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
Intervention: Temsirolimus; Etoposide; Cyclophosphamide; Methotrexate; Hydrocortisone; Cytarabine
Intervention description: 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
Intervention MeSH terms: Cytarabine; Hydrocortisone; Hydrocortisone 17-butyrate 21-propionate; Hydrocortisone acetate; Hydrocortisone hemisuccinate; Cyclophosphamide; Methotrexate; Etoposide; Temsirolimus
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
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)
Enrollment: 16.0
Sex: All
Minimum age: 1 Year
Maximum age: 21 Years
Healthy volunteers: No
Keywords: Relapse; Lymphoblastic; Leukemia; Refractory; Temsirolimus; Acute; Childhood; Pediatric; ALL; NHL; LL; PTL

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).
    

Eligibility 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

          -  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.