AflacLL1602 ENCERT

T- cell acute lymphoblastic leukemia (T-ALL) or T-cell lymphoblastic lymphoma (T-LLy) has an
increase in proteins in a specific pathway called the mTOR pathway within the cancer cells.
In cancer cells it can encourage untimely cell growth, cell production, and cell survival.
Everolimus is an inhibitor of the mTOR pathway and can decrease the growth and survival of
cancer cells. It also prevents communication within cells and stops proteins from being made
that may contribute to leukemia.

Two to six participants will receive the starting dose of everolimus. If the side effects are
not too severe, the next group of participants will take the study drug at a higher dose
level. Up to two dose levels of the study drug will be tested. The main purpose of the study
is to find the maximum tolerated dose of everolimus when used together with standard
chemotherapy. Everolimus has been found to be safe and effective in adults and children for
treatment of T- and B-cell leukemias and lymphomas.

Inclusion Criteria:

1.1 Age: Subjects must be > than 1 year and < 30 years of age at the time of study
enrollment.

1.2 Diagnosis Leukemia

Patients must have relapsed (first or greater relapse) or refractory T-cell acute
lymphoblastic leukemia (T-ALL) with:

1. Relapsed T-ALL with an M2 (blasts ≥ 5 to ≤ 25%) or M3 (>25% blasts) marrow with or
without an extramedullary site of relapse; including CNS 2 OR

2. Refractory disease after induction failure of newly diagnosed patients OR no more than
two more cycles of therapy OR

3. Refractory disease with no more than one prior salvage attempt following the current
relapse

Lymphoma

Patients must have relapsed (first or greater relapse) or refractory lymphoma with:

1. Lymphoblastic lymphoma or peripheral T-cell lymphoma.

2. Histologic verification of disease at original diagnosis or subsequent relapse.

3. Evaluable or measurable disease documented by clinical or radiographic criteria or
bone marrow disease present at study entry.

4. Patient may have CNS 2 status if other sites of leukemia or lymphoma involvement are
present.

1.3 Performance Score Patients must have a Karnofsky ≥ 50% for subjects > 16 years of
age and Lansky score ≥ 50 for subjects ≤ 16 years of age (See Appendix I).

Note: Subjects who are unable to walk because of paralysis, but who are up in a
wheelchair, will be considered ambulatory for the purpose of assessing the performance
score.

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

B. Patients who relapse on therapy other than standard ALL maintenance therapy must
have fully recovered from the acute toxic effects of all prior chemotherapy,
immunotherapy, or radiotherapy prior to entering this study.

- Cytotoxic Chemotherapy: At least 7 days must have elapsed since the completion of
cytotoxic therapy (other than standard ALL maintenance therapy as per 4.1.4.B)
with the exception of hydroxyurea, which is permitted up to 24 hours prior to the
start of protocol therapy.

- Nitrosureas: At least 42 days must have elapsed since administration of
nitrosureas.

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

- Radiation: At least 84 days must have elapsed since administration of
craniospinal, hemipelvic or other radiation therapy to more than 25% of the bone
marrow containing spaces. At least 42 days must have elapsed if other substantial
marrow radiation has been given.

- Nelarabine Prior therapy: Patients who have previously been treated with
nelarabine are eligible, however if they have previously received a regimen of
nelarabine, cyclophosphamide and etoposide, they are not eligible.

- Biologic (anti-neoplastic agent): At least 7 days after the last dose of a
biologic agent. 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 42 days after the completion of any type of immunotherapy
(e.g., tumor vaccines or chimeric antigen receptor T cell (CART) therapy

- Monoclonal Antibodies: Monoclonal antibodies: At least 3 half-lives of the
antibody must have elapsed after the last dose of a monoclonal antibody (See
Appendix II for details)

- Stem Cell Infusion: No evidence of active graft vs. host disease and at least 84
days must have elapsed after transplant or stem cell infusion.

- Study specific limitations on prior therapy: Patient may not have previously
received therapy with an mTOR inhibitor.

- Prior Intrathecal Therapy: Patients may be enrolled on study regardless of the
timing of prior Intrathecal therapy; however, they MAY NOT BEGIN TREATMENT ON
THIS PROTOCOL UNTIL A MINIMUM OF 7 DAYS HAS ELAPSED SINCE PRIOR INTRATHECAL
THERAPY.

1.5 Adequate organ function

A. Adequate Bone Marrow Function Defined as:

• Patients should not be known to be refractory to red blood cell or platelet
transfusions.

• Blood counts are not required to be normal prior to enrollment on trial.

B. Adequate Hepatic Function defined as:

• Total bilirubin (sum of conjugated + unconjugated) ≤ 1.5 x institutional upper limit
of normal for age

- SGPT (ALT) and SGOT (AST) must be ≤ 3 x institutional upper limit of normal
(Grade 1 or less per CTCAE 4).

- GGT must be ≤ 2.5 x institutional upper limit of normal (Grade 1 or less per
CTCAE 4).

- Serum albumin ≥ 2 g/dL.

- The hepatic requirements may be waived for patients with Grade 1 or 2 elevations
of hepatic transaminases clearly due to leukemic infiltration after consultation
with a study Co-Chair.

C. Adequate Renal Function defined as:

• Serum creatinine ≤ 1.5x upper limit of normal (ULN) for age. If the serum creatinine
is above these values, the calculated creatinine clearance or radioisotope GFR must be
≥ 70 mL/min/1.73m2.

