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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

Phase 1
1 Year
21 Years
Not Enrolling
Lymphoblastic Leukemia, Acute, Childhood, Lymphoblastic Lymphoma, Peripheral T-cell Lymphoma

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Trial Information

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

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:


- 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.


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

- 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

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

- 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

- 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

- 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

- 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.


- 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

- 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

- 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.

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

The dose of temsirolimus that can be safely given with dexamethasone, etoposide and cyclophosphamide.

Outcome Description:

The incidence of dose limiting toxicity (DLT) will be measured. The maximum tolerated dose will be the highest study dose at which 1 or fewer of six patients experience DLT during cycle 1 of therapy.

Outcome Time Frame:

5 weeks

Safety Issue:


Principal Investigator

Susan Rheingold, MD

Investigator Role:

Study Chair

Investigator Affiliation:

Children's Hospital of Philadelphia


United States: Food and Drug Administration

Study ID:




Start Date:

May 2012

Completion Date:

Related Keywords:

  • Lymphoblastic Leukemia, Acute, Childhood
  • Lymphoblastic Lymphoma
  • Peripheral T-cell Lymphoma
  • Relapse
  • Lymphoblastic
  • Leukemia
  • Refractory
  • Temsirolimus
  • Acute
  • Childhood
  • Pediatric
  • ALL
  • NHL
  • LL
  • PTL
  • Leukemia
  • Leukemia, Lymphoid
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Lymphoma
  • Lymphoma, Non-Hodgkin
  • Lymphoma, T-Cell
  • Lymphoma, T-Cell, Peripheral



Johns Hopkins University Baltimore, Maryland  21205
Children's Hospital of Philadelphia Philadelphia, Pennsylvania  19104
Stanford University Medical Center Stanford, California  94305-5408
Children's National Medical Center Washington, District of Columbia  20010-2970
Phoenix Children's Hospital Phoenix, Arizona  85016-7710
Children's Hospital Central California Madera, California  93638-8762
Childrens Hospital Los Angeles Los Angeles, California  90027
Vanderbilt Children's Hospital Nashville, Tennessee  37232-6310
New York University Medical Center New York, New York  10016
Oregon Health and Science University Portland, Oregon  97201
Seattle Children's Hospital Seattle, Washington  98105
Children's Mercy Hospitals and Clinics Kansas City, Missouri  64108
Memorial Sloan Kettering New York, New York  10021
Cook Children's Medical Center Fort Worth, Texas  76104
Dana Farber Boston, Massachusetts  02115-6084
UCSF School of Medicine San Francisco, California  94143-0106
University of Miami Cancer Center Miami, Florida  33136
C.S. Mott Children's Hospital Ann Arbor, Michigan  48109-0914
Childrens Hospital & Clinics of Minnesota Minneapolis, Minnesota  55404-4597
Children's Hospital New York-Presbyterian New York, New York  10032
Miller Children's Hospital Long Beach, California  90806
Children's Memorial Chicago, Illinois  60614
Oakland Children's Hospital Oakland, California  
University of Minnesota Children's Hospital Minneapolis, Minnesota  
Nationwide Childrens Hospital Columbus, Ohio  
Levine Children's Hospital at Carolinas Medical Center Charlotte, North Carolina  28203
Children's Healthcare of Atlanta, Emory University Atlanta, Georgia  
St. Jude Memphis, Tennessee  38105-3678
The Children's Hospital, University of Colorado Aurora, Colorado  80045
University of Texas at Southwestern Dallas, Texas