Dasatinib, Temsirolimus, and Cyclophosphamide in Treating Patients With Advanced, Recurrent, or Refractory Solid Tumors
Dasatinib, Temsirolimus, and Cyclophosphamide in Treating Patients With Advanced, Recurrent, or Refractory Solid Tumors
This phase I trial studies the side effects and best dose of dasatinib and temsirolimus when
 given together with cyclophosphamide in treating patients with solid tumors that have spread
 to other places in the body, have come back, or have not respond to previous treatment.
 Dasatinib and temsirolimus may stop the growth of tumor cells by blocking some of the enzymes
 needed for cell growth. Drugs used in chemotherapy, such as 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 dasatinib and temsirolimus
 together with cyclophosphamide may be a better treatment for advanced solid tumors.
PRIMARY OBJECTIVES:

 I. To determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of
 combination treatment with dasatinib, cyclophosphamide and temsirolimus.

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

 SECONDARY OBJECTIVES:

 I. To preliminarily define the antitumor activity of the combination of dasatinib,
 cyclophosphamide and temsirolimus within the confines of a phase 1 study.

 II. Preliminary assessment of biological markers and correlates of response.

 OUTLINE: This is a dose-escalation study of dasatinib and temsirolimus.

 Patients receive dasatinib orally (PO) twice daily (BID) on days 1-21, cyclophosphamide PO
 once daily (QD) on days 1-21, and temsirolimus intravenously (IV) over 30-60 minutes on days
 1, 8, and 15. Treatment repeats every 28 days for 6 courses in the absence of disease
 progression or unacceptable toxicity. Patients experiencing stable disease or better may
 continue treatment with the approval of the study chair.

 After completion of study treatment, patients are followed up for 4 weeks.
Inclusion Criteria:

 -  Patients must be >/= 12 months and < 21 years of age at the time of study enrollment.

 -  Patients must have had a previous histological verification of a solid tumor at the
 original diagnosis and/or recurrence including brain tumors; for patients with brain
 stem gliomas and optic pathway tumors, the requirement for histological evaluation may
 be waived; the patient's disease must be considered refractory to
 conventional/standard therapy, or a disease for which no conventional therapy exists
 and is progressive

 -  The patient must have a stable clinical (neurologic in case of brain tumors) exam and
 be on a stable dose of steroids for at least 1 week prior to study entry; the patient
 should have a measurable and/or evaluable disease; measurable disease which is defined
 as the presence of at least one lesion that can be accurately measured in two
 dimensions (each measures at least 10 mm) or evaluable disease which is defined as at
 least one lesion that can be accurately measured in at least one dimension (measure at
 least 10 mm)

 -  Karnofsky performance status >= 50 for patients >= 16 years of age and a Lansky
 performance status >= 50 for patients aged < 16 years

 -  Life expectancy: must be >= 12 weeks

 -  Chemotherapy:

 -  Must not have received myelosuppressive chemotherapy within 3 weeks of the study
 entry (6 weeks if prior nitrosourea); prior treatment with either dasatinib or
 temsirolimus but not both is allowed; at least 3 weeks must have elapsed from the
 last dose

 -  Biologic therapy (anti-neoplastic)

 -  Must not have received oral tyrosine kinase inhibitors (other than dasatinib) or
 other similar agents within 3 weeks of the study entry and all toxicities must
 have resolved to < grade 2 prior to enrollment

 -  Must not have received bevacizumab or other monoclonal antibody therapy within 4
 weeks of study the entry

 -  Radiotherapy (XRT): at least 4 weeks for focal XRT or 8 weeks for craniospinal XRT
 must have elapsed prior to study entry

 -  Stem cell transplant (SCT): at least 8 weeks following autologous SCT and 12 weeks for
 allogeneic SCT

 -  Surgery: at least 2 weeks following surgery including brain and spine provided
 post-operative magnetic resonance imaging (MRI) shows no active bleeding

 -  Concomitant medications: the following drugs need to be stopped at the time of
 beginning therapy: patient cannot be on liver enzyme inducing anticonvulsants;
 patients must not have received growth factors to support the number or function of
 white cells or platelets within the past 7 days and pegfilgrastim within the past 14
 days; patients must not be receiving any anti-thrombotic or anti-platelet agents;
 patient cannot be on drugs that cause significant prolonged QT (category I drug)

 -  Absolute neutrophil count (ANC) greater than or equal to 1000/mm^3

 -  Platelets greater than or equal to 75,000/mm^3 (transfusion independent; no
 transfusion for >= 7 days prior to study enrollment)

 -  Hemoglobin greater than 8.0 g/dL (transfusion independent; no transfusion for >= 7
 days prior to study enrollment)

 -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x upper limit
 of normal for age (ULN)

 -  Bilirubin =< 1.5 x ULN

 -  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 1 to < 2 years, 0.6 mg/dL (male) and 0.6 mg/dL (female)

 -  Age > 2 and < 6 years, 0.8 mg/dL(male) and 0.8 mg/dL (female)

 -  Age > 6 and < 10 years, 1.0 mg/dL (male) and 1.0 mg/dL (female)

