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

NCT01324180 | Completed Phase 1 DMC FDA Drug

• 2 other identifiers: MCC-16601Sunshine Project 001
• Study Type: interventional
• Target: 14
• Locations: 1 country
• Sites: 5

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.

Conditions

Acute Lymphoblastic Leukemia

Keywords

ALL; Relapsed; Refractory

Outcome Measures

Primary Outcomes (1)

• Maximum Tolerated Dose (MTD)

  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.

  45 days

Secondary Outcomes (3)

• The Number of Participants with Complete Remission

  45 days

• The Number of Participants with Biological Response to Treatment

  45 days

• The Number of Participants with Adverse Events as a Measure of Safety and Feasibility

  45 Days

Study Arms (1)

VLPD Regimen

EXPERIMENTAL

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.

Drug: Metformin; Drug: Vincristine; Drug: Dexamethasone; Drug: PEG-asparaginase; Drug: Doxorubicin; Drug: Intrathecal chemotherapy

Interventions

Metformin 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.

VLPD Regimen

Vincristine DRUG

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

Also known as: Oncovin®, VCR, LCR, NSC #67574

VLPD Regimen

Dexamethasone DRUG

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

Also known as: Decadron®, Hexadrol®, Dexone®, Dexameth®, NSC #34521 (112004)

VLPD Regimen

PEG-asparaginase 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.

Also known as: Oncaspar, NSC #644954, Pegaspargase, Oncaspar®, Polyethylene, Glycol Conjugated L-asparaginase-H

VLPD Regimen

Doxorubicin DRUG

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

Also known as: Adriamycin®, NSC #123127 (102004)

VLPD Regimen

Intrathecal chemotherapy 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.

Also known as: Cytosine Arabinoside, Ara-C, Cytosar®, NSC #63878 (102004)

VLPD Regimen

Eligibility Criteria

• Age: 1 Year - 30 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• H. Lee Moffitt Cancer Center and Research Institute: lead
• Pediatric Cancer Foundation: collaborator

Study Sites (5)

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

Miami, Florida, 33136, United States

Location

Arnold Palmer Hospital for Children

Orlando, Florida, 32806, United States

Location

All Children's Hospital

St. Petersburg, Florida, 33701, United States

Location

Montefiore Medical Center, The Children's Hospital at Montefiore

The Bronx, New York, 10467, United States

Location

Nationwide Children's Hospital

Columbus, Ohio, 43205, United States

Location

MeSH Terms

Conditions

Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence

Interventions

Metformin; Vincristine; Dexamethasone; Calcium Dobesilate; pegaspargase; Polyethylene; Doxorubicin; Cytarabine

Condition Hierarchy (Ancestors)

Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals; Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Alkaloids; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indolizidines; Indolizines; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated; Benzenesulfonates; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Arylsulfonates; Arylsulfonic Acids; Sulfonic Acids; Sulfur Acids; Sulfur Compounds; Polyethylenes; Polyenes; Alkenes; Hydrocarbons, Acyclic; Plastics; Polymers; Macromolecular Substances; Biomedical and Dental Materials; Manufactured Materials; Technology, Industry, and Agriculture; Daunorubicin; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Aminoglycosides; Glycosides; Carbohydrates; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides

Study Officials

• Julio M. Barredo, M.D.

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

  STUDY CHAIR

• Damon Reed, M.D.

  H. Lee Moffitt Cancer Center and Research Institute

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 24, 2011
• First Posted: March 28, 2011
• Study Start: July 18, 2011
• Primary Completion: November 16, 2016
• Study Completion: July 27, 2017
• Last Updated: August 7, 2017

Record last verified: 2017-08

Locations

US (5)