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Phase 1/1b Study of the Efficacy and Safety of the Combination of Panobinostat Plus Carfilzomib in Patients With Relapsed/Refractory Myeloma


Phase 1
18 Years
N/A
Open (Enrolling)
Both
Myeloma

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Trial Information

Phase 1/1b Study of the Efficacy and Safety of the Combination of Panobinostat Plus Carfilzomib in Patients With Relapsed/Refractory Myeloma


The Study Drugs Carfilzomib is designed to keep cancer cells from repairing themselves. If
the cancer cells cannot repair themselves, this may cause them to die.

Panobinostat is designed to slow down the growth of cancer cells or kill cancer cells by
blocking certain enzymes (proteins produced by cells).

Study Groups:

If you are found to be eligible to take part in this study, you will be assigned to a study
group based on when you join this study. Up to 4 groups of 3-6 participants will be
enrolled in the Phase 1A portion of the study, and up to 42 total participants will be
enrolled in Phase 1B.

If you are enrolled in the Phase 1A portion, the doses of carfilzomib and panobinostat you
receive will depend on when you joined this study. The first group of participants will
receive the lowest dose levels of carfilzomib and panobinostat . Each new group will
receive a higher dose of carfilzomib and/or panobinostat than the group before it, if no
intolerable side effects were seen. Sometimes, the new dose level for one drug will be
raised, while the dose level for the other drug will be the same as the dose given to the
earlier group. The study staff will explain which group you are assigned to. This
dose-raising pattern will continue until the highest tolerable dose of the study drug
combination is found.

If you are enrolled in the Phase 1B portion, you will receive carfilzomib and panobinostat
at the highest doses that were tolerated in the Phase 1A portion.

Study Drug Administration:

Each study cycle is 28 days.

You will receive carfilzomib on Days 1, 2, 8, 9, 15, and 16 of each cycle. Carfilzomib will
be given by vein over about 30 minutes. The study staff will check you for any side effects
for at least 1 hour after receiving carfilzomib. You will also be given fluids by vein
during this hour, during every Cycle 1 dose.

Starting 2 days before your first dose of carfilzomib, you must drink 6-8 cups (8 ounces
each) of water each day. This is to make sure you are properly hydrated before your first
dose of carfilzomib. The study staff will tell you how many days you need to drink this
much water. All study participants will do this during Cycle 1. If the doctor thinks it is
needed, based on your risk of developing certain side effects, you may need to keep up this
hydration plan during Cycle 2 and beyond.

Before each dose of carfilzomib during Cycle 1, and every dose increase, you will receive
dexamethasone by vein. This drug is given to try to avoid or lessen side effects (such as
allergic reaction) that may occur when you receive the study drug.

You will take panobinostat by mouth once a day on Days 1, 3, 5, 8, 10, and 12 of each study
cycle. On Days 1 and 8 of each cycle, your panobinostat dose should be taken about 4 hours
after the end of your carfilzomib infusion.

The panobinostat capsule(s) should be swallowed by mouth with a glass (8 ounces) of water.
You should try to take the dose at around the same time each day. If you vomit after taking
panobinostat, you should not take it again until your next scheduled dose. If you forget to
take a dose in the morning, you can take it up to 12 hours later. If you miss a dose for
more than 12 hours, wait until your next scheduled dose. Do not make up missed doses.

On Day 1 of every new study cycle, you should wait to take your dose until you come to the
clinic for study tests. Some of the Day 1 tests need to be performed before dosing.

You need to follow all dosing instructions as written. Do not miss any capsules. You will
be asked to return all unused study drug in the bottles provided, along with empty bottles,
on Day 1 of every cycle, starting with Cycle 2. Capsules should not be transferred between
bottles at any time. Please do not allow anyone else to handle or touch the study drug.

Maintenance Dosing:

After 8 cycles of therapy, you may continue receiving carfilzomib on Days 1, 2, 15, and 16,
and panobinostat on Days 1, 3, 5, 8, 10, and 12 of each cycle, as tolerated, as long as your
doctor thinks it is in your best interest.

