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Sirolimus and Metronomic Chemotherapy in Treating Younger Patients with Recurrent and / or Refractory Solid or Central Nervous System Tumors

Trial Status: Active

This phase II trial studies how well sirolimus and continuous or frequent treatment with low doses of chemotherapy work in treating younger patients with solid or central nervous system (CNS) tumors that have come back (recurrent) or have not responded to previous treatment (refractory). Biological therapies, such as sirolimus, use substances made from living organisms that may stimulate or suppress the immune system in different ways and stop tumor cells from growing. Drugs used in chemotherapy, such as etoposide, celecoxib, and cyclophosphamide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving sirolimus together with metronomic chemotherapy may be an effective treatment for solid and CNS tumors.

Inclusion Criteria

  • Subjects with any of the following tumors who have experienced relapse following front-line therapy, or who are refractory to front-line therapy, and subjects with tumors that carry a poor prognosis and have no known standard curative therapy are eligible; * Brain tumors of all World Health Organization (WHO) grades except diffuse intrinsic pontine glioma (DIPG); patients with DIPG are not eligible * Extracranial solid tumors including histiocytoses (e.g. Langerhans cell histiocytosis [LCH], juvenile xanthogranuloma [JXG], histiocytic sarcoma)
  • Subjects must have had histologic verification of malignancy at original diagnosis or relapse, except in subjects with optic pathway gliomas, or subjects with pineal tumors and elevations of serum or cerebrospinal fluid (CSF) alpha-fetoprotein (AFP) or beta-human chorionic gonadotropin (HCG)
  • Tissue blocks or slides must be sent if available, with the exception of intrinsic brain stem tumors, optic pathway gliomas, or subjects with pineal tumors; if tissue blocks or slides are unavailable, the study chair must be notified prior to study enrollment
  • Subjects must have radiographically measurable disease at the time of study enrollment to be eligible; patients with neuroblastoma who do not have measurable disease but have metaiodobenzylguanidine (MIBG)+ evaluable disease are eligible; measurable disease in patients with CNS involvement is defined as tumor that is measurable in two perpendicular diameters on magnetic resonance imaging (MRI) and visible on more than one slice
  • Subject’s current disease state must be one for which there is no known curative therapy
  • Karnofsky >= 50% for subjects > 16 years of age and Lansky >= 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
  • Subjects must have fully recovered from the acute toxic effects of all prior anti-cancer therapy
  • Myelosuppressive chemotherapy: at least 21 days after the last dose of myelosuppressive chemotherapy (42 days if prior nitrosourea)
  • Hematopoietic growth factors: at least 14 days after the last dose of a long-acting growth factor (e.g. pegfilgrastim) or 7 days for short acting growth factor; for agents that have known histologic verification of malignancy at original diagnosis or relapse 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
  • Antibodies: >= 21 days must have elapsed from infusion of last dose of antibody, and toxicity related to prior antibody therapy must be recovered to grade =< 1
  • Radiation therapy (XRT): at least 14 days after local palliative XRT (small port); 6 weeks must have elapsed since treatment with therapeutic doses of 131-meta-iodobenzylguanidine sulfate (I^131-MIBG); at least 150 days must have elapsed if prior traumatic brain injury (TBI), craniospinal XRT, or if >= 50% radiation of pelvis; at least 42 days must have elapsed if other substantial brain metastases (BM) radiation
  • Stem cell infusion without TBI: no evidence of active graft versus host disease and at least 84 days must have elapsed after transplant, and 42 days for autologous stem cell infusion after I^131-MIBG therapy
  • Absolute neutrophil count (ANC) >= 750/uL for subjects without bone marrow involvement
  • Platelet count >= 75,000/uL (transfusion independent, defined as not receiving platelet transfusions within 7 days prior to enrollment) for subjects without bone marrow involvement
  • Absolute neutrophil count (ANC) >= 750/uL for subjects with bone marrow involvement; these subjects will not be evaluable for hematologic toxicity or hematologic dose limiting toxicity (DLT), but will be subject to dose modifications based on hematologic criteria
  • Platelet count >= 75,000/uL (platelet transfusions allowed provided the patient is not known to be refractory to red cell or platelet transfusions) for subjects with bone marrow involvement; these subjects will not be evaluable for hematologic toxicity or hematologic DLT, but will be subject to dose modifications based on hematologic criteria
  • Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 ml/min/1.73 m^2 OR
  • Serum creatinine based on age/gender as follows: * Age 0 month to < 6 months; male 0.4; female 0.4 * Age 6 months to < 1 year; male 0.5; female 0.5 * Age 1 to < 2 years; male 0.6; female 0.6 * Age 2 to < 6 years; male 0.8; female 0.8 * Age 6 to < 10 years; male 1; female 1 * Age 10 to < 13 years; male: 1.2; female: 1.2 * Age 13 to < 16 years; male: 1.5; female: 1.4 * Age >= 16 years; male: 1.7; female: 1.4
  • Total bilirubin =< 2 x upper limit of normal (ULN)
  • Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) and serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 225 U/L (=< grade 2); the ULN for AST and ALT will be 45 U/L
  • Serum triglyceride level =< 300 mg/dL and serum cholesterol =< 300 mg/dL; if these labs were drawn non-fasting and do not meet the eligibility criteria then it is suggested that they are repeated fasting, i.e. no food or drink other than water for 8 hours; the use of medication to achieve these parameters is not allowed
  • Random or fasting blood glucose within the upper normal limits for age; if the initial blood glucose is a random sample that is outside of the normal limits, then a follow-up fasting (no food or drink other than water for 8 hours) blood glucose can be obtained and must be within the upper limits for age
  • Normal pulmonary functions tests (including carbon monoxide diffusing capability test [DLCO]) if there is a clinical indication for determination (dyspnea at rest, known requirement for supplemental oxygen); for subjects who do not have respiratory symptoms (no dyspnea at rest, oxygen [O2] saturation [sat] >= 93% on room air), full pulmonary function tests (PFTs) are NOT required

