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

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.

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.