Phase I / II Vorinostat, Erlotinib and Temozolomide for Recurrent Glioblastoma Multiforme (GBM)
Phase I / II Vorinostat, Erlotinib and Temozolomide for Recurrent Glioblastoma Multiforme (GBM)
Phase I Objectives:

 -To determine the maximum tolerated dose (MTD) of vorinostat + erlotinib versus vorinostat +
 erlotinib + temozolomide in adult patients with recurrent glioblastoma multiforme (GBM) and
 anaplastic gliomas.

 Phase II Objectives:

 Primary: To determine the efficacy of vorinostat + erlotinib versus vorinostat + erlotinib +
 temozolomide in patients with recurrent glioblastoma multiforme as progression free survival
 using a two arm adaptive randomization phase II trial design.

 Secondary: To determine the radiological response, progression free survival (PFS) at 6
 months, overall survival and unexpected toxicity in the two treatment arms; and to obtain
 exploratory data regarding histone 3 and 4 acetylation, treatment related changes in the
 epidermal growth factor receptor (EGFR) pathway proteins, and changes in e-cadherin and
 vimentin expression (mRNA /protein) levels in tumor tissue and peripheral monocytes in a
 subset of surgical patients.
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 not otherwise specified (NOS). 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, magnetic resonance (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 </= grade 2 hematological toxicity (except deep vein thrombosis): 4
 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 </= 3 times normal and alkaline
 phosphatase </= 2 times normal, bilirubin </= 1.5 mg/dl), adequate renal function (BUN
 and creatinine </= 1.5 times institutional normal) prior to 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 histone
 deacetylase (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 MD Anderson Cancer Center (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%.