Temsirolimus, Irinotecan Hydrochloride, and Temozolomide in Treating Younger Patients With Relapsed or Refractory Solid Tumors
Temsirolimus, Irinotecan Hydrochloride, and Temozolomide in Treating Younger Patients With Relapsed or Refractory Solid Tumors
This phase I trial studies the side effects and the best dose of temsirolimus when given
 together with irinotecan hydrochloride and temozolomide in treating younger patients with
 recurrent or refractory solid tumors. Temsirolimus may stop the growth of tumor cells by
 blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as
 irinotecan hydrochloride and temozolomide, work in different ways to stop the growth of tumor
 cells, either by killing the cells or by stopping them from dividing. Giving temsirolimus
 with combination chemotherapy may kill more tumor cells.
PRIMARY OBJECTIVES:

 I. To estimate the maximum tolerated dose (MTD) or recommended Phase 2 dose and schedule of
 temsirolimus administered in combination with irinotecan (irinotecan hydrochloride) and
 temozolomide every three weeks to children with recurrent or refractory solid tumors.

 II. To define and describe the toxicities of the combination of temsirolimus, irinotecan and
 temozolomide administered on this schedule.

 SECONDARY OBJECTIVES:

 I. To preliminarily define the antitumor activity of the combination of temsirolimus,
 irinotecan, and temozolomide within the confines of a Phase 1 study.

 II. To collect preliminary data regarding the biologic effects of temsirolimus on proteins
 involved in signaling pathways of interest in pediatric solid tumors.

 OUTLINE: This is a multicenter study, dose-escalation study of temsirolimus.

 Patients receive temsirolimus intravenously (IV) over 30 minutes on days 1 and 8 or on days
 1, 8, and 15 and temozolomide orally (PO) and irinotecan hydrochloride PO on days 1-5.
 Treatment repeats every 21 days for up to 17 courses in the absence of disease progression or
 unacceptable toxicity.

 After completion of study therapy, patients are followed up for 30 days.
Inclusion Criteria:

 -  Patients must have had histologic verification of malignancy at original diagnosis or
 relapse except in patients with intrinsic brain stem tumors, patients with optic
 pathway gliomas, and patients with pineal tumors and elevations of serum or
 cerebrospinal fluid (CSF) alpha-fetoprotein or beta-human chorionic gonadotropin (HCG)

 -  Patients 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; Note: neurologic deficits in patients with central nervous system (CNS)
 tumors must have been relatively stable for a minimum of 1 week prior to study
 enrollment; 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

 -  Patients must have fully recovered from the acute toxic effects of all prior
 anti-cancer chemotherapy;

 -  Myelosuppressive chemotherapy: patients must not have received myelosuppressive
 therapy within 3 weeks of enrollment onto this study (6 weeks if prior
 nitrosourea)

 -  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 of a biologic
 agent that is not a monoclonal antibody and enrollment on this study; 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 6 weeks since the completion of any type of
 immunotherapy, e.g. tumor vaccines

 -  Monoclonal antibodies: at least 3 half-lives must have elapsed after treatment
 with a monoclonal antibody and enrollment on this study

 -  Radiation therapy (XRT): >= 2 weeks must have elapsed for local palliative XRT
 (small port) and enrollment on study; at least 24 weeks must have elapsed since
 radiation if prior total body irradiation (TBI), craniospinal XRT or if radiation
 to >= 50% radiation of pelvis has been administered; >= 6 weeks must have elapsed
 if the patient has received other substantial bone marrow (BM) radiation

 -  Stem Cell Infusion without TBI: the patient must have no evidence of active graft
 versus (vs.) host disease, and >= 12 weeks must have elapsed since transplant or
 stem cell infusion and enrollment on this study

 -  Prior treatment with irinotecan, temozolomide, or temsirolimus: patients
 previously treated with any of these drugs as single agents will be eligible for
 this study; patients previously treated with two of the three drugs (including
 irinotecan + temozolomide) will also be eligible, however patients previously
 treated with all three agents in combination will not be eligible

 -  Peripheral absolute neutrophil count (ANC) >= 1,000/mm^3

 -  Platelet count >= 100,000/mm^3 (transfusion independent defined as not receiving
 platelet transfusions within a 7 day period prior to enrollment)

 -  Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min OR
 a serum creatinine based on age and/or 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 times upper limit of normal (ULN)

 -  Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 110
 U/L; for the purpose of this study, the ULN for SGPT is 45 U/L

 -  Serum albumin > 2 g/dL

 -  Prothrombin time (PT) < 1.2 times ULN

 -  Serum triglyceride level =< 300 mg/dL

 -  Serum cholesterol =< 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 outside of the normal limits, then a
 follow-up fasting blood glucose can be obtained and must be within the upper normal
 limits for age

 -  Normal pulmonary function tests, including diffusion capacity of carbon monoxide
 (DLCO), if there is clinical indication for determination (e.g., dyspnea at rest,
 known requirement for supplemental oxygen); for patients who do not have respiratory
 symptoms, full pulmonary function tests (PFTs) are NOT required

 -  Patients with seizure disorder may be enrolled if on non-enzyme inducing
 anticonvulsants and if seizures are well controlled

 -  Nervous system disorders (Common Terminology Criteria for Adverse Events [CTCAE]
 version 4.0 [v4]) resulting from prior therapy must be =< grade 2

 -  All patients and/or their parents or legal guardians 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 chronic systemic corticosteroids are not eligible; patients must
 have been off systemic corticosteroids for 7 days prior to enrollment

 -  Patients who are currently receiving another investigational drug are not eligible

 -  Patients who are currently receiving other anti-cancer agents are not eligible

 -  Patients who are currently receiving enzyme inducing anticonvulsants are not eligible

 -  Patients must not be receiving any of the following potent Cytochrome P450 family 3,
 subfamily A, polypeptide 4 (CYP3A4) inducers or inhibitors: erythromycin,
 clarithromycin, ketoconazole, azithromycin, itraconazole, grapefruit juice or St.
 John's worth

 -  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

 -  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.

 -  Patients who have an uncontrolled infection 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

 -  Patients with history of allergic reactions attributed to compounds of similar
 composition to irinotecan hydrochloride, temozolomide, or temsirolimus are not
 eligible

 -  Patients must not have had major surgery for 6 weeks prior to enrollment on study;
 patients with history of recent minor surgical procedures (vascular catheter
 placement, bone marrow evaluation, laparoscopic surgery and the like) will be eligible