Temsirolimus, Dexamethasone, Mitoxantrone Hydrochloride, Vincristine Sulfate, and Pegaspargase in Treating Young Patients With Relapsed Acute Lymphoblastic Leukemia or Non-Hodgkin Lymphoma

Study Overview
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Brief Summary
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This phase I trial studies the side effects and the best dose of temsirolimus when given together with dexamethasone, mitoxantrone hydrochloride, vincristine sulfate, and pegaspargase in treating young patients with relapsed acute lymphoblastic leukemia or non-Hodgkin lymphoma. Temsirolimus may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as dexamethasone, mitoxantrone hydrochloride, vincristine sulfate, and pegaspargase work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving temsirolimus with combination chemotherapy may be and effective treatment for acute lymphoblastic leukemia or non-Hodgkin lymphoma.

Detailed Description
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PRIMARY OBJECTIVES: I. To estimate the maximum-tolerated dose (MTD) and/or recommended phase 2 dose of temsirolimus administered weekly for 2 doses in combination with intensive re-induction chemotherapy in children with relapsed acute lymphoblastic leukemia (ALL) or non-Hodgkin lymphoma (NHL). II. To define and describe the toxicities of temsirolimus in combination with intensive re-induction chemotherapy in children with relapsed ALL or NHL administered on this schedule. SECONDARY OBJECTIVES: I. To compare minimal-residual disease (MRD) levels present at end of induction to historical control in patients with relapsed ALL or NHL with bone marrow involvement of disease. II. To determine the complete remission (CR) rate in patients with ALL or NHL who receive this regimen. III. To evaluate responsiveness of patient ALL cells to mammalian target of rapamycin (mTOR) inhibition using in vitro and in vivo pharmacodynamic assessment of the response of ALL blasts to temsirolimus. OUTLINE: This is a dose-escalation study of temsirolimus. Patients receive dexamethasone orally (PO) or intravenously (IV) on days 1-5 and 15-19; mitoxantrone hydrochloride IV over 30 minutes on days 1-2; temsirolimus IV over 30 minutes on days 1 and 8; vincristine sulfate IV on days 1, 8, 15, and 22; and pegaspargase IV over 1 hour on days 3 and 17. Some patients may also receive methotrexate intrathecally (IT) up to 72 hours prior to or on day 1 and on day 8. After completion of study therapy, patients are followed up for 30 days.

Official Title
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A Phase 1 Study of Temsirolimus in Combination With Intensive Re-induction Therapy for Children With Relapsed Acute Lymphoblastic Leukemia and Non-Hodgkin Lymphoma

Conditions
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Childhood B Acute Lymphoblastic Leukemia, Childhood T Acute Lymphoblastic Leukemia, Mature T-Cell and NK-Cell Non-Hodgkin Lymphoma, Recurrent Childhood Acute Lymphoblastic Leukemia, Recurrent Childhood Lymphoblastic Lymphoma

