Metformin in Children With Relapsed or Refractory Solid Tumors

Sponsor

H. Lee Moffitt Cancer Center and Research Institute (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT01528046

Collaborator

Pediatric Cancer Foundation (Other)

Enrollment

Locations

Arm

125.2

Anticipated Duration (Months)

1.9

Patients Per Site

Patients Per Site Per Month

Study Details

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

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 :

Sep 24, 2012

Actual Primary Completion Date :

Sep 26, 2019

Anticipated Study Completion Date :

Mar 1, 2023

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

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

Maximum Tolerated Dose (MTD) [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

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

1 Year to 18 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

	Site	City	State	Country	Postal Code
1	Connecticut Children's Medical Center	Hartford	Connecticut	United States	06106
2	Nemours/Alfred I. duPont Hospital for Children, Delaware	Wilmington	Delaware	United States	19803
3	University of Florida	Gainesville	Florida	United States	32611
4	Nemours Children's Clinic	Jacksonville	Florida	United States	32207
5	University of Miami Sylvester Comprehensive Cancer Center	Miami	Florida	United States	33136
6	Johns Hopkins All Children's Hospital	Saint Petersburg	Florida	United States	33701
7	Tampa General Hospital	Tampa	Florida	United States	33606
8	H. Lee Moffitt Cancer Center and Research Institute	Tampa	Florida	United States	33612
9	University of Kentucky	Lexington	Kentucky	United States	40536
10	Johns Hopkins Sidney Kimmel Comprehensive Cancer Center	Baltimore	Maryland	United States	21231
11	The Children's Hospital at Montefiore	Bronx	New York	United States	10467
12	University of North Carolina at Chapel Hill	Chapel Hill	North Carolina	United States	27599
13	Nationwide Children's Hospital	Columbus	Ohio	United States	43205
14	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