 -  Age > 10 and < 13 years, 1.2 mg/dL (male) and 1.2 mg/dL (female)

 -  Age > 13 and < 16 years, 1.5 mg/dL (male) and 1.4 mg/dL (female)

 -  Age > 16 years, 1.7 mg/dL (male) and 1.4 mg/dL (female)

 -  All post-menarchal females must have a negative serum beta-human chorionic
 gonadotropin (beta HCG); sexually active patients of childbearing potential must agree
 to use an effective method of contraception during the study and for at least 6 months
 after

 -  Adequate pulmonary function as defined as: no evidence of dyspnea at rest, no exercise
 intolerance, and a pulse oximetry > 94% if there is clinical indication for
 determination

 -  Adequate cardiac function defined as: normal 12 lead electrocardiogram (EKG) with
 corrected QT interval (QTc) < 450 msec, and either shortening fraction of >= 28% by
 echocardiogram and qualitatively normal left ventricular function, or ejection
 fraction of >= 55% by echocardiogram

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

 -  Serum cholesterol and serum triglyceride levels must be < grade 2

 -  A written informed consent MUST be obtained from the patients and/or their
 parents/legal guardians prior to enrollment indicating their awareness of
 investigational nature of this study

 Exclusion Criteria:

 -  Patients with evidence of recent intratumoral hemorrhage (within 3 months of study
 enrollment), gastrointestinal bleeding, history of coronary artery disease or on
 anticoagulation therapy

 -  Pregnant or breast-feeding women will not be entered on this study

 -  Uncontrolled current illness including, but not limited to, uncontrolled infection,
 need for hemodialysis, need for ventilatory support, psychiatric illness/social
 situations that would limit compliance with study requirements

 -  History of hypersensitivity to any component of the formulation

 -  Patients with known human immunodeficiency virus (HIV) are ineligible for this study

 -  Patients must not have received prior therapy with dasatinib and temsirolimus for any
 indication

 -  Patients with clinically significant cardiovascular disease: history of ischemic or
 hemorrhagic stroke within past 6 months; uncontrolled hypertension, on at least 2
 repeated determinations on separate days within past 3 months; myocardial infarction
 or unstable angina within past 6 months; New York Heart Association grade III or
 greater congestive heart failure, serious cardiac arrhythmia requiring medication,
 unstable angina pectoris within past 6 months; clinically significant peripheral
 vascular disease within past 6 months; pulmonary embolism, deep vein thrombosis (DVT),
 or other thromboembolic event within past 6 months; diagnosed congenital long QT
 syndrome; any history of clinically significant ventricular arrhythmias (such as
 ventricular tachycardia, ventricular fibrillation, or torsades de pointes); prolonged
 QTc interval on pre-entry electrocardiogram (> 450 msec); subjects with hypokalemia or
 hypomagnesemia if it cannot be corrected prior to dasatinib administration

 -  Anticonvulsants: patients on enzyme inducing anticonvulsants (EIAED) will be excluded;
 if patients were previously on EIAEDs that have been discontinued, patients must have
 been off EIAEDs for >= 2 weeks prior to initiation of dasatinib

 -  Anticoagulants/anti-platelets: patients on therapeutic (treatment) dose of
 anticoagulants (e.g. warfarin, low molecular-weight heparin) are not eligible;
 patients are not allowed to take aspirin, clopidogrel, ticlopidine, Aggrenox; patients
 on prophylactic anticoagulation may be enrolled and treated on study as long as their
 platelet count is monitored closely and maintained at > 75,000 while they are
 receiving dasatinib

 -  Inducers and Inhibitors of cytochrome P450 family 3, subfamily A, polypeptide 4
 (CYP3A4): patients required to be on any CYP3A4/5 inhibitors or inducers will be
 excluded (with the exception of dexamethasone, but all efforts should be made to
 reduce the dose of dexamethasone); patients must discontinue drug at least 7 days
 prior to starting dasatinib

 -  Angiotensin-converting enzyme (ACE) inhibitors: patients who are currently receiving
 ACE inhibitors are not eligible

 -  Anti-graft-versus-host disease (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

 -  Category I drugs that are generally accepted to have a risk of causing torsades de
 pointes including: (patients must discontinue drug at least 7 days prior to starting
 dasatinib)

 -  Quinidine, procainamide, disopyramide

 -  Amiodarone, sotalol, ibutilide, dofetilide

 -  Chlorpromazine, haloperidol, mesoridazine, thioridazine, pimozide

 -  Cisapride, bepridil, droperidol, arsenic, chloroquine, domperidone, halofantrine,
 levomethadyl, sparfloxacin, lidoflazine

 -  Other drugs permitted but use with caution include; drugs are not recommended but can
 be used with caution

 -  Antacids: use of H2 blockers and proton pump inhibitors is not recommended;
 patients who require antacids should use short acting, locally active agents
 (e.g., Maalox, Mylanta etc.); however, these agents should not be taken within
 either 2 hours before or 2 hours after the dasatinib dose

 -  Drugs prolong QT interval; erythromycin, clarithromycin, pentamidine,
 ondansetron, granisetron, and methadone