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Phase I / II Adaptive Randomized Trial of Vorinostat, Erlotinib and Temozolomide in Adults With Recurrent Glioblastoma Multiforme


Phase 1/Phase 2
18 Years
N/A
Open (Enrolling)
Both
Brain Cancer, Glioblastoma Multiforme

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Trial Information

Phase I / II Adaptive Randomized Trial of Vorinostat, Erlotinib and Temozolomide in Adults With Recurrent Glioblastoma Multiforme


Phase I:

The Study Drugs:

Vorinostat is designed to cause chemical changes in different groups of proteins that are
attached to DNA (the genetic material of cells), which may slow the growth of cancer cells
or cause the cancer cells to die.

Erlotinib is designed to block the activity of a protein found on the surface of many tumor
cells that may control tumor growth and survival. This may stop tumors from growing.

Temozolomide is designed to kill cancer cells by damaging DNA (the genetic material of
cells). The damaged DNA may cause tumor cell death.

Study Groups:

There are 2 phases to this study.

If you are found to be eligible to take part in the Phase I portion of this study, you will
be assigned to 1 of 2 groups based on when you join this study. You will remain in the same
group for the entire study. In this study, the dose level of the study drugs is different
from group to group. Up to 4 dose levels of study drug combinations will be tested in Group
1, up to 2 dose levels in Group 2. Three (3) participants will be enrolled at each dose
level. The first 3 participants in each group will receive the lowest dose level. Each 3
new participants will receive a higher dose than the one before it, if no intolerable side
effects were seen. This will continue until the highest tolerable dose of study drugs given
in combination is found.

- If you are in Group 1, you will take vorinostat, erlotinib, and temozolomide.

- If you are in Group 2, you will take vorinostat and erlotinib.

In addition, no matter which group or dose level you are assigned to, if you are on enzyme
inducing anti-seizure drug, you will take a higher dose of erlotinib.

Study Drug Administration:

Each study cycle is 28 days.

If you are in Group 1:

- On Days 1-7 and 15-21 of every cycle, you will take vorinostat by mouth 2 times a day.
You should take vorinostat with food. Do not open, crush, or chew the capsules.

- On Days 1-21 of every cycle, you will take erlotinib by mouth 1 time a day. You should
take erlotinib in the morning 1 hour before or 2 hours after food with 1 cup (about 8
oz.) of water.

- On Days 1-7 and 15-21of every cycle, you will take the temozolomide by mouth 1 time a
day. You should swallow the temozolomide capsules whole, one right after the other,
without chewing them. If you vomit while taking temozolomide, you cannot take more
capsules before the next scheduled dose. They should be taken on an empty stomach (at
least 1 hour before and 2 hours after eating) with 1 cup (about 8 ounces) of water.

If you are in Group 2:

- On Days 1-14 of every cycle, you will take vorinostat by mouth 2 times a day. You
should take vorinostat with food. Do not open, crush, or chew the capsules.

- On Days 1-21 of every cycle, you will take erlotinib by mouth 1 time a day. You should
take erlotinib in the morning 1 hour before or 2 hours after food with 1 cup (about 8
oz.) of water.

Study Visits:

Every 4 weeks for the first 8 weeks, then every 8 weeks after that:

- Your complete medical history will be recorded.

- You will be asked about any drugs you may be taking and if you have experienced any
side effects.

- You will have a physical exam, including measurement of your vital signs and weight.

- You will have a neurological exam.

- Your performance status will be recorded.

Every week for the first 4 weeks, then every 2 weeks after that, blood (about 3 teaspoons)
will be drawn for routine tests and to check your blood's ability to clot normally.

Every 4 weeks, if you are on anti-seizure drugs, blood (about 1 teaspoon) will be drawn to
measure the amount of anti-seizure drugs in your blood.

Every 8 weeks, you will have an MRI scan to check the status of the disease.

Length of Study:

You will be on study for up to 1 year. You may continue to receive the study drugs beyond 1
year and remain on study if your doctor decides that it is in your best interest. You will
be taken off study early if the disease gets worse or you experience intolerable side
effects.

Long-Term Follow-Up Visit:

If you go off study after 12 cycles, blood (about 3 teaspoons) will be drawn for routine
tests and to check your blood's ability to clot normally every 2 weeks during the 30 days
after your last dose of study drugs.

If you go off the study for reasons other than the worsening of the disease, you will have
an MRI every 2 months unless the disease gets worse.

