan

Intervention Type DRUG

Irinotecan (IRN) = 50 mg/m\^2/day, days 1-5, IV over 60 minutes

Temozolomide

Intervention Type DRUG

Temozolomide (TEM) = 50 mg/m\^2/day by mouth (PO) Days 1-5

Metformin

Intervention Type DRUG

Metformin (MET) = dose as per dose escalation, divided twice a day (BID), PO continuously for the 21 day cycle.

Interventions

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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

Intervention Type DRUG

Irinotecan

Irinotecan (IRN) = 50 mg/m\^2/day, days 1-5, IV over 60 minutes

Intervention Type DRUG

Temozolomide

Temozolomide (TEM) = 50 mg/m\^2/day by mouth (PO) Days 1-5

Intervention Type DRUG

Metformin

Metformin (MET) = dose as per dose escalation, divided twice a day (BID), PO continuously for the 21 day cycle.

Intervention Type DRUG

Other Intervention Names

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VCR Oncovin NSC #067574 Vincristine sulfate CPT-11 Camptothecin-11 Camptosar ® NSC#616348 IRN Temodar™ NSC #362856 TEM Glucophage ® MET

Eligibility Criteria

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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.

* 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.
Minimum Eligible Age

1 Year

Maximum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Pediatric Cancer Foundation

OTHER

Sponsor Role collaborator

H. Lee Moffitt Cancer Center and Research Institute

OTHER

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Jonathan Gill, M.D.

Role: STUDY_CHAIR

The Children's Hospital at Montefiore, Pediatric Cancer Foundation, Sunshine Project

Damon Reed, M.D.

Role: PRINCIPAL_INVESTIGATOR

H. Lee Moffitt Cancer Center and Research Institute

Locations

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Connecticut Children's Medical Center

Hartford, Connecticut, United States

Site Status

Nemours/Alfred I. duPont Hospital for Children, Delaware

Wilmington, Delaware, United States

Site Status

University of Florida

Gainesville, Florida, United States

Site Status

Nemours Children's Clinic

Jacksonville, Florida, United States

Site Status

University of Miami Sylvester Comprehensive Cancer Center

Miami, Florida, United States

Site Status

Johns Hopkins All Children's Hospital

St. Petersburg, Florida, United States

Site Status

Tampa General Hospital

Tampa, Florida, United States

Site Status

H. Lee Moffitt Cancer Center and Research Institute

Tampa, Florida, United States

Site Status

University of Kentucky

Lexington, Kentucky, United States

Site Status

Johns Hopkins Sidney Kimmel Comprehensive Cancer Center

Baltimore, Maryland, United States

Site Status

The Children's Hospital at Montefiore

The Bronx, New York, United States

Site Status

University of North Carolina at Chapel Hill

Chapel Hill, North Carolina, United States

Site Status

Nationwide Children's Hospital

Columbus, Ohio, United States

Site Status

Primary Children's Medical Center/Utah

Salt Lake City, Utah, United States

Site Status

Countries

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United States

References

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Metts JL, Trucco M, Weiser DA, Thompson P, Sandler E, Smith T, Crimella J, Sansil S, Thapa R, Fridley BL, Llosa N, Badgett T, Gorlick R, Reed D, Gill J. A phase I trial of metformin in combination with vincristine, irinotecan, and temozolomide in children with relapsed or refractory solid and central nervous system tumors: A report from the national pediatric cancer foundation. Cancer Med. 2023 Feb;12(4):4270-4281. doi: 10.1002/cam4.5297. Epub 2022 Sep 23.

Reference Type DERIVED
PMID: 36151773 (View on PubMed)

Other Identifiers

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SP003

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

MCC-16962

Identifier Type: -

Identifier Source: org_study_id

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