D. Adequate Cardiac Function defined as:

- Shortening fraction of ≥ 27% by echocardiogram, OR

- Ejection fraction of ≥ 50% by gated radionuclide study/echocardiogram

E. Adequate Pulmonary Function defined as:

- Pulse oximetry > 94% on room air

- No evidence of dyspnea at rest and no exercise intolerance.

- Baseline chest x-ray with no evidence of active infectious disease or
pneumonitis.

F. Reproductive Function

• Female patients of childbearing potential must have a negative urine or serum
pregnancy test confirmed prior to enrollment.

- Female patients with infants must agree not to breastfeed their infants while on
the study.

- Male and female patients of child-bearing potential must agree to use an
effective method of contraception approved by the investigator during the study.

G. Normal blood glucose levels as defined as:

- Fasting or random blood glucose within the upper limits of normal for age.

- If random blood glucose is above upper limits for age, a fasting blood glucose
can be obtained and must be within normal limits for age

H. Normal triglyceride and cholesterol as defined as:

• Fasting or non-fasting serum triglyceride level ≤ 300 mg/dL and serum cholesterol
level ≤ 300 mg/dL.

1.6 Informed Consent Patients and/or their parents or legal guardians must be capable
of understanding the investigational nature, potential risks and benefits of the
study. All patients and/or their parents or legal guardians must sign a written
informed consent. Age appropriate assent will be obtained per institutional
guidelines. To allow non-native speaking patients to participate in this study,
bilingual health services will be provided in the appropriate language, when feasible,
according to individual institutional practices and guidelines

1.7 Protocol Approval All institutional, local, state, FDA, and OHRP requirements for
human studies must be met.

Exclusion Criteria:

2.1 Diagnosis

• Patients with CNS3 disease as defined in section 4.3.1

• Patients with isolated extra-medullary relapse involving only sanctuary sites (eg.
Testicular relapse) but patients with extramedullary disease involving nodal or other
non-sanctuary sites are eligible

• Patients with isolated testicular relapse

• Patients with Ph+ T-ALL/T-LLy

- Patients with Down Syndrome

- Patients with pre-existing Grade 2 (or higher) peripheral motor or sensory
neurotoxicity per CTCAE 4.03

- Patients with a history of prior veno-occlusive disease (VOD)/sinusoidal
obstruction syndrome (SOS) or findings consistent with a diagnosis of VOD/SOS,
defined as: conjugated serum bilirubin >1.4 mg/dL AND unexplained weight gain
greater than 10% of baseline weight or ascites AND hepatomegaly or right upper
quadrant pain without another explanation, OR reversal of portal vein flow on
ultrasound, OR pathological confirmation of VOD on liver biopsy.

2.2 Infection Criteria

• Positive blood culture within 48 hours of study enrollment;

• Fever above 38.2 within 48 hours of study enrollment with clinical signs of
infection. Fever that is determined to be due to tumor burden is allowed if patients
have documented negative blood cultures for at least 48 hours prior to enrollment and
no concurrent signs or symptoms of active infection or hemodynamic instability.

• Active fungal, viral, bacterial, or protozoal infection requiring IV treatment.
Chronic prophylaxis therapy to prevent infections is allowed

2.3 Skin condition Patients with pre-existing Grade 1 or higher ulcerations, fistulas,
mucosal lesions, or skin barrier breakdown

2.4 Concomitant Medications

- Corticosteroids: Patients receiving corticosteroids who have not been on a stable
or decreasing dose of corticosteroid for at least 7 days prior to enrollment are
not eligible. Corticosteroids must be held for 24 hours prior to initiation of
study therapy.

- Investigational Drugs: Patients who are currently receiving another
investigational drug are not eligible. The definition of "investigational" for
use in this protocol means any drug that is not licensed by the FDA

- Anti-cancer agents: Patients who are currently receiving or may receive while on
therapy, other anti-cancer agents, radiation therapy or immunotherapy are not
eligible [except leukemia patients who relapsed on Maintenance therapy or
patients receiving hydroxyurea, which may be continued until 24 hours prior to
start of protocol therapy]. Intrathecal therapy may be given up to one week prior
to initiation of study treatment.

- Anti-GVHD or agents to prevent organ rejection post-transplant: Patients who are
receiving cyclosporine, tacrolimus or other agents to prevent either
graft-versus-host disease post bone marrow transplant or organ rejection
post-transplant are not eligible for this trial. At least 3 half-lives must have
elapsed after the last dose of GVHD meds.

- Angiotensin-converting enzyme (ACE) inhibitors: Patients who are currently
receiving ACE inhibitors are not eligible due to the development of angioneurotic
edema-type reactions in some subjects who received concurrent treatment with
everolimus + ACE inhibitors. At least 3 half-lives must have elapsed after the
last dose of ACE inhibitors.

- Anti-convulsants: Patients who are currently receiving CYP3A4/PgP enzyme inducing
anticonvulsants (eg. phenytoin, phenobarbitol, or carbamazepine) are not
eligible. Stabilizing on a non-hepatic inducing metabolizing anti-convulsant (ie:
gabapentin or levetiracetam) prior to study entry is acceptable. At least 3
half-lives must have elapsed after the last dose of enzyme inducing
anti-convulsants.

- Inhibitors of everolimus metabolism: Patients receiving treatment with azoles
such as fluconazole or voriconazole which are potent inhibitors of everolimus
metabolism. At least 3 half-lives must have elapsed after the last dose of
azoles.

2.5 Patients with significant concurrent disease, illness, psychiatric disorder or
social issue that would compromise patient safety or compliance with protocol
treatment or required observations, interfere with consent, study participation,
follow up, or interpretation of study results.