If you have an MRI that shows worsening of the disease, every 2-3 months from then on, you
may be called and asked how you are feeling and about any new cancer treatment that you may
have received. This phone call should take about 5-10 minutes.

This is an investigational study. Erlotinib is FDA approved drug for treatment of some
types of non-small cell lung cancer, temozolomide for some types of brain cancer, and
vorinostat for some types of lymphoma. All are commercially available. The use of these
drugs in this combination is investigational.

Up to 182 participants will take part in this study. Up to 72 patients will be enroll in the
Phase 1 portion of this study. All will be enrolled at MD Anderson.

Phase II:

The Study Drugs:

Vorinostat is designed to cause chemical changes in different groups of proteins that are
attached to DNA (the genetic material of cells), which may slow the growth of cancer cells
or cause the cancer cells to die.

Erlotinib is designed to block the activity of a protein found on the surface of many tumor
cells that may control tumor growth and survival. This may stop tumors from growing.

Temozolomide is designed to kill cancer cells by damaging DNA (the genetic material of
cells). The damaged DNA may cause tumor cell death.

Study Groups:

There are 2 phases to this study.

If you are found to be eligible to take part in the Phase 2 portion of this study, you will
be randomly assigned (as in the roll of the dice) to 1 of 2 groups.

- If you are in Group 1, you will take vorinostat and erlotinib.

- If you are in Group 2, you will take vorinostat, erlotinib, and temozolomide.

Subset Group:

If your doctor has recommended that you have surgery to remove a tumor that has come back,
you will be eligible for this subset group. You would have the surgery before being assigned
to a main study group. This subset group of the study is done to learn the effects of
vorinostat on tumor tissue and blood cells.

Before surgery, you will be randomly assigned to 1 of 3 groups.

- If you are in Group A, you will receive vorinostat alone.

- If you are in Group B, you will receive erlotinib alone.

- If you are in Group C, you will receive both vorinostat and erlotinib.

You will take the study drug(s) for 3 days in a row before your surgery.

About 2 weeks after the surgery, you will be randomly assigned to 1 of 2 main study groups
described above (Group 1 or 2).

In addition, no matter which group you are assigned to, if you are on enzyme inducing
anti-seizure drug, you will take the higher dose of erlotinib.

Study Drug Administration:

Every cycle is 28 days.

If you are in Group 1:

- On Days 1-14 of every cycle, you will take vorinostat by mouth 2 times a day. You
should take vorinostat with food. Do not open, crush, or chew the capsules.

- On Days 1-21 of every cycle, you will take erlotinib by mouth 1 time a day. You should
take erlotinib in the morning 1 hour before or 2 hours after food with 1 cup (about 8
oz.) of water.

If you are in Group 2:

- On Days 1-7 and 15-21 of every cycle, you will take vorinostat by mouth 2 times a day
.You should take vorinostat with food. Do not open, crush, or chew the capsules.

- On Days 1-21 of every cycle, you will take erlotinib by mouth 1 time a day . You should
take erlotinib in the morning 1 hour before or 2 hours after food with 1 cup (about 8
oz.) of water.

- On Days 1-7 and 15-21 of every cycle, you will take the temozolomide by mouth 1 time a
day. You should swallow the temozolomide capsules whole, one right after the other,
without chewing them. If you vomit while taking temozolomide, you cannot take more
capsules before the next scheduled dose. They should be taken on an empty stomach (at
least 1 hour before and 2 hours after eating) with 1 cup (about 8 ounces) of water.

Subset group:

For 3 days in row before surgery:

- If you are in Group A, you will take vorinostat by mouth 2 times a day.

- If you are in Group B, you will take erlotinib by mouth 1 time a day.

- If you are in Group C, you will take vorinostat by mouth 2 time a day and erlotinib by
mouth 1 time a day.

After you have recovered from the effects of surgery (about 2 weeks), you will follow the
study group schedule (Group 1 or 2) described above.

Study Visits

Every 4 weeks for the first 8 weeks, then every 8 weeks after that:

- Your complete medical history will be recorded.

- You will be asked about any drugs you may be taking and if you have had any side
effects.

- You will have a physical exam, including measurement of your vital signs and weight.

- You will have a neurological exam.

- Your performance status will be recorded.

Every week for the first 4 weeks, then every 2 weeks after that, blood (about 3 teaspoons)
will be drawn for routine tests and to check your blood's ability to clot normally.

Every 4 weeks, if you are on anti-seizure medications, blood (about 1 teaspoon) will be
drawn to measure the amount of anti-seizure medications in your blood.

