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

You will receive the drug sirolimus in addition to standard chemotherapy drugs.

Just like your original cancer treatment, relapsed leukemia/lymphoma treatment is divided
into different parts. You will get sirolimus during the first two parts:

1. Re-induction: We give chemotherapy drugs to try to put your cancer back into remission,
meaning that no cancer cells are found in the bone marrow samples (if you have leukemia)
or on imaging studies (if you have lymphoma). From start to finish, this part of therapy
lasts 35 days. On this study, you will take the drug sirolimus daily in addition to the
normal re-induction chemotherapy drugs. You will swallow liquid sirolimus and you must
take it with food. You will take sirolimus three times on the first day and two times
each day after that during re-induction.

Altogether, this is the schedule for re-induction:

- Sirolimus by mouth starting 7 days before standard re-induction starts, and
continuing every day through day 28

- Mitoxantrone by vein on days 1 and 2

- Vincristine by vein on days 3, 10, 17 and 24

- Dexamethasone by vein or by mouth on days 1-5 and 15-19

- PEG-asparaginase* on days 3 and 17

- IT Methotrexate given in spinal fluid on day 1 (all patients) day 8,29 (if no
cancer found in spinal fluid)

- IT Triples given in spinal fluid on days 8,15,22,29 (if cancer found in spinal
fluid)

(If you have an allergic reaction to PEG-asparaginase, you may be given 6 doses of
Erwinia L-asparaginase instead)

2. Consolidation: We give drugs to continue to kill cancer cells in your body and prevent
them from coming back. From start to finish, this part of therapy will last 63 days (it
could be longer if we have to interrupt your treatment because you have low blood
counts, and you need to wait for them to come up). On this study, you will take the drug
sirolimus daily in addition to the normal consolidation chemotherapy drugs. You will
take sirolimus three times on the first day and two times each day after that during
consolidation.

Altogether, this is the schedule for consolidation:

- Sirolimus by mouth starting 7 days before consolidation starts, and continuing
every day through day 56.

- Cyclophosphamide by vein on days 1 and 29

- Cytarabine by vein or under skin on days 1-4, 8-11, 29-32, 36-39

- 6-mercaptopurine by mouth on days 1-14, 29-42

- PEG-asparaginase* by vein on days 15 and 43

- Vincristine by vein on days 15 and 43

- It Methotrexate in spinal fluid on Days 1 and 29

3. After you complete re-induction and consolidation, your doctor will determine the next
steps of your treatment. This will depend on how you are doing and it will be up to you
and your doctor. It will not be part of this study.

This research only includes the re-induction and consolidation portions of treatment (1 and
2, above). If you have already done re-induction, you can enter the study for consolidation
only.

In addition to all the regular tests and procedures done to check on your cancer during this
study, we will also take additional blood samples to monitor the levels of sirolimus in your
blood (in order to adjust your dose) and we will also take blood samples to find certain
markers in your blood that might indicate that the sirolimus is doing what it is supposed to
do.

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 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 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.