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

Phase 1

Completed

• Conditions: Acute Lymphoblastic Leukemia
• Interventions: Drug: Metformin; Drug: Vincristine; Drug: Dexamethasone; Drug: PEG-asparaginase; Drug: Doxorubicin; Drug: Intrathecal chemotherapy

• Registration Number: NCT01324180
• Lead Sponsor: H. Lee Moffitt Cancer Center and Research Institute

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.

Study Timeline

• Study First Submitted: 2011-03-24
• Study First Submitted QC: 2011-03-25
• Study First Posted: 2011-03-28
• Study Start: 2011-07-18
• Primary Completion: 2016-11-16
• Study Completion: 2017-07-27
• Status Verified: 2017-08
• Last Update Submitted: 2017-08-04
• Last Update Posted: 2017-08-07

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 14

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.

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
VLPD Regimen	Intrathecal chemotherapy	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.
VLPD Regimen	Metformin	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.
VLPD Regimen	Vincristine	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.
VLPD Regimen	Dexamethasone	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.
VLPD Regimen	PEG-asparaginase	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.
VLPD Regimen	Doxorubicin	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.

Primary Outcome Measures

Name	Time	Method
Maximum Tolerated Dose (MTD)	45 days	MTD determined by Dose Limiting Toxicity (DLT), any time during the first course of therapy. Dose Limiting Toxicities: Any Grade 3 or 4 non-hematological toxicity by Common Toxicity Criteria for Adverse Effects (CTCAE) version 4.0 felt to be probably or definitely related to the study agent, persistent marrow aplasia at day 44, lactic acidosis for grade 3 or 4, grade 3 and 4 hypoglycemia.

Secondary Outcome Measures

Name	Time	Method
The Number of Participants with Complete Remission	45 days	Patients who have: * No evidence of circulating blasts or extramedullary disease; * A bone marrow with \<5% blasts (M1 marrow); and; * Recovery of peripheral counts (platelets ≥75,000 and absolute neutrophil count (ANC) ≥750); * Qualifying marrow and peripheral counts should be performed within 1 week of each other
The Number of Participants with Biological Response to Treatment	45 days	To evaluate the biological response of ALL blasts from children receiving metformin in a window fashion and in later time points.
The Number of Participants with Adverse Events as a Measure of Safety and Feasibility	45 Days	To demonstrate the safety and feasibility of the addition of metformin to induction chemotherapy for recurrent ALL.

Trial Locations

Locations (5)

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; 🇺🇸 Saint Petersburg, Florida, United States

Nationwide Children's Hospital; 🇺🇸 Columbus, Ohio, United States

Montefiore Medical Center, The Children's Hospital at Montefiore; 🇺🇸 The Bronx, New York, United States