Intervention / Treatment
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* Drug: Dexamethasone
* Other: Laboratory Biomarker Analysis
* Drug: Methotrexate
* Drug: Mitoxantrone Hydrochloride
* Drug: Pegaspargase
* Other: Pharmacological Study
* Drug: Temsirolimus
* Drug: Vincristine Sulfate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis: Patients must have second (2nd) or greater relapse of pre-B ALL, T-cell ALL, lymphoblastic lymphoma, or peripheral T-cell lymphoma; patients may not have refractory disease Patients with leukemia must have had histologic verification of the malignancy at the most recent relapse, including immunophenotyping to confirm diagnosis Disease Status: Leukemia: patients with leukemia must have an M3 marrow with or without extramedullary site of relapse OR an M2 bone marrow with an extramedullary site of relapse; patients with central nervous system (CNS) 3 status are not eligible for enrollment Lymphoma: patients with non-Hodgkin lymphoma must have either measurable or evaluable disease Patient's current disease state must be one for which there is no known curative therapy or therapy proven to prolong survival with an acceptable quality of life Karnofsky >= 50% for patients > 16 years of age and Lansky >= 50 for patients =< 16 years of age; patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score Prior Therapy: Patients must have fully recovered from the acute toxic effects of all prior anti-cancer chemotherapy, defined as resolution of all such toxicities to =< grade 2 or per the inclusion/exclusion criteria Myelosuppressive chemotherapy: Patients with leukemia or lymphoma who relapse while receiving standard maintenance chemotherapy with steroid, vincristine pulses and oral outpatient chemotherapy will not be required to have a waiting period before enrollment onto this study Patients who relapse while they are not receiving standard maintenance therapy, must have fully recovered from all acute toxic effects of prior therapy; at least 14 days must have elapsed after the completion of cytotoxic therapy, with the exception of hydroxyurea Note: cytoreduction with hydroxyurea in patients can be initiated and continued for up to 24 hours prior to the start of protocol therapy 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; 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 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 after the last dose of a monoclonal antibody with the exception of blinatumomab; patients must have been off blinatumomab infusion for at least 7 days and all drug-related toxicity must have resolved to grade 1 or lower as outline in the inclusion and exclusion criteria Radiation therapy (XRT): at least 14 days after local palliative XRT (small port); at least 84 days must have elapsed if prior total body irradiation (TBI), craniospinal XRT or if >= 50% radiation of pelvis; at least 42 days must have elapsed if other substantial bone marrow (BM) radiation Stem cell infusion: no evidence of active graft versus (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 prior therapy with an mTOR inhibitor Note: intrathecal (IT) methotrexate (MTX) that is given up to 72 hours prior to initiation of systemic chemotherapy per ADVL1114 counts as protocol therapy and not prior anti-cancer therapy; IT MTX given > 72 hours prior does not count as protocol therapy Platelet count >= 20,000/mm^3 (may receive platelet transfusions) to initiate therapy Patients must not be known to be refractory to red cell or platelet transfusion Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70ml/min/1.73 m^2 or a serum creatinine based on age/gender as follows: 0.6 mg/dL (1 to < 2 years of age) 0.8 mg/dL (2 to < 6 years of age) 1.0 mg/dL (6 to < 10 years of age) 1.2 mg/dL (10 to < 13 years of age) 1.5 mg/dL (male) or 1.4 mg/dL (female) (13 to < 16 years of age) 1.7 mg/dL (male) or 1.4 mg/dL (female) (>= 16 years of age) Bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN) for age Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 225 U/L; for the purpose of this study, the ULN for SGPT is 45 U/L Gamma-glutamyl transpeptidase (GGT) =< ULN for age Serum albumin >= 2 g/dL Shortening fraction of >= 27% by echocardiogram, or ejection fraction of >= 50% by gated radionuclide study Pulse oximetry > 94% on room air Baseline chest x-ray; patients with active infectious disease or pneumonitis are not eligible Serum triglyceride level =< 300 mg/dL and serum cholesterol level =< 300 mg/dL Random or fasting blood glucose within the upper normal limits for age; if the initial blood glucose is a random sample that is above the upper normal limits, then a follow-up fasting blood glucose can be obtained and must be within the upper normal limits for age All patients and/or their parents or legally authorized representatives must sign a written informed consent; assent, when appropriate, will be obtained according to institutional guidelines Exclusion Criteria: Pregnant or breast-feeding women will not be entered on this study; pregnancy tests must be obtained in girls who are post-menarchal; males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method Patients receiving stable or decreasing doses of corticosteroids for =< 7 days prior to enrollment, or who are receiving increasing doses of corticosteroids, are not eligible for enrollment; the exception to this is pulsed steroids used for maintenance chemotherapy Patients who are currently receiving another investigational drug are not eligible Patients who are currently receiving other anti-cancer agents are not eligible (except patients receiving hydroxyurea, which may be continued until 24 hours prior to start of protocol therapy) Patients who are receiving cyclosporine, tacrolimus or other agents to prevent graft-versus-host disease post bone marrow transplant are not eligible for this trial Patients who cannot receive asparaginase are not permitted on trial; substitution with Asparaginase Erwinia Chrysanthemi is acceptable Cumulative prior anthracycline exposure must not exceed 400 mg/m^2 (each 10 mg/m^2 of idarubicin or mitoxantrone should be calculated as the isotoxic equivalent of 30 mg/m^2 of daunorubicin or doxorubicin) Patients who are currently receiving therapeutic anticoagulants (including aspirin, low molecular weight heparin, and others) are not eligible Patients who are currently receiving angiotensin-converting enzyme (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 anti-convulsants (i.e., phenytoin, phenobarbital, or carbamazepine) are not eligible Patients with CNS 3 status at enrollment are not eligible Patients must have no pre-existing grade 1 or higher ulcerations, fistulas, mucosal lesions, or skin barrier breakdown Patients who have an uncontrolled infection are not eligible 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 magnetic resonance imaging (MRI) within 14 days prior to enrollment to determine whether there is optic nerve or retinal involvement Patients with known Down syndrome, Fanconi anemia, Kostmann syndrome, Shwachman syndrome or any other known bone marrow failure syndrome are not eligible Patients who have received a prior solid organ transplantation are not eligible Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (temsirolimus, combination chemotherapy)<br>Patients receive dexamethasone PO or IV on days 1-5 and 15-19; mitoxantrone hydrochloride IV over 30 minutes on days 1-2; temsirolimus IV over 30 minutes on days 1 and 8; vincristine sulfate IV on days 1, 8, 15, and 22; and pegaspargase IV over 1 hour on days 3 and 17. Some patients may also receive methotrexate IT up to 72 hours prior to or on day 1 and on day 8. | Drug: Dexamethasone<br>* Given PO or IV<br>* Other names: Visumetazone;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Methotrexate<br>* Given IT<br>* Other names: WR-19039;Drug: Mitoxantrone Hydrochloride<br>* Given IV<br>* Other names: Pralifan;Drug: Pegaspargase<br>* Given IV<br>* Other names: Polyethylene Glycol-L-Asparaginase;Other: Pharmacological Study<br>* Correlative studies<br>Drug: Temsirolimus<br>* Given IV<br>* Other names: Torisel;Drug: Vincristine Sulfate<br>* Given IV<br>* Other names: Vincristine, sulfate;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-limiting toxicity of temsirolimus in combination with intensive re-induction chemotherapy graded according to the NCI CTCAE v4.0 | A descriptive summary of all toxicities will be reported. | Up to 30 days post-treatment | 
| MTD and/or recommended phase II dose defined as the maximum dose at which fewer than one-third of patients experience dose-limiting toxicity graded by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0 | A descriptive summary of all toxicities will be reported. | Up to day 36 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CR rate according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria |  | Up to 30 days post-treatment | 
| MRD levels present at the end of induction | Compared to a historical control in patients with bone marrow involvement of disease using a t-test or nonparametric analog. | Up to 30 days post-treatment | 
| mTOR inhibitor effects on downstream signaling in patient lymphoblasts In vitro and in vivo | The pharmacodynamic data will be summarized with simple summary statistics, including means, medians, ranges, and standard deviations (if numbers and distribution permit). | Up to 30 days post-treatment |