Clinical trial NCT01528046: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Solid Tumors
Primary Brain Tumors
Keywords: central nervous system (CNS)
malignancy
relapsed
refractory
pediatric
recurrent
Lead sponsor: H. Lee Moffitt Cancer Center and Research Institute
Sponsor class: OTHER
Collaborators: name: Pediatric Cancer Foundation
First posted: 2012-02-07
Enrollment: 26
Sex: ALL
Minimum age (years): 1
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Maximum Tolerated Dose (MTD)
timeFrame: Average of 3 Months
Secondary outcomes:
measure: Number of Participants with Antitumor Activity
timeFrame: Average of 3 Months
measure: Pharmacokinetics
timeFrame: Average of 3 Months
measure: Pharmacodynamics
timeFrame: Average of 3 Months
measure: Metformin Concentrations
timeFrame: Average of 3 Months
Other outcomes:
Locations:
city: Hartford
country: United States
facility: Connecticut Children's Medical Center
state: Connecticut
city: Wilmington
country: United States
facility: Nemours/Alfred I. duPont Hospital for Children, Delaware
state: Delaware
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Jacksonville
country: United States
facility: Nemours Children's Clinic
state: Florida
city: Miami
country: United States
facility: University of Miami Sylvester Comprehensive Cancer Center
state: Florida
city: Saint Petersburg
country: United States
facility: Johns Hopkins All Children's Hospital
state: Florida
city: Tampa
country: United States
facility: Tampa General Hospital
state: Florida
city: Tampa
country: United States
facility: H. Lee Moffitt Cancer Center and Research Institute
state: Florida
city: Lexington
country: United States
facility: University of Kentucky
state: Kentucky
city: Baltimore
country: United States
facility: Johns Hopkins Sidney Kimmel Comprehensive Cancer Center
state: Maryland
city: Bronx
country: United States
facility: The Children's Hospital at Montefiore
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina at Chapel Hill
state: North Carolina
city: Columbus
country: United States
facility: Nationwide Children's Hospital
state: Ohio
city: Salt Lake City
country: United States
facility: Primary Children's Medical Center/Utah
state: Utah
Study officials:
affiliation: The Children's Hospital at Montefiore, Pediatric Cancer Foundation, Sunshine Project
name: Jonathan Gill, M.D.
role: STUDY_CHAIR
affiliation: H. Lee Moffitt Cancer Center and Research Institute
name: Damon Reed, M.D.
role: PRINCIPAL_INVESTIGATOR
References: