Clinical trial NCT01169636
Conditions: Hodgkin's Lymphoma
Keywords: Chemotherapy Panobinostat Ifosfamide Mesna Etoposide Carboplatin Pegfilgrastim ICE
Sponsor: M.D. Anderson Cancer Center
Start date: 2011-01-31; Completion date: 2017-05-17
Enrollment: 62 participants; Allocation: RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
Objectives:

Primary objective:

* Phase-I: To determine the maximal tolerated dose (MTD) of panobinostat (LBH589) + Ifosfamide + Mesna, Carboplatin and Etoposide (ICE) combination
* Randomized Phase-II: To estimate the complete response (CR) rate in patients with relapsed and refractory classical Hodgkins Lymphoma (HL) receiving ICE versus PANOBINOSTAT plus ICE therapy

Secondary Objectives:

* To assess the safety and tolerability of the novel combination of PANOBINOSTAT (LBH589) plus ICE versus ICE in patients with relapsed and refractory HL
* To estimate the overall response rate (CR + partial response PR)
* To estimate the success rate of stem cell collection in patients eligible for stem cell transplant
* To estimate the percentage of patients who subsequently undergo autologous stem cell transplantation (ASCT)
* To estimate the event free survival (EFS) at 1 year after randomization
* To determine pretreatment expression level of histone deacetylases (HDAC1), HDAC2, and pSTAT3 and Signal transducer and activator of transcription protein (pSTAT6) by Immunohistochemistry (IHC) and correlate the results with treatment response

Detailed description:
Phase I:

The Study Drugs:

Panobinostat is designed to block the function of enzymes that are found inside cancer cells. These enzymes trigger cells to grow and multiply out of control. By blocking these enzymes, it may slow down the growth of or kill cancer cells.

Ifosfamide is designed to slow or stop the growth of cancer cells.

Carboplatin is designed to interfere with the growth of cancer cells by stopping cell division, which may cause the cells to die.

Etoposide is designed to block cell growth.

Baseline Tests:

If you are found to be eligible to take part in this study, the following tests and procedures will be performed about 7 days before the first dose of the study drug:

* You will have a physical exam, including measurement of your height, weight, and vital signs (blood pressure and heart rate).
* You will have 1 electrocardiogram (ECG -- a test that measures the electrical activity of the heart).
* Blood (about 2 1/2 teaspoons) will be drawn for routine tests.
* Women who are able to become pregnant must have a negative blood (about 1 1/2 teaspoons) pregnancy test.

Study Groups:

You will be assigned to a dose level of panobinostat based on when you join this study. Up to 2 dose levels of panobinostat will be tested. Up to 6participants will be enrolled at each dose level. The first group of participants will receive the lowest dose level. Each new group will receive a higher dose than the group before it, if no intolerable side effects were seen. This will continue until the highest tolerable dose of panobinostat is found.

All participants will receive the same dose level of ICE.

Once the highest tolerable dose is found, up to 20 extra participants, called the expansion group, will receive the study drugs at that dose.

Study Drug Administration:

Each cycle is 14 days.

ICE Administration:

On Day 1 (+/- 2 days) of Cycles 1-3, you will receive ifosfamide by vein over 24 hours.

On Day 1 (+/- 2 days) of Cycles 1-3, you will receive carboplatin by vein over 1 hour.

On Days 1-3 (+/- 2 days) of Cycles 1-3, you will receive etoposide by vein over 2 hours.

You will also receive mesna to help prevent side effects. On Day 2 (+/- 2 days) of Cycles 1-3, you will receive mesna by vein over 12 hours.

You will also receive pegfilgrastim to help prevent side effects. Beginning 24-48 hours after the completion of chemotherapy of Cycles 1-3, you will take pegfilgrastim through a needle under the skin.

