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Phase I Study of Panobinostat Plus ICE Chemotherapy Followed by a Randomized Phase-II Study of ICE Compared With Panobinostat Plus ICE for Patients With Relapsed and Refractory Classical Hodgkin Lymphoma


Phase 1/Phase 2
16 Years
N/A
Open (Enrolling)
Both
Hodgkin's Lymphoma

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Trial Information

Phase I Study of Panobinostat Plus ICE Chemotherapy Followed by a Randomized Phase-II Study of ICE Compared With Panobinostat Plus ICE for Patients With Relapsed and Refractory Classical Hodgkin Lymphoma


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.

- Blood (about 2 teaspoons) will be drawn for biomarker testing. Biomarkers are chemical
"markers" in the blood/tissue that may be related to your reaction to the study drug.

- 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 1 (+/- 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 8 of Cycle 1 (±1 day), blood (about 2 teaspoons) will be drawn for biomarker testing.
Biomarkers are chemical "markers" in the blood/tissue that may be related to your reaction
to the study drug.

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.

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.

- Blood (about 2 teaspoons) will be drawn for biomarker testing. Biomarkers are chemical
"markers" in the blood/tissue that may be related to your reaction to the study drug.

- 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 1 (+/- 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, 5, 8, 10, and 12 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 8 of Cycle 1 (±1 day), blood (about 2 teaspoons) will be drawn for biomarker testing.
Biomarkers are chemical "markers" in the blood/tissue that may be related to your reaction
to the study drug.

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.


Inclusion Criteria:



1. Histologically confirmed classical Hodgkin lymphoma (nodular sclerosis, mixed
cellularity, or lymphocyte-rich classical HL).

2. Patients must have failed (relapsed or refractory) front-line standard
anthracycline-containing regimen, such as ABVD, Stanford V, or BEACOPP.

3. Bidimensionally measurable disease with at least 1 lesion >/= 2.0 cm in a single
dimension

4. Acceptable hematologic status:Hemoglobin >/= 9.0 g/dL, Absolute neutrophil count >/=
1500 cells/mm3, Platelet count >/= 100,000 cells/mm3

5. Normal serum K+, Mg+, PO4, and total Ca++ (pre-treatment abnormal values may be
therapeutically corrected before starting therapy and must be documented as normal or
if abnormal values persist must be documented as clinically insignificant). Albumin
should be >/= 3

6. Pre-study World Health Organization (WHO) performance status of 0, 1, or 2

7. Age >/= 16 years

8. Voluntary signed IRB approved consent informed before performance of any
study-related procedure not part of normal medical care, with the understanding that
consent may be withdrawn by the subject at any time without prejudice to future
medical care.

9. Patients of reproductive potential (female of child bearing potential has not been
postmenopausal for at least 12 consecutive months or not surgically sterile; male of
child bearing potential has not been surgically sterile)must follow accepted birth
control methods (e.g. barrier method) during treatment.

10. Clinically euthyroid. Note: Patients are permitted to receive thyroid hormone
supplements to treat underlying hypothyroidism.

Exclusion Criteria:

1. Lymphocyte predominant histology

2. More than one prior chemotherapy regimens.

3. Prior therapy with other HDAC inhibitors, including valproic acid

4. Prior therapy with heat shock protein (HSP)-90 inhibitors

5. Prior stem cell transplant

6. Abnormal liver function: Bilirubin > 2.0 mg/dL (26 µmol/L), Alkaline phosphatase > 2
x upper limits of normal (ULN), aspartate aminotransferase AST (SGOT) and/or alanine
aminotransferase ALT > 2 x ULN

7. Serum creatinine >1.5 mg/dl

8. Presence of Central Nervous System (CNS) involvement with Hodgkin lymphoma

9. Presence of Human immunodeficiency virus (HIV) infection or acquired immune
deficiency syndrome (AIDS).

10. Another primary malignancy (other than squamous cell and basal cell carcinoma of the
skin, in situ carcinoma of the cervix, or treated prostate cancer with a stable
Prostate Specific Antigen PSA) for which the patient has not been disease free for at
least 3 years.

11. Serious nonmalignant disease (e.g., congestive heart failure, hydronephrosis); active
uncontrolled bacterial, viral, or fungal infections; or other conditions which would
compromise protocol objectives in the opinion of the investigator

12. Impaired cardiac function or clinically significant cardiac diseases, including any
one of the following:History or presence of sustained ventricular tachyarrhythmia,
Any history of ventricular fibrillation or torsade de pointes, Bradycardia defined as
HR< 50 bpm, Patients with pacemakers are eligible if HR >/= 50 bpm, Screening ECG
with a QTc > 450 msec, Right bundle branch block + left anterior hemiblock
(bifascicular block), Patients with myocardial infarction or unstable angina months prior to starting study drug, Other clinically significant heart disease
(e.g., CHF NY Heart Association class III or IV , uncontrolled hypertension, history
of labile hypertension, or history of poor compliance with an antihypertensive
regimen)

13. Baseline Multiple Gated Acquisition (MUGA) or ECHO must demonstrate left ventricular
ejection fraction (LVEF) >/= 50%..

14. Female subject is pregnant or breast-feeding. Confirmation that the subject is not
pregnant must be established by a negative serum Beta-human chorionic gonadotropin
(Beta-hCG) pregnancy test result obtained during screening. Pregnancy testing is not
required for post-menopausal or surgically sterilized women.

15. Patient has received other investigational drugs within 14 days before enrollment or
who have not recovered from side effects of those therapies.

16. Serious medical or psychiatric illness likely to interfere with participation in this
clinical study.

17. Impairment of gastrointestinal (GI) function or GI disease that may significantly
alter the absorption of panobinostat

18. Patients with diarrhea > Common Terminology Criteria for Adverse Events Version 4
(CTCAE V.4) grade 2

19. Patients using medications that have a relative risk of prolonging the QT interval or
inducing torsade de pointes if treatment cannot be discontinued or switched to a
different medication prior to starting study drug.

20. Patients who have received either immunotherapy within within 30% of marrow-bearing bone within weeks prior to starting study treatment; or who have not yet recovered from side
effects of such therapies.

21. Patients who have undergone major surgery who have not recovered from side effects of such therapy

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:

Phase I Maximal Tolerated Dose (MTD) of Panobinostat + ICE

Outcome Description:

MTD defined by patient dose limiting toxicities (DLT) at each dose level, monitored for 14 days (1 cycle) from first dose of ICE.

Outcome Time Frame:

Each cycle, 14 days from first dose of ICE

Safety Issue:

Yes

Principal Investigator

Yasuhiro Oki, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

UT MD Anderson Cancer Center

Authority:

United States: Food and Drug Administration

Study ID:

2010-0065

NCT ID:

NCT01169636

Start Date:

January 2011

Completion Date:

Related Keywords:

  • Hodgkin's Lymphoma
  • Chemotherapy
  • Panobinostat
  • Ifosfamide
  • Mesna
  • Etoposide
  • Carboplatin
  • Pegfilgrastim
  • ICE
  • Hodgkin Disease
  • Lymphoma

Name

Location

UT MD Anderson Cancer CenterHouston, Texas  77030