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

H. Lee Moffitt Cancer Center and Research Institute

Status and phase: Completed; Phase 1

Conditions: Acute Lymphoblastic Leukemia

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

Study type: Interventional

Funder types: Other

Identifiers

NCT01324180

MCC-16601

Sunshine Project 001 (Other Grant/Funding Number)

Details and patient eligibility

About

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.

Full 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.

Enrollment: 14 patients

Sex: All

Ages: 1 to 30 years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: N/A

Interventional model: Single Group Assignment

Masking: None (Open label)

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14 participants in 1 patient group

VLPD Regimen

Experimental group

Description:

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.

Treatment:

Drug: Dexamethasone

Drug: Metformin

Drug: Intrathecal chemotherapy

Drug: Doxorubicin

Drug: PEG-asparaginase

Drug: Vincristine