Summary

This pilot phase I trial studies the side effects and best dose of everolimus and to see how well it works when given together with nelarabine, cyclophosphamide, and etoposide phosphate in treating patients with T cell lymphoblastic leukemia or lymphoma that has come back (relapsed) or does not respond to treatment (refractory). Drugs used in chemotherapy, such as everolimus, nelarabine, cyclophosphamide, and etoposide phosphate, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading.

Objectives

PRIMARY OBJECTIVE:
I. To determine the maximum tolerated dose (MTD) and describe the dose-limiting toxicity (DLT) of everolimus when given in combination with nelarabine, etoposide phosphate (etoposide) and cyclophosphamide to children with bone marrow relapse of T cell acute lymphoblastic leukemia (T-ALL) or relapsed T cell lymphoblastic lymphoma (T-LL).

SECONDARY OBJECTIVES:
I. To determine the pharmacokinetics of everolimus when given in combination with nelarabine, cyclophosphamide and etoposide.
II. To describe changes in phosphoprotein (pAkt and p4EBP1) and Mer expression at time points pre- and post everolimus therapy in peripheral blood mono-nuclear cells (PBMCs) and bone marrow.
III. To determine the response rate as defined by the ability to achieve complete remission (CR) after 1 and 2 courses of this therapy in children with bone marrow relapse of T-ALL or relapsed T cell lymphoblastic lymphoma (T-LLy).
IV. For patients that proceed to allogeneic stem cell transplantation, to determine the time from start of study treatment to transplant in patients with bone marrow relapse of T-ALL or relapsed T-LLy.

OUTLINE: This is a dose-escalation study of everolimus.

Patients receive everolimus orally (PO) once daily (QD) on days 1-28, nelarabine intravenously (IV) over 60 minutes on days 1-5, etoposide phosphate IV over 1 hour on days 1-5, and cyclophosphamide IV over 30-60 minutes on days 1-5. Patients may also receive methotrexate intrathecally (IT), therapeutic hydrocortisone IT, and cytarabine IT between days 29-36. Patients with stable disease or with partial/complete response after course 1 may receive a second course.