If you have any unusual symptoms or intolerable side effects at your assigned dose level,
then your dose may be lowered. If needed, you may also have to stop taking panobinostat for
a short time, and the side effect(s) will be closely watched by your doctor until they get
better.

If you have a history of herpes simplex or zoster, and your study doctor thinks it is
needed, you will take acyclovir (an anti-viral drug) while on this study. Your doctor will
explain how often you will need to take this anti-viral drug.

Study Visits:

On Day 1 of every cycle:

- You will have a complete physical exam, including measurement of your vital signs,
height, and weight. Your BSA will also be calculated.

- Your performance status will be measured.

- You will be asked about any drugs you may be taking and any symptoms or side effects
you may be having (including numbness and/or tingling).

- You will have ECGs before your dose of panobinostat. On Day 1 of Cycle 1, you will
also have ECGs performed about 3 hours after your dose.

- Blood (about 2 teaspoons) will be drawn for routine tests.

- Starting in Cycle 2, this routine blood draw will also include a pregnancy test if you
are able to become pregnant. To keep taking part in this study, the pregnancy test
must be negative.

- Blood (about 1 tablespoon) and urine will be collected to check the status of the
disease. This urine will be collected over a 24-hour period. You will be given a
container for urine collection.

- Starting in Cycle 2, part of this urine sample may be used for a pregnancy test for
women who are able to become pregnant.

On Days 2, 9, and 16 of Cycle 1:

-Your vital signs will be measured.

On Day 5 of Cycle 1, you will have ECGs before and after your dose of panobinostat. You will
need to wait to take your panobinostat dose until you are told to do so at the clinic.

On Days 8 and 15 of Cycle 1:

- You will have measurement of your vital signs.

- Blood (about 2 teaspoons) will be drawn for routine tests.

On Days 2, 9, and 16 of Cycle 2 and beyond:

Your vital signs will be measured.

On Days 8 and 15 of Cycle 2 and beyond:

Your vital signs will be measured. Blood (about 2 teaspoons) will be drawn for routine
tests.

Length of Study:

You may continue taking the study drugs for as long as the doctor thinks it is in your best
interest. You will no longer be able to take the study drugs if the disease gets worse, if
intolerable side effects occur, or if you are unable to follow study directions.

Your participation on the study will be over once you have completed the end-of-dosing
visit.

End-of-Dosing Visit:

Within 30 days after you stop taking the study drugs, you will have an End-of-Treatment
Visit. At this visit, the following tests and procedures will be performed:

- You will have a physical exam, including measurement of your height, weight, and vital
signs. Your BSA will also be calculated.

- Your performance status will be recorded.

- You will have an ECG.

- Blood (about 1-2 teaspoons) and urine will be collected for routine tests.

- You will be asked about any drugs you may be taking and any side effects or symptoms
(such as numbness and/or tingling) that you may have.

- Blood (about 1 tablespoon) and urine will be collected to check the status of the
disease. This urine will be collected over a 24-hour period. You will be given a
container for urine collection.

This is an investigational study. Carfilzomib is FDA approved and commercially available
for the treatment of certain types of multiple myeloma. Its use in this study is
investigational. Panobinostat is not FDA approved or commercially available. It is
currently being used for research purposes only.

Up to 66 patients will take part in this study. All will be enrolled at MD Anderson.


Inclusion Criteria:



1. Relapsed/refractory MM with failure to two lines of MM treatment which must include
at least one IMiD (thalidomide, lenalidomide) and proteosome inhibitor (bortezomib)
and measurable levels of myeloma paraprotein in serum ( >/= 0.5 g/dl), urine ( >/=
0.2 g excreted in a 24-hour collection sample), or abnormal free light chain (FLC)
ratio. Oligo or non secretory myeloma patients may be included, if there is
measurable plasmacytosis in the bone marrow biopsy or measurable extramedullary
disease.

