Metformin in Children With Relapsed or Refractory Solid Tumors

• ClinicalTrials.gov Identifier: NCT01528046
• Recruitment Status: Completed
• First Posted: February 7, 2012
• Last Update Posted: January 13, 2023
• Sponsor: H. Lee Moffitt Cancer Center and Research Institute
• Collaborator: Pediatric Cancer Foundation
• Information provided by (Responsible Party): H. Lee Moffitt Cancer Center and Research Institute

Study Description

Brief Summary:

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 26 participants
• Allocation: N/A
• 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: September 24, 2012
• Actual Primary Completion Date: September 26, 2019
• Actual Study Completion Date: February 3, 2020

Arms and Interventions

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

Outcome Measures

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.

Eligibility Criteria

• Ages Eligible for Study: 1 Year to 18 Years (Child, Adult)
• Sexes Eligible for Study: All
• 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 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.

Contacts and Locations

Locations

United States, Connecticut

Connecticut Children's Medical Center

Hartford, Connecticut, United States, 06106

United States, Delaware

Nemours/Alfred I. duPont Hospital for Children, Delaware

Wilmington, Delaware, United States, 19803

United States, Florida

University of Florida

Gainesville, Florida, United States, 32611

Nemours Children's Clinic

Jacksonville, Florida, United States, 32207

University of Miami Sylvester Comprehensive Cancer Center

Miami, Florida, United States, 33136

Johns Hopkins All Children's Hospital

Saint Petersburg, Florida, United States, 33701

Tampa General Hospital

Tampa, Florida, United States, 33606

H. Lee Moffitt Cancer Center and Research Institute

Tampa, Florida, United States, 33612

United States, Kentucky

University of Kentucky

Lexington, Kentucky, United States, 40536

United States, Maryland

Johns Hopkins Sidney Kimmel Comprehensive Cancer Center

Baltimore, Maryland, United States, 21231

United States, New York

The Children's Hospital at Montefiore

Bronx, New York, United States, 10467

United States, North Carolina

University of North Carolina at Chapel Hill

Chapel Hill, North Carolina, United States, 27599

United States, Ohio

Nationwide Children's Hospital

Columbus, Ohio, United States, 43205

United States, Utah

Primary Children's Medical Center/Utah

Salt Lake City, Utah, United States, 84113

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:

Moffitt Cancer Center Clinical Trials website 

• Responsible Party: H. Lee Moffitt Cancer Center and Research Institute
• ClinicalTrials.gov Identifier: NCT01528046
• Other Study ID Numbers: MCC-16962; SP003 ( Other Grant/Funding Number: Pediatric Cancer Foundation )
• First Posted: February 7, 2012
• Last Update Posted: January 13, 2023
• Last Verified: January 2023

• 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); malignancy; relapsed; refractory; pediatric; recurrent

Additional relevant MeSH terms:

Neoplasms; Brain Neoplasms; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Metformin; Irinotecan; Camptothecin; Vincristine; Temozolomide; Hypoglycemic Agents; Physiological Effects of Drugs; Topoisomerase I Inhibitors; Topoisomerase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Alkylating; Alkylating Agents