Eligibility

1. Patients must have relapsed (first or greater relapse) or refractory T-cell acute lymphoblastic leukemia (T-ALL) with: * Relapsed T-ALL with an M2 (blasts >= 5 to =< 25%) or M3 (> 25% blasts) marrow with or without an extramedullary site of relapse * Central nervous system (CNS) 3 patients are eligible (note timing of last IT) * Newly diagnosed patients with induction failure are eligible * If bone marrow cannot be obtained due to any cause, a complete blood count (CBC) documenting the presence of at least 1000/ul circulating leukemia cells is acceptable for establishing diagnosis of relapse
2. Patients must have relapsed (first or greater relapse) or refractory lymphoma with: * Lymphoblastic lymphoma or peripheral T-cell lymphoma * Histologic verification of disease at original diagnosis or subsequent relapse * Evaluable or measurable disease documented by clinical or radiographic criteria or bone marrow disease present at study entry * CNS3 patients are eligible, if other sites of leukemia or lymphoma involvement are present (note timing of last IT)
3. Patients must have a Karnofsky >= 50% for subjects > 16 years of age and Lansky score >= 50 for subjects =< 16 years of age * Note: Subjects 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
4. Patients who relapse while receiving standard ALL maintenance chemotherapy will not be required to have a waiting period before entry onto this study
5. Patients who relapse on therapy other than standard ALL maintenance therapy must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study * Cytotoxic chemotherapy: At least 7 days must have elapsed since the completion of cytotoxic therapy (other than standard ALL maintenance therapy) with the EXCEPTION of: ** Hydroxyurea, which is permitted up to 24 hours prior to the start of protocol therapy ** Steroid pre-treatment: *** Prednisone/methylprednisolone/decadron for =< 120 hours (5 days) in the 7 days prior to initiation of chemotherapy. The dose of prednisone or methylprednisolone doesn’t affect study eligibility. Steroids must be held for 24 hours prior to initiation of study chemotherapy *** Dexamethasone pre-treatment as a single dose used during sedation or to treat airway disease within 28 days prior to initiation of protocol therapy ** Inhalation steroids and topical steroids are not considered pre-treatment * Nitrosoureas: At least 42 days must have elapsed since administration of nitrosoureas * Hematopoietic growth factors: At least 14 days after the last dose of long acting hematopoietic growth factor (e.g. Neulasta) or 7 days for short acting growth factor (e.g. Neupogen) * Radiation: At least 84 days must have elapsed since administration of craniospinal, hemipelvic or other radiation therapy to more than 25% of the bone marrow containing spaces; at least 42 days must have elapsed if other substantial marrow radiation has been given. The following is an exception – 600 cGy chest irradiation, if medically necessary * Nelarabine prior therapy: Patients who have previously been treated with nelarabine are eligible, however if they have previously received a regimen of nelarabine, cyclophosphamide and etoposide, they are not eligible * 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 or chimeric antigen receptor T cell (CART) therapy * Monoclonal antibodies: Monoclonal antibodies: At least 3 half-lives or 21 days (whichever is shorter) of the antibody must have elapsed after the last dose of a monoclonal antibody * 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 previously received therapy with an mTOR inhibitor * Prior intrathecal therapy: Patients may be enrolled on study regardless of the timing of prior intrathecal therapy; however, they MAY NOT BEGIN TREATMENT ON THIS PROTOCOL UNTIL A MINIMUM OF 7 DAYS HAS ELAPSED SINCE PRIOR INTRATHECAL THERAPY
6. Patients should not be known to be refractory to red blood cell or platelet transfusions
7. Blood counts are not required to be normal prior to enrollment on trial
8. Total bilirubin (sum of conjugated + unconjugated) =< 1.5 x institutional upper limit of normal for age
9. Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) and serum glutamic-oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) must be =< 3 x institutional upper limit of normal (grade 1 or less per Common Terminology Criteria for Adverse Events [CTCAE] 5.0)
10. Gamma-glutamyl transpeptidase (GGT) must be =< 2.5 x institutional upper limit of normal (grade 1 or less per CTCAE 5.0)
11. Serum albumin >= 2 g/dL
12. The hepatic requirements may be waived for patients with grade 1 or 2 elevations of hepatic transaminases suggestive of leukemic infiltration after consultation with a study chair/co-chair
13. Serum creatinine =< 1.5 x upper limit of normal (ULN) for age; if the serum creatinine is above these values, the calculated creatinine clearance or radioisotope glomerular filtration rate (GFR) must be >= 70 mL/min/1.73 m^2
14. Shortening fraction of >= 27% by echocardiogram, OR
15. Ejection fraction of >= 50% by gated radionuclide study/echocardiogram
16. Pulse oximetry > 94% on room air
17. No evidence of dyspnea at rest and no exercise intolerance
18. Baseline chest x-ray with no evidence of active infectious disease or pneumonitis
19. Female patients of childbearing potential must have a negative urine or serum pregnancy test confirmed prior to enrollment
20. Female patients with infants must agree not to breastfeed their infants while on the study
21. Male and female patients of child-bearing potential must agree to use an effective method of contraception approved by the investigator during the study; males should not get females pregnant for 90 days after last dose of everolimus
22. Fasting or random blood glucose within the upper limits of normal for age
23. If random blood glucose is above upper limits for age, a fasting blood glucose can be obtained and must be within normal limits for age
24. Fasting or non-fasting serum triglyceride level =< 300 mg/dL and serum cholesterol level =< 300 mg/dL
25. Patients and/or their parents or legal guardians must be capable of understanding the investigational nature, potential risks and benefits of the study; all patients and/or their parents or legal guardians must sign a written informed consent

Treatment Sites in Georgia