Panobinostat Administration:

You will take panobinostat by mouth starting Day -6 of Cycle 1 (6 days before your first dose of ICE). You will take the panobinostat on Days -6, -4, and -2 of Cycle 1 and Days 1, 3, 5, 8, 10, and 12 of Cycles 1 and 2.

If you are in the expansion group, you will take panobinostat by mouth starting Day -6 of Cycle 1 (6 days before your first dose of ICE). You will take the panobinostat on Days -6, -4, and -2 of Cycle 1 and Days 1, 3, and 5 of Cycles 1 and 2.

You should take panobinostat around the same time each day with 1 cup (8 ounces) of water. You should swallow the capsules whole and not chew them. You must avoid grapefruit or grapefruit juice and seville (sour) oranges while on study.

If you miss a dose of panobinostat, take it as soon as you remember it on the same day. However, if more than 12 hours have passed since you were supposed to take the dose, you should skip that day's dose. In that case, wait to take panobinostat until the next scheduled dosing day.

Study Visits:

On Days -6 and -2 of Cycle 1, you will have 2 ECGs.

Within 7 days before each ICE therapy:

* You will have a physical exam, including measurement of your height, weight, and vital signs.
* Blood (about 2 1/2 teaspoons) will be drawn for routine tests.
* You will be asked if you have had any side effects.

One (1) time a week, blood (2 1/2 teaspoons) will be drawn for routine tests.

On Day 1 of Cycles 2 and beyond, you will have an ECG.

After Cycle 3:

* You will have a CT scan of your head and neck, chest, abdomen, and pelvis to check the status of the disease.
* If your bone marrow was positive at screening, you will have a positron emission tomography (PET) scan to check the status of the disease.

Length of Study:

You be on study for up to 3 cycles (about 42 days). You will be taken off study early if the disease worsens or you experience intolerable side effects.

End-of-Study Visit:

After you are off study, you will have an end-of-study visit at which the following will be performed:

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

You will have an ECG.

This is an investigational study. Panobinostat is not FDA approved or commercially available. It is currently being used for research purposes only.

ICE is FDA approved and commercially available for the treatment of several types of lymphoma, including relapsed and refractory Hodgkins lymphoma. The combination of panobinostat and ICE for the treatment of Hodgkin's lymphoma is investigational.

Up to 102 patients will take part in this study. All will be enrolled at MD Anderson.

Phase II:

The Study Drugs:

Panobinostat is designed to block the function of enzymes that are found inside cancer cells. These enzymes trigger cells to grow and multiply out of control. By blocking these enzymes, it may slow down the growth of or kill cancer cells.

Ifosfamide is designed to slow or stop the growth of cancer cells.

Carboplatin is designed to interfere with the growth of cancer cells by stopping cell division, which may cause the cells to die.

Etoposide is designed to block cell growth.

Baseline Tests:

If you are found to be eligible to take part in this study, the following tests and procedures will be performed about 7 days before the first dose of the study drug:

* You will have a physical exam, including measurement of your height, weight, and vital signs (blood pressure and heart rate).
* You will have 1 electrocardiogram (ECG -- a test that measures the electrical activity of the heart).
* Blood (about 2 1/2 teaspoons) will be drawn for routine tests.
* Women who are able to become pregnant must have a negative blood (about 1 1/2 teaspoons) pregnancy test.

Study Groups:

You will be randomly assigned (as in the flip of a coin) to 1 of 2 groups.

* If you are in Group 1, you will receive ICE.
* If you are in Group 2, you will receive ICE and panobinostat.

Study Drug Administration:

Each cycle is 14 days.

ICE Administration:

On Day 1 (+/- 2 days) of Cycles 1-3, you will receive ifosfamide by vein over 24 hours.

On Day 1 (+/- 2 days) of Cycles 1-3, you will receive carboplatin by vein over 1 hour.

On Days 1-3 (+/- 2 days) of Cycles 1-3, you will receive etoposide by vein over 2 hours.

