A Trial of Temsirolimus With Etoposide and Cyclophosphamide in Children With Relapsed Acute Lymphoblastic Leukemia and Non-Hodgkins Lymphoma
Condition: Lymphoblastic Leukemia, Acute, Childhood; Lymphoblastic Lymphoma; Peripheral T-cell Lymphoma
MeSH terms: Lymphoma; Leukemia; Lymphoma, Non-Hodgkin; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Lymphoma, T-Cell, Peripheral
Study type: Interventional
Phase: Phase 1

Summary: 
      This is a phase I study of temsirolimus (Torisel) combined with dexamethasone,
      cyclophosphamide and etoposide in patients with relapsed acute lymphoblastic leukemia (ALL),
      lymphoblastic lymphoma (LL) or peripheral T-cell lymphoma (PTL).
    

Detailed description: 
      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.
    

Intervention name(s): Temsirolimus; Etoposide; Cyclophosphamide; Methotrexate; Hydrocortisone; Cytarabine
Intervention type(s): Drug; Drug; Drug; Drug; Drug; Drug
Intervention description(s): Dose will be assigned at study entry. Give IV over 30 minutes on days 1 and 8.; 100 mg/m2 IV over 1-2 hours daily x 5 on Days 1-5.; 440 mg/m2 IV daily x 5 on Days 1-5 given over 30-60 minutes.; PATIENTS WITH CNS 1 COURSES 2, 4, 6, 8: Give intrathecally to patients who were CNS1 at study entry day 1 of each course at the doses listed below.
Age 1 - 1.99 give 8 mg of methotrexate
Age 2 - 2.99 give10 mg of methotrexate
Age 3 - 8.99 give 12 mg of methotrexate
Age ≥ 9 give 15 mg of methotrexate
PATIENTS WITH CNS 2 or 3 DISEASE
-COURSE 1: Give intrathecally to patients with CNS 2 or 3 disease at the doses defined by age below on day 6 and then weekly until the patient is CNS 1.
COURSES 2-8: Give intrathecally to patients who were CNS 3 at study entry on day 1 of each course.
8 mg for patients age 1-1.99
10 mg for patients age 2-2.99
12 mg for patients 3-8.99 years of age
15 mg for patients >9 years of age; Given with Methotrexate and Cytarabine for patients with CNS 2 or 3 disease.
COURSE 1: Give intrathecally to patients with CNS 2 or 3 disease at the doses defined by age below on day 6 and then weekly until the patient is CNS 1.
COURSES 2-8: Give intrathecally to patients who were CNS 3 at study entry on day 1 of each course.
8 mg for patients age 1-1.99
10 mg for patients age 2-2.99
12 mg for patients 3-8.99 years of age
15 mg for patients >9 years of age; For Patients who are CNS1 COURSE 1: Give intrathecally to patients with CNS1 disease at the dose defined by age below on day 1 of course 1 if no other IT was given within 1 week of day 1 of course 1
Age 1 - 1.99 give 30 mg of Cytarabine
Age 2 - 2.99 give 50mg of Cytarabine
Age ≥ 3 give 70 mg of Cytabine
For Patients with CNS 2 or 3 Disease COURSE 1: Give intrathecally to patients with CNS 2 or 3 disease at the doses defined by age below on day 1 if no other IT chemotherapy given within 1 week of day 1 of course 1. Then give weekly until the patient is CNS 1 or 2 (investigator discretion). No more than 5 weekly doses to be given in cycle 1.
COURSES 2-8: Give intrathecally to patients who were CNS 2or 3 at study entry on day 1 of each course.
16 mg for patients age 1-1.99
20 mg for patients age 2-2.99
24 mg for patients 3-8.99 years of age
30 mg for patients >9 years of age
Other intervention name(s): Torisel; CCI-779; Toposar; VePesid; VP-16; Cytoxan; Neosar; MTX; Amethopterin; Trexall; Hydrocortisone sodium succinate; Solu-cortef; Cytosine arabinoside; Ara-C; Cytosar
Intervention MeSH terms: Cytarabine; Hydrocortisone; Hydrocortisone 17-butyrate 21-propionate; Hydrocortisone acetate; Hydrocortisone hemisuccinate; Cyclophosphamide; Methotrexate; Etoposide; Temsirolimus
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Intervention model description: This study follows a standard 3+3 patient cohort escalation design, as described below:
Three patients are entered at the first dose level
If 0/3 experiences DLT at a given dose level, then the dose is escalated to the next higher level, if a higher dose level exists, and three patients are enrolled. If a higher dose level does not exists, up to three more patients are accrued at the same dose level.
If 1/3 experiences DLT at current dose, then up to three more patients are accrued at the same dose level.
If 2 or more DLTs are observed in a three-patient or six-patient cohort at a given dose level, then the MTD has been exceeded, dose escalation will be stopped, and up to three additional patients will be enrolled at the next lower dose level, if a lower dose level exists (unless six patients have already been treated at that prior dose).
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Relapse; Lymphoblastic; Leukemia; Refractory; Temsirolimus; Acute; Childhood; Pediatric; ALL; NHL; LL; PTL