A Trial of Dasatinib (PDGFR and SRC Inhibitor), Temsirolimus and Cyclophosphamide in Patients With Advanced Solid Tumors

Study Groups:

If you are found to be eligible to take part in this study, you will be assigned to a dose
level of temsirolimus and dasatinib based on when you join this study. Up to 2 dose levels of
both drugs will be tested. Up to 6 participants will be enrolled in each group. The first
group of participants will receive the lowest dose level of both drugs. If no intolerable
side effects are seen, the next group will receive a higher dose level of temsirolimus. If no
intolerable side effects are seen in this second group, the third group will receive the
higher dose level of temsirolimus and a higher dose level of dasatinib.

All participants will receive the same dose level of cyclophosphamide.

Study Drug Administration:

Every study cycle will be 28 days.

You will take tablets of dasatinib 2 times each day on Days 1-21 of each cycle while you are
on study, with or without food. Each dose should be taken about 12 hours apart. The tablets
should be swallowed whole, not crushed or broken. If you are unable to swallow the tablets
whole, they can be placed and allowed to dissolve in 1 ounce of lemonade, apple juice, or
orange juice (note that any juice must be preservative-free). You will receive detailed
instructions about how to prepare the liquid form of dasatinib.

You will take tablets of cyclophosphamide by mouth 1 time each day on Days 1-21 of each cycle
when you take the second dose of dasatinib.

You will receive temsirolimus by vein over about 30-60 minutes on Days 1, 8, and 15 of each
cycle.

Study Visits:

Every week during the study, blood (about 2-3 teaspoons) will be drawn for routine tests.

Every week during Cycle 1, you will also have a physical exam and urine will be collected for
routine tests.

On Day 1 of Cycles 2 and beyond:

- You will have a physical exam.

- You will have an EKG.

- Urine and blood will be collected for routine tests.

On Day 15 of Cycles 2 and beyond, you will have a physical exam and blood will be collected
for routine tests.

Every 2 cycles:

- You will have an MRI or CT scan to check the status of the disease.

- You will have an ECHO, if the study doctor thinks it is needed.

- If the study doctor thinks it is needed, you will have a spinal tap to compare to the
earlier samples taken.

If the study tests show abnormal results, you may need to have some of them performed more
frequently.

Length of Treatment:

You may continue taking the study drugs for as long as the doctor thinks it is in your best
interest. You will no longer be able to take the study drugs if the disease gets worse, if
intolerable side effects occur, or if you are unable to follow study directions.

Your participation on the study will be over after the end-of-treatment visit.

End-of-Treatment Visit:

About 4 weeks after you stop receiving the study drugs:

- You will have a physical exam.

- Blood (about 1 tablespoon) will be drawn for routine tests.

- You will have an MRI or CT scan to check the status of the disease.

- If the study doctor thinks it is needed, you will have a spinal tap.

This is an investigational study. Dasatinib is FDA-approved and commercially available for
the treatment of various types of leukemia. Cyclophosphamide is FDA-approved and commercially
available for the treatment of several types of cancer, including brain cancer and many types
of blood cancers. Temsirolimus is FDA-approved and commercially available for the treatment
of kidney cancer. The use of these drugs in combination against solid tumors is
investigational.

The study doctor can explain how the study drugs are designed to work.

Up to 36 participants will be enrolled in this study. All will take part at MD Anderson.

Inclusion Criteria:

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

2. Diagnostic criteria: 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.

3. Disease Evaluation: 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).

4. Performance Status: Karnofsky performance status >/= 50 for patients >/= 16 years of
age and a Lansky performance status >/= 50 for patients aged < 16 years.

5. Life Expectancy: Must be >/= 12 weeks.

6. a. 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. b. Biologic therapy (anti-neoplastic) i. 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. ii. Must not have received Bevacizumab or other monoclonal antibody
therapy within 4 weeks of study the entry.

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

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

9. Surgery: At least 2 weeks following surgery including brain and spine provided
post-operative MRI shows no active bleeding.

10. 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) as
discussed below, section 3.6 (F) for exclusion criteria. For full list of drug that
cause prolonged QT, appendix IV.

11. Adequate Bone Marrow Function Defined As: 1) Absolute neutrophil count (ANC) greater
than or equal to 1000/mm3, 2) Platelets greater than or equal to 75,000/mm3
(transfusion independent; no transfusion for >/= 7 days prior to study enrollment), 3)
Hemoglobin greater than 8.0 g/dL (transfusion independent; no transfusion for >/= 7
days prior to study enrollment).

12. Adequate Liver Function Defined As: Aspartate aminotransferase (AST) and alanine
aminotransferase (ALT) x ULN.

13. Adequate Renal Function as Defined As: Creatinine clearance or radioisotope GFR >
70ml/min/1.73 m2 OR Serum creatinine based on age/gender as follows: Age 1 to < 2
years, Maximum Serum Creatinine Male 0.6 mg/dL/Female 0.6 mg/dL; > 2 and < 6 years,
Male 0.8/ Female 0.8; > 6 and < 10 years, Male 1.0/ Female 1.0; > 10 and < 13 years,
Male 1.2/ Female1.2; > 13 and < 16 years, Male 1.5/ Female 1.4; > 16 years, Male 1.7/
Female 1.4.

14. Reproductive Function: 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.

15. 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.

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

17. Central Nervous Function Defined As; Patients with seizure disorder may be enrolled if
on non-enzyme inducing anticonvulsants and well controlled.

18. Lipid Function: Serum cholesterol and serum triglyceride levels must be < Grade 2.

19. 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:

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

2. Pregnancy or breast-feeding: Pregnant or breast-feeding women will not be entered on
this study due to the risk of fetal or teratogenic effects.

3. 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.

4. History of hypersensitivity to any component of the formulation.

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

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

7. 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.

8. Patients on the following medication will be excluded: a. 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. b. 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.

9. Exclusion #8 continued: c. Inducers and Inhibitors of Cytochrome P450 3A4 (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.d. Angiotensin-converting enzyme (ACE) inhibitors: Patients who are
currently receiving 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. e. 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.

10. Exclusion #8 continued: f. 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) 1. quinidine, procainamide, disopyramide 2.
amiodarone, sotalol, ibutilide, dofetilide 3. chlorpromazine, haloperidol,
mesoridazine, thioridazine, pimozide 4. cisapride, bepridil, droperidol, arsenic,
chloroquine, domperidone, halofantrine, levomethadyl, sparfloxacin, lidoflazine Other
drugs permitted but use with caution include;

11. Exclusion #8 continued: g. Drugs are not recommended but can be used with caution; 1.
Antacids: Use of H2 blockers and proton pump inhibitors is not recommended because
systemic antacids (H2 inhibitors, proton pump inhibitors) decrease dasatinib
absorption. 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. 2. Drugs prolong QT
interval; erythromycin, clarithromycin, pentamidine, ondansetron, granisetron, and
methadone.