Every 8 weeks, you will have an MRI scan to check the status of the disease.

Subset Group:

In addition to the above tests, blood (about 1 teaspoon each time) will be drawn 1 time
before and 3 times after the first dose of vorinostat, and during surgery. This blood will
be used to study the drug levels, the effects of the drug in normal blood cells, and to
match these findings with that in the tumor.

After the surgery, part of the leftover tumor tissue from the surgery will be used to
measure the drug levels and the effects of vorinostat on the tumor and be used for biomarker
tests.

Length of Study:

You will be on study for up to 1 year. You may continue to receive treatment beyond 1 year
and remain on study if your doctor decides that it is in your best interest. You will be
taken off study early if the disease gets worse or you have intolerable side effects.

Long-Term Follow-Up Visit:

If you go off study after 12 cycles, blood (about 3 teaspoons) will be drawn for routine
tests and to check your blood's ability to clot normally every 2 weeks during the 30 days
after your last dose of study drugs.

If you go off the study for reasons other than the worsening of the disease, you will have
an MRI every 2 months unless the disease gets worse.

If you have an MRI that shows worsening of the disease, every 2-3 months from then on, you
may be called and asked how you are feeling and about any new cancer treatment that you may
have received. This phone call will take about 5-10 minutes.

This is an investigational study. Erlotinib is FDA approved drug for treatment of some
types of non-small cell lung cancer, temozolomide for some types of brain cancer, and
vorinostat for some types of lymphoma. All are commercially available. The use of these
drugs in this combination is investigational.

Up to 182 participants will take part in this study. Up to 110 patients will be enrolled in
the Phase 2 portion of this study. Up to 15 participants will take part in the subset
portion of the study. All will be enrolled at MD Anderson.


Inclusion Criteria:



1. Patients with histologically proven glioblastoma multiforme, gliosarcoma or
anaplastic glioma will be eligible for the Phase I component. Anaplastic gliomas
include anaplastic astrocytoma (AA), anaplastic oligodendroglioma (AO), anaplastic
oligoastrocytoma (AOA), or malignant glioma NOS (not otherwise specified). Patients
will be eligible if the original histology was low-grade glioma and a subsequent
histological diagnosis of a malignant glioma is made. Only patients with
histologically proven supratentorial glioblastoma multiforme or gliosarcoma will be
eligible for the Phase II component.

2. Patients must have shown unequivocal evidence for tumor recurrence or progression by
MRI scan and should have failed radiation therapy. Patients should have completed
radiation therapy at least 3 months prior to entry into the study. The scan done
prior to study entry documenting progression will be reviewed by the treating
physician to document changes in tumor dimension to confirm recurrence.

3. (2. continued) Patients with prior therapy that included interstitial brachytherapy
or stereotactic radiosurgery must have reasonable confirmation of true progressive
disease rather than radiation necrosis as determined by the treating physician and
neuro-radiologist; for example, through MRI, MR spectroscopy, or PET scan of the
brain.

4. For the Phase I component, any number of prior relapses is allowed, provided the
patient fulfills all other eligibility criteria particularly that of the functional
status. For the phase II component, patients may have had up to 2 prior relapses

5. All patients must sign an informed consent indicating their awareness of the
investigational nature of this study in keeping with the policies of this hospital.

6. The baseline on-study MRI should be performed within 14 days (+/- 3 days) prior to
registration and on a steroid dosage that has been stable or decreasing for at least
5 days. If the steroid dose is increased between the date of imaging and the
initiation of therapy (or at that time), a new baseline MRI is required. The same
type of scan, i.e., MRI, must be used throughout the period of protocol treatment for
tumor measurement.

7. Patients having undergone recent resection of recurrent or progressive tumor will be
eligible as long as all of the following conditions apply: a) They have recovered
from the effects of surgery. b) Evaluable or measurable disease following resection
of recurrent tumor is not mandated for eligibility into the study. c) To best assess
the extent of residual measurable disease post-operatively, a MRI should be done no
later than 96 hours in the immediate post-operative period or 4-6 weeks
post-operatively.

8. Patients must be 18 years old or older.

9. Patients must have a Karnofsky performance status (KPS) equal or greater than 60

10. Patients must have recovered from the toxic effects of prior therapy to grade 1 non
hematological or weeks from prior cytotoxic therapy or bevacizumab and/or at least two weeks from
vincristine, 6 weeks from nitrosoureas, 3 weeks from procarbazine administration, and
1 week for non-cytotoxic agents, e.g., interferon, tamoxifen, cis-retinoic acid, etc.
(radiosensitizer does not count).

