Conditions: Brain Cancer Glioblastoma Multiforme
Keywords: 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
Allocation: RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 21
Healthy volunteers: no

Brief summary:
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.

Detailed description:
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.

Arms:
arm 1: Phase I 3-Drug Combination Vorinostat with Erlotinib + Temozolomide

Starting doses Vorinostat 200 mg orally twice daily on Days 1-7 and 15-21 of every cycle; Erlotinib 200 mg orally once daily on Days 1-21; Temozolomide 125 mg/m\^2 orally once daily on Days 1-7 and 15-21. arm 2: This Phase I arm to be activated only after completion of Part A of the Phase II trial of the 3-Drug combination. If part A of the Phase II trial shows lack of efficacy, trial will be terminated.

Vorinostat orally twice daily, Days 1-14; and Erlotinib orally once daily Days 1-21 of every cycle. arm 3: Vorinostat+Erlotinib+Temozolomide where drug dosing based on the MTD identified in the Phase I portion of the study.

Vorinostat 200 mg orally twice daily on Days 1-7 and 15-21 of every cycle; Erlotinib 200 mg orally once daily on Days 1-21; Temozolomide 100 mg/m\^2 orally once daily on Days 1-7 and 15-21. arm 4: This Phase II Part B arm to be activated only after completion of Part A of the Phase I and II Part A trial of the 3-Drug combination. If part A of the Phase II trial shows lack of efficacy, trial will be terminated.

Vorinostat orally twice daily, Days 1-14; and Erlotinib orally once daily Days 1-21 of every cycle.

Interventions: intervention 1: Vorinostat intervention 2: Erlotinib intervention 3: Temozolomide
Intervention descriptions: intervention 1: Phase I Starting Dose: 200 mg twice daily by mouth on Days 1-7, 15-21 of each 28 day cycle.

Phase II Dose: MTD from Phase I. intervention 2: Phase I Starting Dose: 200 mg by mouth daily on Days 1-21 of 28 day cycle. For patients on enzyme inducing anticonvulsants (EIACs), starting dose of 400 mg.

Phase II Dose: MTD from Phase I. intervention 3: 125 mg/m2 by mouth daily on days 1-7, 15-21 of each 28 day cycle.

Protocol document: