Study of Suberoylanilide Hydroxamic Acid (SAHA) With Temsirolimus in Children With Diffuse Intrinsic Pontine Glioma (DIPG)

Study Groups:

If participant is found to be eligible to take part in this study, participant will be in 1
of 2 study groups based on when participant was diagnosed with DIPG:

- If participant is newly diagnosed with DIPG, participant will be in Group 1. Participant
will receive radiation therapy and vorinostat, then the combination of vorinostat and
temsirolimus.

- If participant has been diagnosed with DIPG before and the disease has gotten worse
since, participant will be in Group 2. Participant will receive the combination of
vorinostat and temsirolimus without receiving radiation therapy.

Study Drug Administration:

Participant will be assigned to a dose level of temsirolimus based on when participant joined
this study. Up to 2 dose levels of temsirolimus will be tested. Up to 6 participants will be
enrolled at each dose level. The first group of participants will receive the lowest dose
level. The second group will receive a higher dose than the group before it, if no
intolerable side effects were seen.

All participants will receive the same dose level of vorinostat, though the dose may be
lowered if there are intolerable side effects.

Vorinostat should be taken with food. Participant should be careful not to open or break the
capsules of vorinostat. If a capsule breaks, participant should try to clean it up carefully
without breathing in any of the powder. Participant should wash the spill area at least 3
times with ethyl alcohol, and then rinse it 1 time with water. If the powder comes in contact
with participant's skin, participant should wash the affected area thoroughly with soap and
water.

If participant has trouble swallowing, participant may receive vorinostat in liquid form. The
dose amount will be based on participant's body surface area. The MD Anderson pharmacy will
give participant the drug in liquid form. Participant should store the liquid form of the
drug at room temperature, away from excessive heat or humidity. The liquid form of the drug
should be taken with food.

Participant should avoid spilling the powder from the capsules or the liquid form of the drug
on participant's skin. If contact occurs, participant should wash the area thoroughly with
water.

Group 1:

Participant will receive 30 treatments of radiation therapy over 6-7 weeks. Participant will
sign a separate consent form for this treatment that will explain the procedure, as well as
its risks and benefits. Participant will take capsules of vorinostat with food, every morning
that participant has a radiation treatment (Monday - Friday) at least 1-2 hours before
radiation.

After participant has finished radiation therapy, participant will rest for 4 weeks in which
participant does not receive radiation therapy or study drug.

After this, participant will start receiving the chemotherapy combination of vorinostat and
temsirolimus in 28-day study cycles:

- Participant will take capsules of vorinostat with food 1 time every day on Days 1-8 of
each cycle.

- Participant will receive temsirolimus by vein over about 30 minutes on Days 1 and 8 of
each cycle.

Group 2:

Participant will receive the chemotherapy combination of vorinostat and temsirolimus in
28-day study cycles:

- Participant will take capsules of vorinostat with food 1 time every day on Days 1-8 of
each cycle.

- Participant will receive temsirolimus by vein over about 30 minutes on Days 1 and 8 of
each cycle.

Study Visits for Group 1 during Radiation Therapy:

Every week:

- Participant will have a physical exam.

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

Study Visits for All Participants during Chemotherapy:

Every week:

- Participant will have a physical exam.

- Blood (about 2-6 teaspoons) will be drawn for routine tests.

Every week during Cycle 1, then at the beginning of every cycle after that, urine will be
collected for routine tests.

At the beginning of every odd-numbered cycle (1, 3, 5, and so on), participant will have an
MRI of the brain to check the status of the disease. If the doctor thinks it is needed, this
will also include an MRI of the spine. If participant is in Group 2, this will not need to be
performed at Cycle 1 since participant's screening scans were recently performed.

Length of Study:

If participant is in Group 1, participant will receive radiation therapy and chemotherapy for
up to 7 weeks, followed by 4 weeks of rest, followed by up to 10 cycles of chemotherapy
alone.

If participant isin Group 2, participant will receive up to 12 cycles of chemotherapy.

Participant will no longer be able to receive the study treatment if the disease gets worse,
if intolerable side effects occur, or if participant is unable to follow study directions.

Participation on the study will be over after the follow-up visits.

End-of-Dosing Visi:t After participant has finished receiving chemotherapy, blood (about 1
teaspoon) will be drawn for routine tests.

Follow-Up:

Participant will have follow-up visits 3, 6, 9, and 12 months after participants' finishes
receiving chemotherapy. The following tests and procedures will be performed:

- Participant will have a physical exam.

- Participant will have an MRI of the brain and spine to check the status of the disease.

- Blood (about 1 teaspoon) and urine will be collected for routine tests (Month 3
follow-up visit only).

This is an investigational study. Vorinostat is FDA approved and commercially available for
the treatment of cutaneous T-cell lymphoma (CTCL). Temsirolimus is FDA approved and
commercially available for the treatment of kidney cancer. The use of these drugs in
combination is investigational. The radiation therapy is delivered using FDA-approved and
commercially available methods.

The study doctor can explain how the study drug(s) are designed to work.

Up to 18 participants will be enrolled in this study. All will take part at MD Anderson.

