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

Status: complete

This phase I trial studies the side effects and best dose of metformin hydrochloride when given together with combination chemotherapy in treating younger patients with acute lymphoblastic leukemia that has returned after a period of improvement (relapsed) or does not respond to treatment (refractory). Metformin hydrochloride may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as vincristine sulfate, dexamethasone, doxorubicin hydrochloride, and pegaspargase, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving metformin hydrochloride together with combination chemotherapy may kill more cancer cells.

Inclusion Criteria

ALL or lymphoblastic lymphoma patients in first or higher relapse
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)
Serum creatinine =< 1.5 x upper limit of normal (ULN) for age
Total bilirubin =< 1.5 x ULN for age
Alanine aminotransferase (ALT) =< 5 x ULN for age, unless the elevation is disease-related
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
Patients 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 * Please note: patient may still enroll if IT therapy was given within 72 hours of study enrollment as part of the diagnostic lumbar procedure
Patients who have a need to continue hydroxyurea while on study * Please note: patients may continue on hydroxyurea only until the first dose of metformin is to be 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

PRIMARY OBJECTIVES:

I. To demonstrate the safety and feasibility of the addition of metformin (metformin hydrochloride) to induction chemotherapy for recurrent acute lymphoblastic leukemia (ALL).

II. To demonstrate the maximum tolerated dose (MTD) of metformin when given twice daily by mouth to children receiving induction chemotherapy and describe the pharmacokinetics of metformin when given in this setting.

SECONDARY OBJECTIVES:

I. To evaluate the clinical response to the addition of metformin to induction chemotherapy and to estimate a response rate.

II. To evaluate the biological response of ALL blasts from children receiving metformin in a window fashion and in later time points.

III. To describe the toxicity profile of children treated with concurrent metformin and vincristine sulfate, dexamethasone, doxorubicin hydrochloride, and pegaspargase (VPLD) therapy.

OUTLINE: This is a dose-escalation study of metformin hydrochloride.

Patients receive metformin hydrochloride orally (PO) twice daily (BID) on days 1-28; vincristine sulfate intravenously (IV) on days 2, 9, 16, and 23; dexamethasone PO BID on days 2-15; pegaspargase intramuscularly (IM) or IV on days 3, 9, 16, and 23, patients with allergic reaction to pegaspargase may receive asparaginase erwinia chrysanthemi IM thrice weekly on a Monday, Wednesday, and Friday schedule beginning on days 3-5 through day 28; and doxorubicin hydrochloride IV over 15 minutes on day 2. Patients also receive cytarabine intrathecally (IT) on day 1 and methotrexate IT on day 16. Patients with central nervous system (CNS) positive also receive methotrexate IT, cytarabine IT and hydrocortisone IT on days 9, 16, and 23. Treatment repeats every 25-44 days in the absence of disease progression or unacceptable toxicity. Patients receive 1 course of this induction with intention to go to hematopoietic stem cell transplant (HSCT) or appropriate maintenance after this first course, with the option to receive a second course, depending on investigator preference and the clinical situation.

After completion of study treatment, patients are followed up for 30 days.

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

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