11. (10. continued) Patients who receive anticancer agents for non-therapeutic purposes
unrelated to this study (such as presurgically for obtaining pharmacology data for
the agent) will be eligible to enter the study provided they have recovered from the
toxic effects of the agent if any. Any questions related to the definition of
non-cytotoxic agents should be directed to the Study Chair.

12. Patients must have adequate bone marrow function (ANC>/= 1,500/mm^3 and platelet
count of >/= 100,000/mm^3), adequate liver function (SGPT alkaline phosphatase function (BUN and creatinine registration.

13. Women of childbearing potential on treatment must not be pregnant, must not be
breast-feeding and must practice adequate contraception. Male patients on treatment
with vorinostat must agree to use an adequate method of contraception for the
duration of the study, and for 30 days after the last dose of study medication.

Exclusion Criteria:

1. Patients with a history of any other cancer (except non-melanoma skin cancer or
carcinoma in-situ of the cervix or bladder), unless in complete remission and off of
all therapy for that disease for a minimum of 3 years are ineligible.

2. Patients must not have: a) active infection b) disease that will obscure toxicity or
dangerously alter drug metabolism, especially liver disease including cirrhosis or
hepatic dysfunction c) serious intercurrent medical illness

3. Patients who are currently on active treatment for AIDS or hepatitis will be excluded
due to the potential for adverse interaction with ongoing treatment agents and for
unknown toxicity.

4. Patients receiving valproic acid (VPA), an anticonvulsant drug with HDAC inhibitor
properties, will be excluded, unless they are switched to an alternative agent prior
to treatment initiation. A 5 day wash out period is required.

5. Prior treatment with EGFR inhibitors or temozolomide on a standard day 1-5 dosing and
low dose daily dosing as part of chemoradiation therapy is allowed because the trial
is based on the hypothesis that the combination of agents used will be synergistic in
their effects, and that HDAC inhibition will potentially overcome resistance to EGFR
inhibitors and temozolomide. However, prior treatment with dose dense regimens of
temozolomide (7 days on/ 7 days off, 21 days/28 days or continuous low dose daily
dosing not with chemoradiation) and HDAC inhibitors other than valproic acid (such as
depsipeptide, LBH-589 or vorinostat) are not permitted.

6. Patients with a known allergy to any component of vorinostat, or a known allergy to
Temozolomide or erlotinib will be excluded.

7. Patient must be able to tolerate the procedures required in this study including
periodic blood sampling, study related assessments, and management at the treating
institution for the duration of the study. Inability to comply with protocol or study
procedures (for example, an inability to swallow tablets) will be an exclusion
criteria.

8. This study was designed to include women and minorities, but was not designed to
measure differences of intervention effects. Males and females will be recruited with
no preference to gender.

9. No exclusion to this study will be based on race. The malignant glioma patient
population treated at MDACC over the past year is as follows: American Indian or
Alaskan Native - 0; Asian or Pacific Islander - <2%; Black, not of Hispanic Origin -
3%; Hispanic - 6%; White, not of Hispanic Origin - 88%; Other or Unknown - 2%;
Total-100%.

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum Tolerated Dose (MTD)

Outcome Time Frame:

Evaulated with each 28 day (+2 days) cycle

Safety Issue:

Yes

Principal Investigator

John DeGroot, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

UT MD Anderson Cancer Center

Authority:

United States: Institutional Review Board

Study ID:

2009-0651

NCT ID:

NCT01110876

Start Date:

June 2011

Completion Date:

Related Keywords:

  • Brain Cancer
  • Glioblastoma Multiforme
  • Recurrent Glioblastoma Multiforme
  • GBM
  • Brain
  • Central Nervous Center
  • Malignant glioma
  • Glioblastoma multiforme
  • Gliosarcoma
  • Anaplastic astrocytoma
  • Anaplastic oligodendroglioma
  • Anaplastic oligoastrocytoma
  • Vorinostat
  • SAHA
  • Suberoylanilide Hydroxamic Acid
  • MSK-390
  • Zolinza
  • Erlotinib
  • Erlotinib Hydrochloride
  • OSI-774
  • Tarceva
  • Temozolomide
  • Temodar
  • Brain Neoplasms
  • Glioblastoma

Name

Location

UT MD Anderson Cancer CenterHouston, Texas  77030