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 during treatment and for 3 months after stopping treatment
  • Subjects receiving corticosteroids must be on a stable or decreasing dose of corticosteroid for the prior 7 days
  • Subjects who are currently receiving enzyme inducing anticonvulsants are not eligible
  • Subjects must not be receiving potent CYP3A4 inducers or inhibitors
  • Subjects who are currently receiving another investigational drug are not eligible
  • Subjects who are currently receiving any other anti-cancer agents are not eligible
  • The use of cannabis oil is prohibited during the first 2 cycles of this protocol; patients must be off of cannabis oil for 3 days prior to enrollment
  • Subjects who have an uncontrolled infection are not eligible
  • Subjects who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible

Arizona

Phoenix
Phoenix Childrens Hospital
Status: APPROVED
Contact: Cynthia Wetmore
Phone: 602-933-0920

Delaware

Wilmington
Alfred I duPont Hospital for Children
Status: APPROVED
Contact: Debra Bertz
Phone: 302-651-5757

Florida

Jacksonville
Wolfson Childrens Hospital
Status: ACTIVE
Contact: Howard Mark Katzenstein
Phone: 904-697-3793

Georgia

Atlanta
Children's Healthcare of Atlanta - Egleston
Status: ACTIVE
Contact: William Thomas Cash
Phone: 404-785-0910
Children's Healthcare of Atlanta - Scottish Rite
Status: APPROVED
Contact: William Thomas Cash
Phone: 404-785-0910

Missouri

Kansas City
Children's Mercy Hospitals and Clinics
Status: ACTIVE
Contact: Amber Nicole Jenkins
Phone: 816-302-6891

Virginia

Charlottesville
University of Virginia Cancer Center
Status: APPROVED
Contact: Cindy A. Fischer
Phone: 434-243-0901

PRIMARY OBJECTIVE:

I. To determine the objective response rate in children with recurrent and refractory solid tumors, including brain tumors, who are treated with continuous sirolimus administered orally once daily with celecoxib, and oral etoposide alternating every 21 days with oral cyclophosphamide in a 42 day cycle. (metronomic chemotherapy).

SECONDARY OBJECTIVES:

I. To determine time to progression in children with recurrent and refractory solid tumors, including brain tumors, who are treated with sirolimus administered orally once daily for 42 days in combination with metronomic chemotherapy.

II. To define and describe the toxicities of sirolimus administered in combination with metronomic chemotherapy administered on this schedule.

III. To evaluate the expression of pS6 kinase and other mechanistic target of rapamycin (mTOR) pathway components as measured in the blood and correlate this with time to progression and clinical response.

IV. To evaluate the expression of pS6 kinase and other mTOR pathway components as measured in tumor tissue and correlate this with time to progression and clinical response.

OUTLINE:

Patients receive sirolimus orally (PO) once daily (QD) and celecoxib PO twice daily (BID) on days 1-42, etoposide PO QD on days 1-21, and cyclophosphamide PO QD on days 22-42. Treatment repeats every 42 days for up to 16 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 5 years.

Trial Phase Phase II

Trial Type Treatment

Lead Organization
Children's Healthcare of Atlanta - Egleston

Principal Investigator
William Thomas Cash

  • Primary ID AflacST1502
  • Secondary IDs NCI-2015-01637, IRB00082488
  • Clinicaltrials.gov ID NCT02574728