2. Male or female patients aged >/= 18 years old

3. Ability to provide written informed consent obtained prior to participation in the
study and any related procedures being performed

4. Patients must meet the following laboratory criteria within 28 days of starting
therapy: * Absolute neutrophil count (ANC) >/= 1.0 x 10^9/L * Hemoglobin >/= 8 g/dl (
transfusion are permitted) * Platelet count > 70,000 cells/mm^3 for patients with <
50% of bone marrow plasma cells or platelet count > 25,000 cells/mm^3 for patients in
whom > 50% of the bone marrow nucleated cells were plasma cells * aspartate
aminotransferase (AST) and Alanine aminotransferase (ALT) bilirubin
5. ECOG Performance Status of
6. Creatinine clearance (CrCl) >/= 30 mL/minute within 28 days prior to registration,
either measured or calculated using a standard formula (eg, Cockcroft and Gault)

7. Multiple Gated Acquisition (MUGA) or echocardiogram (ECHO) must demonstrate LVEF >/=
45%.

8. Female patients who: Are postmenopausal for at least 1 year before the screening
visit, OR Are surgically sterile, OR If they are of childbearing potential, agree to
practice 2 effective methods of contraception, at the same time, from the time of
signing the informed consent through 30 days after the last dose of study drug, or
agree to completely abstain from heterosexual intercourse. Male patients, even if
surgically sterilized (ie, status postvasectomy), who: Agree to practice effective
barrier contraception during the entire study treatment period and through 30 days
after the last dose of study drug, OR Agree to completely abstain from heterosexual
intercourse.

Exclusion Criteria:

1. Valproic acid for the treatment of cancer

2. Patients who will need valproic acid for any medical condition during the study or
within 5 days prior to first panobinostat treatment

3. Impaired cardiac function or clinically significant cardiac diseases, including any
one of the following: * History or presence of sustained ventricular tachyarrhythmia.
(Patients with a history of atrial arrhythmia are eligible) * Any history of
ventricular fibrillation or torsade de pointes * Bradycardia defined as heart rate
(HR)< 50 bpm. Patients with pacemakers are eligible if HR >/= 50 bpm. * Screening
electrocardiogram (ECG) with a corrected QT interval (QTc) or QTcF > 450 msec * Right
bundle branch block + left anterior hemiblock (bifascicular block) * Patients with
myocardial infarction or unstable angina Other clinically significant heart disease (e.g., Congestive Heart Failure (CHF) New
York Heart Association (NYHA) class III or IV , uncontrolled hypertension, history of
labile hypertension (e.g. blood pressure greater than 160/90), or history of poor
compliance with an antihypertensive regimen)

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

5. Patients with diarrhea > Common Terminology Criteria for Adverse Events (CTCAE) grade
2

6. Other concurrent severe and/or uncontrolled medical conditions (e.g., uncontrolled
diabetes or active or uncontrolled infection) including abnormal laboratory values,
that could cause unacceptable safety risks or compromise compliance with the protocol

7. 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

8. Patients who have received chemotherapy within of therapy on trial ; or radiation therapy to > 30% of marrow-bearing bone within 2
weeks prior to starting study treatment; or who have not yet recovered from side
effects of such therapies.

9. Female patients who are lactating or have a positive serum or urine pregnancy test
during the Screening period.

10. Patients with any significant history of non-compliance to medical regimens or
unwilling or unable to comply with the instructions given to him/her by the study
staff.

11. Known history of allergy to CaptisolĀ® (a cyclodextrin derivative used to solubilize
carfilzomib)

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

Maximum Tolerated Dose (MTD)

Outcome Description:

The MTD of panobinostat and carfilzomib defined as highest dose level in which 6 patients have been treated with less than 2 instances of dose limiting toxicity (DLT) following one cycle (28 days) of combination therapy.

Outcome Time Frame:

28 days

Safety Issue:

Yes

Principal Investigator

Jatin J. Shah, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

UT MD Anderson Cancer Center

Authority:

United States: Food and Drug Administration

Study ID:

2010-0733

NCT ID:

NCT01301807

Start Date:

August 2011

Completion Date:

Related Keywords:

  • Myeloma
  • Relapsed/refractory multiple myeloma
  • RRMM
  • Carfilzomib
  • Panobinostat
  • LBH589B
  • Multiple Myeloma
  • Neoplasms, Plasma Cell

Name

Location

UT MD Anderson Cancer Center Houston, Texas  77030