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

Tracking Information

• First Submitted Date: February 3, 2012
• First Posted Date: February 7, 2012
• Last Update Posted Date: January 13, 2023
• Actual Study Start Date: September 24, 2012
• Actual Primary Completion Date: September 26, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 6, 2012)

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.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: February 6, 2012)

• Number of Participants with Antitumor Activity [ Time Frame: Average of 3 Months ]
  To evaluate the antitumor activity of the addition of metformin to VIT.
• Pharmacokinetics [ Time Frame: Average of 3 Months ]
  To describe the pharmacokinetics of metformin in children with relapsed malignancies receiving VIT combination chemotherapy.
• Pharmacodynamics [ Time Frame: Average of 3 Months ]
  To define the pharmacodynamics of metformin.
• Metformin Concentrations [ Time Frame: Average of 3 Months ]
  To determine tissue and tumor metformin concentrations in patients undergoing resection.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Metformin in Children With Relapsed or Refractory Solid Tumors
• 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
• 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.
• 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
• Study Phase: Phase 1
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Solid Tumors
• Primary Brain Tumors

Intervention

• 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

Study Arms

Experimental: Metformin in Combination with VIT

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

Interventions:

• Drug: Vincristine
• Drug: Irinotecan
• Drug: Temozolomide
• Drug: Metformin

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: July 22, 2019): 26
• Original Estimated Enrollment (submitted: February 6, 2012): 25
• Actual Study Completion Date: February 3, 2020
• Actual Primary Completion Date: September 26, 2019 (Final data collection date for primary outcome measure)

Eligibility 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 1 Year to 18 Years (Child, Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01528046
• Other Study ID Numbers: MCC-16962; SP003 ( Other Grant/Funding Number: Pediatric Cancer Foundation )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• 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

• IPD Sharing Statement: Not Provided
• Current Responsible Party: H. Lee Moffitt Cancer Center and Research Institute
• Original Responsible Party: Same as current
• Current Study Sponsor: H. Lee Moffitt Cancer Center and Research Institute
• Original Study Sponsor: Same as current
• Collaborators: 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

• PRS Account: H. Lee Moffitt Cancer Center and Research Institute
• Verification Date: January 2023