A Trial of Temsirolimus With Etoposide and Cyclophosphamide in Children With Relapsed Acute Lymphoblastic Leukemia and Non-Hodgkins Lymphoma

Studies have shown that mTOR inhibitors (MTI) inhibit growth of pre-B and T-cell ALL cell
lines in vitro and in ALL xenograft models. The MTI temsirolimus was chosen for use in this
study due to its weekly intravenous dosing, its more predictable blood levels, and
availability of a single-agent pediatric MTD and its sustained biologic effect due to
conversion to sirolimus. This study will determine the maximum tolerated dose of temsirolimus
that can given in combination with dexamethasone, cyclophosphamide and etoposide in relapsed
ALL, LL or PTL. A standard 3-patient cohort dose-escalation design will be used. Response to
treatment will be evaluated. Biology tests will be done to evaluate minimal residual disease
(MRD), temsirolimus' effect on glucocorticoid resistance, and mTOR inhibition.

INCLUSION CRITERIA

-Patients must be greater than or equal to 12 months and ≤ 21 years of age at the time of
study enrollment.

Patients must have one of the following:

Leukemia

- Bone marrow involvement defined as ALL ≥ 25% blasts (M2 or M3) with or without
extramedullary involvement.

- Refractory bone marrow involvement defined as MRD ≥ 0.1% blasts done at a COG-approved
MRD testing lab after most recent treatment regimen. in the bone marrow (M23) and any
CNS status. OR

- Newly diagnosed patients (T or B-cell ALL) with refractory bone marrow involvement
after Consolidation therapy are eligible.

- First relapse B-cell ALL patients are eligible with refractory disease.

- Second or greater relapse B-cell patients are eligible at time of relapse or with
refractory disease.

- First or greater relapse T-cell ALL patients are eligible at time of relapse or with
refractory disease.

- Isolated CNS 2 or 3 patients with < 0.1% MRD bone marrow involvement are not eligible.

Lymphoma

- Patient must have relapsed or refractory lymphoblastic lymphoma or peripheral T-cell
lymphoma.

- Patient must have histologic verification of disease at original diagnosis.

- Patient must have evaluable or measurable disease documented by clinical or
radiographic criteria or bone marrow disease present at study entry.

- Patients may have CNS 2 or 3 disease

Karnofsky greater than or equal to 50% for patients > 16 years of age and Lansky greater
than or equal to 50 for patients ≤ 16 years of age.

Patients must have fully recovered from the acute toxic effects of all prior anti-cancer
chemotherapy.

Patients with leukemia or lymphoma who relapse while receiving maintenance chemotherapy
will not be required to have a waiting period before enrollment onto this study.

At least 14 days must have elapsed after the completion of cytotoxic therapy, with the
exception of hydroxyurea.

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.
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 30 days after the completion of any type of immunotherapy, e.g.
tumor vaccines. or chimeric antigen receptor T cell (CART) therapy or tumor vaccines.

Monoclonal antibodies: At least 3 half-lives of the antibody must have elapsed after the
last dose of a monoclonal antibody. (ie: Rituximab = 66 days, Epratuzumab = 69 days).
Patients must have been off blinatumomab infusion for at least 4 days and all drug-related
toxicity must have resolved to grade 2 or lower as outlined in the inclusion and exclusion
criteria

XRT: At least 14 days after local palliative XRT (small port); At least 84 days must have
elapsed if prior TBI, craniospinal XRT or if greater than or equal to 50% radiation of
pelvis; At least 42 days must have elapsed if other substantial marrow radiation.

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.

Adequate Bone Marrow Function Defined as: Blood counts are not required to be normal prior
to enrollment on trial. However, platelet count must be greater than or equal to 20,000/mm3
to initiate therapy (may receive platelet transfusions). Patients should not be known to be
refractory to red blood cell or platelet transfusions.

Adequate Renal Function Defined as:

- Creatinine clearance or radioisotope GFR greater than or equal to 70ml/min/1.73 m2 or

- Normal serum creatinine based on age and gender.

Adequate Liver Function Defined as:

- Total bilirubin (sum of conjugated + unconjugated) must be less than or equal to 1.5 x
normal per institutional normal values for age.

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

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

- Serum albumin greater than or equal to 2 g/dL.

- The hepatic requirements may be waived for patients with elevations clearly due to
leukemic infiltration after consultation with the Study Chair or Vice Chair.

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

Adequate Cardiac Function Defined As:

- Shortening fraction of ≥ 27% by echocardiogram, or

- Ejection fraction of ≥ 50% by gated radionuclide study.

Adequate Pulmonary Function Defined as:

- Pulse oximetry > 94% on room air (> 90% if at high altitude)

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

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

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 this
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.

- Random or fasting glucose within the upper limits of normal for age. If the initial
blood glucose is non-fasting and above normal limits a fasting glucose can be obtained
and must be within the upper limits of normal for age.

EXCLUSION CRITERIA

- 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.

- 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, Health Canada or the Therapeutic Goods
Administration to be sold in the countries they govern. (United States, Canada and
Australia)

- 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 receiving hydroxyurea, which may be continued until 24 hours
prior to start of protocol therapy]. Intrathecal chemotherapy (at the discretion of
the primary oncologist) may be given up to one week prior to the initiation of study
therapy.

- 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.

- Anticoagulants: Patients who are currently receiving therapeutic anticoagulants
(including aspirin, low molecular weight heparin, and others) are not eligible. At
least 3 half-lives must have elapsed after the last dose of anticoagulants.

- 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 temsirolimus + ACE
inhibitors. At least 3 half-lives must have elapsed after the last dose of ACE
inhibitors.

- Calcium Channel Blockers: Patients who are currently receiving Calcium Channel
Blockers are not eligible due to the development of angioneurotic edema-type reactions
in some subjects who received concurrent treatment with temsirolimus + Calcium Channel
Blockers. At least 3 half-lives must have elapsed after the last dose of Calcium
Channel Blockers.

- Enzyme inducing Anti-convulsants: Patients who are currently receiving enzyme inducing
anticonvulsants (ie 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-coagulants.

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

- Patient with Burkiett's leukemia and /or lymphoma are not eligible.

Infection Criteria

Patients are excluded if they have:

- 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.

- A positive fungal culture within 30 days.

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

Patients with Down syndrome and Fanconi Anemia are excluded.

Patients will be excluded if they have 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.

Patients with known optic nerve and/or retinal involvement (because it may not be possible
to safely delay irradiation) are not eligible. Patients presenting with visual disturbances
by history or physical exam should have an ophthalmological exam and, if indicated, an MRI
to determine optic nerve or retinal involvement.