Vincristine, Dexamethasone, Doxorubicin, and PEG-asparaginase (VPLD) and Metformin for Relapsed Childhood Acute Lymphoblastic Leukemia (ALL)

NCT ID: NCT01324180

Last Updated: 2017-08-07

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 14 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-07-18
• Study Completion Date: 2017-07-27

Brief Summary

H. Lee Moffitt Cancer Center and Research Institute will be the Sunshine Project Coordinator, but will not be recruiting locally.

The purpose of the trial is to study the clinical and biological effects of metformin in combination with standard systemic chemotherapy in a disease (relapsed ALL) that has a dismal outcome, as well as to do a dose escalation study to find the Maximum Tolerated Dose (MTD) of metformin in conjunction with ALL therapy. There have also been analysis of patients enrolled on trials who were diabetics on metformin and their outcome was better than patients on the same trial that were not on metformin as their antihyperglycemic.

Detailed Description

This will be a phase I protocol of Vincristine, Dexamethasone, Doxorubicin, and PEG-asparaginase (VPLD) and metformin conducted in the Sunshine Project sites for children with recurrent ALL. All sites will be eligible to open this study, provided they agree to adhere to all study procedures and make a good faith effort to obtain all pharmacodynamic and pharmacokinetic evaluations requested.

Conditions

Acute Lymphoblastic Leukemia

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

VLPD Regimen

Induction will consist of vincristine, dexamethasone, doxorubicin and PEG asparaginase (so called VPLD - dexamethasone is substituted for prednisone and PEG asparaginase is substituted for L-asparaginase) in combination with metformin. Eligible patients will receive 24 hours of metformin followed by induction. Intrathecal chemotherapy with standard dose cytarabine will be administered at the start of each cycle, with central nervous system (CNS) therapy afterwards determined by findings on staging lumbar puncture.

Group Type: EXPERIMENTAL

Metformin

Intervention Type: DRUG

Will be dosed orally BID as per dose level of subject as defined in dose escalation schema. Both liquid and tablet forms are allowed and can be chosen based on convenience. Metformin will be continued throughout the cycle until Day 28 or until the patient is removed from study (e.g. to pursue new lines of therapy such as transplant), whichever occurs sooner.

Vincristine

Intervention Type: DRUG

1.5 mg/m\^2/dose IV push (maximum single dose 2 mg) on days 2, 9, 16 and 23

Dexamethasone

Intervention Type: DRUG

• 10 mg/m^2/day divided BID
• Take dexamethasone by mouth days 2-15

PEG-asparaginase

Intervention Type: DRUG

• 2500 IU's/m^2/day
• Intramuscular injection (IM) or intravenous infusion per institutional standard on days 3, 9, 16 and 23
• If the patient develops an allergic reaction to PEG while being treated on this protocol, eliminate all future doses of PEG and substitute Erwinia if not intolerant of Erwinia and has no history of pancreatitis.
• Patients will receive Erwinase® 25,000 IU/m^2 x 6 doses intramuscularly (IM) on a Monday/Wednesday/Friday schedule as a replacement for each scheduled dose of PEG-asparaginase on the original protocol.

Doxorubicin

Intervention Type: DRUG

60 mg/m\^2/day IV over 15 minutes on day 2

Intrathecal chemotherapy

Intervention Type: DRUG

IT cytarabine given intrathecally to all patients on day 1 of each cycle. Dose defined by age. May be given with staging lumbar puncture before enrollment, but must be within 72 hours of starting therapy. If not done at study entry or before, may be done on Day 2 prior to doxorubicin administration.

• 30 mg for patients age 1-1.99
• 50 mg for patients age 2-2.99
• 70 mg for patients greater than 3 years of age IT methotrexate given Intrathecally to all patients who are CNS negative at study entry on day 16 at the dose defined by age.

Interventions

Metformin

Will be dosed orally BID as per dose level of subject as defined in dose escalation schema. Both liquid and tablet forms are allowed and can be chosen based on convenience. Metformin will be continued throughout the cycle until Day 28 or until the patient is removed from study (e.g. to pursue new lines of therapy such as transplant), whichever occurs sooner.

Intervention Type: DRUG

Vincristine

1.5 mg/m\^2/dose IV push (maximum single dose 2 mg) on days 2, 9, 16 and 23

Intervention Type: DRUG

Dexamethasone

• 10 mg/m^2/day divided BID
• Take dexamethasone by mouth days 2-15

Intervention Type: DRUG

PEG-asparaginase

• 2500 IU's/m^2/day
• Intramuscular injection (IM) or intravenous infusion per institutional standard on days 3, 9, 16 and 23
• If the patient develops an allergic reaction to PEG while being treated on this protocol, eliminate all future doses of PEG and substitute Erwinia if not intolerant of Erwinia and has no history of pancreatitis.
• Patients will receive Erwinase® 25,000 IU/m^2 x 6 doses intramuscularly (IM) on a Monday/Wednesday/Friday schedule as a replacement for each scheduled dose of PEG-asparaginase on the original protocol.

