A Phase I Trial of Temsirolimus (CCI-779, Pfizer, Inc.) in Combination With Etoposide and Cyclophosphamide in Children With Relapsed Acute Lymphoblastic Leukemia and Non-Hodgkins Lymphoma

Inclusion Criteria

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

- Patients must have relapsed or refractory acute lymphoblastic leukemia (ALL) with
greater than or equal to 25% blasts in the bone marrow (M3). OR

- Patients may have an M2 marrow (greater than or equal to 5% to < 25% blasts) with an
extramedullary site of relapse; including CNS 2 and CNS 3.

- Patients may not have isolated CNS relapse.

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, if other sites of involvement.

- 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 must have had 2 or more prior therapeutic attempts defined as:

1. Relapse after going into remission from re-induction for the first or subsequent
relapse (ie: 2nd , 3rd, 4th…relapse), or

2. Refractory disease after first or greater relapse and a single re-induction
attempt.

3. Patients who are refractory to 2 or more frontline induction attempts are
eligible.

- 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.

- Intrathecal chemotherapy (at the discretion of the primary oncologist) may be given
up to one week prior to the initiation of the dexamethasone.

- 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 42 days after the completion of any type of immunotherapy,
e.g. 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).

- 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.

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

- Patients with avascular necrosis may enroll on study but must receive the full dose
dexamethasone prophase in Cycle 1.

- 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
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).

- 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 the dexamethasone.

- 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.

- Anticoagulants: Patients who are currently receiving therapeutic anticoagulants
(including aspirin, low molecular weight heparin, and others) are not eligible.

- 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.

- 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.

- Patients receiving treatment with azoles such as fluconazole or voriconazole which
are potent inhibitors of temsirolimus metabolism.

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.

- 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.