Inclusion Criteria:

1. Patients must be > than 6 months and less than or equal to 21 years of age at the time
of study enrollment.

2. Patients with newly diagnosed or progressive DIPG as confirmed by gadolinium enhanced
MRI are eligible. MRI must demonstrate that at least 2/3 of the tumor is situated in
the pons and that the origin of the tumor is clearly in the pons. Biopsy is not
required. Tumors with features not typical of diffuse intrinsic brainstem glioma are
not eligible. These include dorsally exophytic brainstem gliomas, cervicomedullary
junction tumors, and focal low grade gliomas of the midbrain or brainstem which should
undergo resection and pathologic evaluation. Patients, who have received
re-irradiation for progression of the tumor, will be eligible if they show evidence of
measurable progressive disease after the re-irradiation. Patients at diagnosis with
involvement of the spine will not be eligible, however if at progression features of
spine involvement are present they will be eligible for Stratum II.

3. Performance level: At the time of study enrollment patients must have a Karnofsky
greater than or equal to 50% for patients > 16 years of age and Lansky greater than or
equal to 50 for patients less than or equal to 16 years of age. 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.

4. Prior Therapy: Patients must have fully recovered from the acute toxic effects of all
prior anti-cancer chemotherapy or radiation to grade 2 or less.

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

6. Hematopoietic growth factors: At least 14 days must have passed after the last dose of
a long-acting growth factor (e.g. Neulasta) or 7 days for short-acting growth factor.

7. Biologic (anti-neoplastic agent): At least 7 days must have elapsed after the last of
a biologic agent that is not a monoclonal antibody, to be enrolled on this study.

8. Immunotherapy: At least 6 weeks since the completion of any type of immunotherapy,
e.g. tumor vaccines.

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

10. Radiotherapy: greater than or equal to 2 weeks must have elapsed for local palliative
radiotherapy (re-irradiation for progressive disease or upfront RT at initial
diagnosis) and enrollment on study for stratum II. At least 24 weeks must have elapsed
if patient received craniospinal radiotherapy due to any other prior malignancies.

11. Stem Cell Infusion without Total Body Irradiation: The patient must have no evidence
of active graft vs. host disease, and greater than or equal to 12 weeks must have
elapsed since transplant or stem cell infusion and enrollment on this study for any
other pathology.

12. Prior treatment with vorinostat is allowed but at least 3 weeks must have elapsed from
the last dose and effects of prior therapy have resolved.

13. Concomitant medications: Patients with CNS tumors who are receiving steroids are
eligible.

14. Organ function requirements: Adequate Bone Marrow Function Defined As- Peripheral
absolute neutrophil count (ANC) greater than or equal to 1000/microL- Platelet count
greater than or equal to 100,000/microL (transfusion independent)- Hemoglobin greater
than or equal to 10.0 gm/dL (transfusion independent). Adequate Renal Function Defined
As- Serum creatinine less than or equal to 1.5 x institutional upper limit of normal
for age. Adequate Liver Function Defined As- Bilirubin (sum of conjugated +
unconjugated) less than 1.5 x upper limit of normal (ULN) for age- SGPT (ALT) less
than or equal to 110U/L. For the purpose of this study, the ULN for SGPT is 45 U/L.-
Serum albumin must be greater than or equal to 2 g/dL.- PT and INR < 1.2 x ULN.

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

16. Lipid Function- Serum cholesterol and serum triglyceride levels must be less than 300
mg/dl.

17. Pregnancy and Contraception- Females > 13 years of age or who have achieved menarche
must have a negative pregnancy test within 2 weeks of starting treatment (urine or
serum) to be eligible and if sexually active must also agree to use contraception.-
Male sexually active patients must agree to use an effective method of contraception.

18. Therapeutic Options- 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

19. Life expectancy: At the time of study enrollment patients must have a life expectancy
of greater than or equal to 2 months. Neurologic deficits in patients with CNS tumors
must have been relatively stable for a minimum of 1 week prior to study enrollment.

Exclusion Criteria:

1. Patients with other malignancies will not be eligible for stratum I or II. Patients
with disseminated disease including to the spine will not be eligible for stratum 1
but will be eligible for stratum II.

2. Patients must not have a history of myocardial infarction, severe or unstable angina,
clinically significant peripheral vascular disease, Grade 2 or greater heart failure,
or serious and inadequately controlled cardiac arrhythmia

3. Pregnant or breast-feeding women will not be entered on this study due to risks of
fetal and teratogenic adverse events as seen in animal/human studies

4. Enzyme-inducing anticonvulsants: Patients who are currently receiving enzyme inducing
anticonvulsants are not eligible

5. Anticoagulants: Patients who are currently receiving therapeutic anticoagulants
(including aspirin, low molecular weight heparin, and others) are not eligible

6. 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

7. Anti-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

8. Patients with history of allergic reactions attributed to compounds of similar
chemical; or biologic composition to vorinostat or temsirolimus are not eligible

9. Infection: Patients who have an uncontrolled infection are not eligible

10. 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

11. Patients with newly diagnosed DIPG who have received vorinostat previously will not be
eligible for stratum I. Patients with progressive DIPG will be eligible if they have
received either one of the two drugs vorinostat or temsirolimus but will not be
eligible for stratum II if have received both the drugs before