Intervention Type: DRUG

Doxorubicin

60 mg/m\^2/day IV over 15 minutes on day 2

Intervention Type: DRUG

Intrathecal chemotherapy

IT cytarabine given intrathecally to all patients on day 1 of each cycle. Dose defined by age. May be given with staging lumbar puncture before enrollment, but must be within 72 hours of starting therapy. If not done at study entry or before, may be done on Day 2 prior to doxorubicin administration.

• 30 mg for patients age 1-1.99
• 50 mg for patients age 2-2.99
• 70 mg for patients greater than 3 years of age IT methotrexate given Intrathecally to all patients who are CNS negative at study entry on day 16 at the dose defined by age.

Intervention Type: DRUG

Other Intervention Names

Oncovin®; VCR; LCR; NSC #67574; Decadron®; Hexadrol®; Dexone®; Dexameth®; NSC #34521 (112004); Oncaspar; NSC #644954; Pegaspargase; Oncaspar®; Polyethylene; Glycol Conjugated L-asparaginase-H; Adriamycin®; NSC #123127 (102004); Cytosine Arabinoside; Ara-C; Cytosar®; NSC #63878 (102004)

Eligibility Criteria

Inclusion Criteria

• ALL or lymphoblastic lymphoma patients in first or higher relapse.
• Male or Female age 1-30 years at initial diagnosis.
• Signed informed consent.
• Karnofsky / Lansky score above 50%.
• No known contraindications to intended therapies.
• Prior anthracycline exposure: Patients must have had less than 350 mg/m^2 lifetime exposure of anthracycline chemotherapy.
• It must be at least 6 months since the last treatment with a "VPLD" induction/re-induction type regimen (i.e. anthracycline, steroid, asparaginase and vincristine).
• Patients must have adequate organ function.

• Adequate renal function defined as serum creatinine < 1.5 x upper limit of normal (ULN) for age.
• Total bilirubin < 1.5 X ULN for age.
• Alanine transaminase (ALT) < 5 X ULN for age, unless the elevation is disease-related.
• Adequate cardiac function as defined as shortening fraction of > 27% by echocardiogram or ejection fraction > 45% by gated radionuclide study.

Exclusion Criteria

• Significant renal impairment as determined per investigator discretion.
• Patients planning on receiving other investigational agents while on this study.
• Patients planning on receiving other anti-cancer therapies while on this study.
• Patients with active infection defined as: positive blood culture within 48 hours of study registration; need for supplemental oxygen or vasopressors within 48 hours of study entry.
• Patient receiving corticosteroids, aside from dexamethasone treatment directed at leukemia.
• Known intolerance to doxorubicin, metformin, or vincristine.
• Patients who have started protocol therapy prior to enrollment. Patient may still enroll if IT therapy was given within 72 hours of study enrollment as part of the diagnostic lumbar procedure.
• Patients may be on hydroxurea until the first dose of metformin is to be given.
• Patients who have a need to continue hydroxurea while on study (Patients may continue on hydroxurea only until the first dose of metformin is to given).
• Patients with creatinine more than 1.5 x the ULN
• Patients must have recovered from the acute side effects of all prior anticancer therapy.

• At least 1 week from prior cytotoxic chemotherapy.
• At least 4 weeks from craniospinal irradiation.
• At least 4 months since hematopoietic stem cell transplant (HSCT) with no evidence of active graft-versus-host disease (GVHD).
• Pregnant or lactating women.

• Minimum Eligible Age: 1 Year
• Maximum Eligible Age: 30 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Pediatric Cancer Foundation

OTHER

Sponsor Role: collaborator

H. Lee Moffitt Cancer Center and Research Institute

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Julio M. Barredo, M.D.

Role: STUDY_CHAIR

Holtz Children's Hospital University of Miami Miller School of Medicine

Damon Reed, M.D.

Role: PRINCIPAL_INVESTIGATOR

H. Lee Moffitt Cancer Center and Research Institute

Locations

Holtz Children's Hospital University of Miami Miller School of Medicine

Miami, Florida, United States

Arnold Palmer Hospital for Children

Orlando, Florida, United States

All Children's Hospital

St. Petersburg, Florida, United States

Montefiore Medical Center, The Children's Hospital at Montefiore

The Bronx, New York, United States

Nationwide Children's Hospital

Columbus, Ohio, United States

Countries

United States

Other Identifiers

Sunshine Project 001

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

MCC-16601

Identifier Type: -

Identifier Source: org_study_id