Pilot Study Of Sirolimus Plus Multiagent Chemotherapy For Relapsed/Refractory Acute Lymphoblastic Leukemia/Lymphoma

Inclusion Criteria:

Age: Patients must be < 30 years of age at the time of enrollment

Diagnosis

- Acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LL)

- Histology: B-precursor or T-cell

- Disease status: first or greater relapse OR primary disease refractory to two prior
induction attempts

- Patients with active relapse (> 5% bone marrow blasts if ALL, detectable disease by
imaging with CT and/or PET scan if LL) without prior re-induction attempt are
eligible for induction (block 1) therapy followed by consolidation (block 2) therapy

- Patients with documented history of relapse who have received alternative induction
therapy are eligible for consolidation (block 2) therapy

- Patients with CNS involvement are eligible for the induction block with intensified
intrathecal therapy. Those enrolling post-induction for the consolidation block must
have cleared the CNS of blasts at the time of enrollment on this study. (See Appendix
I for method of evaluating traumatic lumbar punctures.)

Performance status

-Karnofsky >/= 50 for patients > 10 years of age OR Lansky >/= 50 for children years of age (see Appendix II).

Oral medication -Patient must be able to consume oral medication in the form of solution
or have nasogastric tube placed for administration of medication.

Prior Therapy

- Patients who relapse while receiving standard ALL maintenance chemotherapy will not
be required to have a waiting period before entry onto this study.

- Patients who relapse on therapy other than standard ALL maintenance therapy must have
recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or
radiotherapy prior to entering this study, unless deemed stable and irreversible by
the investigator.

- Recovery is defined as a toxicity grade < 2 as defined by the Common Toxicity
Criteria Version (CTCAE) 4.0, unless otherwise specified in the Inclusion and
Exclusion criteria.

- Cytotoxic chemotherapy: At least 7 days must have elapsed from prior cytotoxic
chemotherapy regimen before initiation of treatment with sirolimus on this
trial, including administration of treatment dosing of corticosteroids
(physiologic replacement for adrenal insufficiency is allowed)

- Hydroxyurea: patients with peripheral blasts may receive hydroxyurea until the
first dose of cytotoxic chemotherapy for cytoreduction.

- Hematopoietic growth factors: At least 14 days after the last dose of a
long-acting growth factor (e.g. Neulasta) or 7 days for short-acting growth
factor.

- Biologic (anti-neoplastic) agent: At least 7 days after the last dose of a
biologic agent or donor lymphocyte infusion (DLI). For agents that have known
adverse events occurring beyond 7 days after administration, this period must be
extended beyond the time during which adverse events are known to occur. The
duration of this interval must be discussed with the study chair.

- Immunotherapy: At least 6 weeks since the completion of any type of
immunotherapy, e.g. tumor vaccines.

- Monoclonal antibodies: At least 3 half-lives since prior therapy with a
monoclonal antibody.

- XRT: >/= 2 wks for local palliative XRT (small port); >/= 24 weeks must have
elapsed if prior TBI, craniospinal XRT or if >/= 50% radiation of pelvis; >/= 6
weeks must have elapsed if other substantial bone marrow radiation.

- Stem Cell Transplant or Rescue without TBI: No evidence of active graft vs. host
disease and ≥ 12 weeks must have elapsed since transplant or stem cell infusion.

Organ Function Requirements

Adequate Renal Function Defined as:

- Creatinine clearance or radioisotope GFR >/= 70ml/min/1.73 m2 or

- A serum creatinine based on age/gender as follows:

The threshold creatinine values in this Table were derived from the Schwartz formula for
estimating GFR (Schwartz et al. J. Peds, 106:522, 1985) utilizing child length and stature
data published by the CDC.

Adequate Liver Function Defined as:

- Total bilirubin >/= 1.5 x upper limit of normal (ULN) for age

- SGPT (ALT)
Fasting serum cholesterol one or both of these thresholds are exceeded, the patient can only be enrolled after
initiation of appropriate lipid lowering medication and improvement in laboratory
parameters to meet eligibility.

Fasting serum glucose
Adequate Cardiac Function Defined as:

- NOTE: this applies for patients enrolling for induction block 1 only. Patients who
do not meet these criteria may be eligible for block 2 therapy after alternative
induction block

- Shortening fraction of >/= 27% by echocardiogram

- Cumulative prior anthracycline exposure must not exceed 400 mg/m2 (each 10 mg/m2 of
idarubicin/mitoxantrone should be calculated as the isotoxic equivalent of 30 mg/m2
of daunorubicin or doxorubicin)

Hematologic parameters

- NOTE: this applies for patients enrolling for consolidation block 2 only. Patients
enrolling for induction have no blood count requirements

- Patients enrolling for consolidation block 2 after receiving alternative re-induction
not on study must have ANC >/= 750/uL, platelets >/= 75,000/uL and bone marrow with

Exclusion Criteria

Pregnancy or Breast-Feeding

-Pregnancy tests must be obtained in females of childbearing potential. Pregnant or
lactating patients are ineligible for this study. Males or females of reproductive
potential may not participate unless they have agreed to use an effective contraceptive
method.

Patients With Uncontrolled Infection

- Patients must have any active infection under control. Fungal disease must be stable
for at least 2 weeks before enrollment. Patients with bacteremia must have
documented negative blood cultures for > 48 hours prior to initiation of treatment.

- Patients who have a known allergy to sirolimus, FK506 (cross-reactive), or other mTOR
inhibitors

- Patients who have a history of asparaginase-associated pancreatitis ARE eligible but
will have asparaginase omitted from therapy. Patients who have a history of E-coli
asparaginase allergy will receive Erwinia asparaginase.

- Patients with active lung disease as defined by presence of pulmonary infiltrates on
screening chest x-ray or baseline room air oxygen saturation of < 93%

- Patients with a known history of hepatitis B, C, or HIV

- Patients who, in the opinion of the investigator, may not be able to comply with the
safety monitoring requirements of the study

Concomitant Medications

- Hematopoietic growth factor(s): Must not have received within 7 days of entry onto
this study for a short-acting growth factor, or within 14 days for a long-acting
growth factor

- Azoles: Due to interference with sirolimus metabolism, voriconazole, itraconazole,
fluconazole, and ketoconazole should be avoided and alternative antifungal therapy
initiated. If one of these agents must be given, sirolimus dosing will be decreased
by 80% and trough levels monitored every other day for the first week and then weekly
per protocol.

- Calcineurin inhibitors: Must be off of tacrolimus and/or cyclosporine for at least 2
weeks prior to entry on this study

- Additional medications that interact with CYP3A4: See Appendix III of the protocol
for medications to be avoided while receiving sirolimus. Patients should be off
these medications at least 2 weeks prior to entry on this study. If the medication is
deemed essential and cannot be discontinued, sirolimus dosing will be adjusted
following discussion with the study pharmacologist, Dr. Vinks, depending on the
degree of expected interaction. Levels should be monitored every other day during the
first week, then weekly per protocol.