You will also receive mesna to help prevent side effects. On Day 2 (+/- 2 days) of Cycles 1-3, you will receive mesna by vein over 12 hours.

You will also receive pegfilgrastim to help prevent side effects. Beginning 24-48 hours after the completion of chemotherapy of Cycles 1-3, you will take pegfilgrastim through a needle under the skin.

Panobinostat Administration:

If you are in a group that will receive panobinostat, you will take panobinostat by mouth starting Day -6 of Cycle 1 (6 days before your first dose of ICE). You will take the panobinostat on 3 times a week during Cycles 1 and 2 (Days -6, -4, and -2 of Cycle 1 and Days 1, 3, and 5 Cycles 1 and 2).

You should take panobinostat around the same time each day with 1 cup (8 ounces) of water. You should swallow the capsules whole and not chew them. You must avoid grapefruit or grapefruit juice and seville (sour) oranges while on study.

If you miss a dose of panobinostat, take it as soon as you remember it on the same day. However, if more than 12 hours have passed since you were supposed to take the dose, you should skip that day's dose. In that case, wait to take panobinostat until the next scheduled dosing day.

Study Visits:

On Days -6 and -2 of Cycle 1, you will have 2 ECGs.

Within 7 days before each ICE therapy:

* You will have a physical exam, including measurement of your height, weight, and vital signs.
* Blood (about 2 1/2 teaspoons) will be drawn for routine tests.
* You will be asked if you have had any side effects.

One (1) time a week, blood (2 1/2 teaspoons) will be drawn for routine tests.

On Day 1 of Cycles 2 and beyond, you will have an ECG.

After Cycle 3:

* You will have a CT scan of your head and neck, chest, abdomen, and pelvis to check the status of the disease.
* If your bone marrow was positive at screening, you will have a PET scan to check the status of the disease.

Length of Study:

You be on study for up to 3 cycles (about 42 days). You will be taken off study early if the disease worsens or you experience intolerable side effects.

End-of-Study Visit:

After you are off study, you will have an end-of-study visit at which the following will be performed:

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

This is an investigational study. Panobinostat is not FDA approved or commercially available. It is currently being used for research purposes only.

ICE is FDA approved and commercially available for the treatment of several types of lymphoma, including relapsed and refractory Hodgkins lymphoma. The combination of panobinostat and ICE for the treatment of Hodgkin's lymphoma is investigational.

Up to 102 patients will take part in this study. All will be enrolled at MD Anderson.

Arms: arm 1: Phase 1: Escalating Panobinostat dose with routine ICE Chemotherapy arm 2: Phase 2: Routine ICE Chemotherapy (Ifosfamide, Carboplatin, + Etoposide) arm 3: Phase 2: Panobinostat with ICE Chemotherapy
Interventions: intervention 1: Panobinostat intervention 2: Ifosfamide intervention 3: Mesna intervention 4: Carboplatin intervention 5: Etoposide intervention 6: Pegfilgrastim
Intervention descriptions: intervention 1: Starting Day -6 of Cycle 1, 20 mg orally on Monday, Wednesday, and Friday during Cycles 1 and 2 (Days -6, -4, and -2 of Cycle 1 and Days 1, 3, 5, 8, 10, and 12 of Cycles 1 and 2); MTD found in Phase 1 used for same schedule in Phase 2. intervention 2: Day 1 of Cycles 1-3, 5 grams/m2 by vein over 24 hours. intervention 3: On Day 1 of Cycles 1-3, 2 grams/m2 by vein over 12 hours. intervention 4: On Day 1 of Cycles 1-3, Standard Dose (Target area under curve (AUC) = 5mg/ml/min) by vein over 1 hour. intervention 5: On Days 1-3 of Cycles 1-3, 100 mg/m2 by vein over 2 hours. intervention 6: Beginning Day 4 of Cycles 1-3, 6 mg under the skin.

Protocol documents:
Prot_SAP_000.pdf: