Phase I/Ib Trial of the Efficacy and Safety of Combination Therapy of Lenalidomide/Bortezomib/Dexamethasone and Panobinostat in Transplant Eligible Patients With Newly Diagnosed Multiple Myeloma (MM)
18 Years
N/A
Both
Myeloma
Trial Information
Phase I/Ib Trial of the Efficacy and Safety of Combination Therapy of Lenalidomide/Bortezomib/Dexamethasone and Panobinostat in Transplant Eligible Patients With Newly Diagnosed Multiple Myeloma (MM)
Study Groups:
If you are found to be eligible to take part in this study, you will be assigned to a dose
level of panobinostat based on when you join this study.
If you are enrolled in Phase 1, up to 4 dose levels of panobinostat will be tested. Three
(3) to 6 participants 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.
If you are enrolled in Phase Ib, you will receive panobinostat at the recommended dose from
Phase 1.
Study Drug Administration:
Induction Therapy:
In the Induction phase of therapy, each cycle is 21 days.
On Days 1, 4, 8, and 11 of Cycles 1-8, you will receive bortezomib either through a needle
under your skin or by vein over 3-5 seconds. You will be watched by the study staff for 30
minutes after the infusion.
On Days 1-14 of every cycle, you will take lenalidomide by mouth 1 time each day. You
should swallow the lenalidomide capsules whole with 1 cup (about 8 ounces) of water. Do not
break, chew, or open the capsules.
You will take panobinostat by mouth 1 time a day with food on Days 1, 3, 5, 8, 10 and 12 for
2 weeks with 1 week of rest at the end of each cycle.
On Days 1, 2, 4, 5, 8, 9, 11, and 12 of Cycles 1-8, you will take dexamethasone by mouth 1
time a day. After 8 cycles, you may continue to take dexamethasone if the doctor thinks it
is needed. Dexamethasone should be taken with food.
Maintenance Therapy:
In the Maintenance phase of therapy, each cycle is 28 days.
You will take lenalidomide by mouth 1 time each day on Days 1-21 of each cycle.
You will take dexamethasone by mouth 1 time a day on Days 1, 8, 15, and 21 of each cycle.
You will take panobinostat by mouth 1 time a day on Days 1, 3, 5, 8, 10, and 12 of each
cycle.
Other Instructions:
You can take the study drugs anytime during the day but you should take them at the same
time every day.
If you miss a dose of lenalidomide, take it as soon as you remember on the same day. If you
miss taking your dose for the entire day, take your regular dose the next scheduled day (do
NOT take double your regular dose to make up for the missed dose). If you take more than
the prescribed dose of lenalidomide, you should seek emergency medical care if needed and
contact the study staff right away.
Your study drug doses may be lowered if you have side effects.
You will be given a drug diary for each cycle to write in to help keep track of your study
drug doses. You should bring the drug diary and pill bottles to your study visit at the
beginning of each new cycle.
The panobinostat capsule(s) should be swallowed with 1 cup 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, you should wait until your next scheduled dose. Do not make up missed doses.
On Day 1 of every new study cycle and Cycle 1, Day 5, you should wait to take your
panobinostat 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 panobinostat dosing instructions as written. Do not miss any
panobinostat 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.
You can stop anytime after Cycle 4 of Induction to have a stem cell transplant. If you
decide with your doctor to delay the transplant, you will still be recommended to have your
stem cells collected. You will continue with Induction therapy until you have had 4-8
cycles. After that, you will receive Maintenance therapy.
You will be given other drugs to help prevent side effects. The study staff will tell you
about these drugs, how they will be given, and the possible risks.
Study Visits:
On Day 1 of each cycle:
- You will have a physical exam, including measurement of your vital signs.
- Your performance status will be recorded.
- Blood (about 5 tablespoons) will be drawn for routine tests and biomarker testing.
- Blood (about 1 teaspoon) and/or urine will be collected to check the status of the
disease. If urine is collected, you will collect the urine over 24 hours. This urine
or blood will also be used for a pregnancy test if you are able to become pregnant.
- You will complete the symptom questionnaire.
- You will be asked about any symptoms you may have had and any drugs you may be taking.
- You will have an ECG.
- If the doctor thinks it is needed, you will have bone x-rays, an MRI and/or a CT scan
to check the status of the disease.
- On Day 1 of Cycles 2 and beyond, you will have a neurological exam.
On Day 5 of Cycle 1, you will have an ECG.
On Days 4, 8, and 11 of Cycles 1-8:
-Blood (about 4 tablespoons) will be drawn for routine tests.
At the end of Cycle 8 (or if you are going to have a stem cell transplant, at the end of
Cycle 4):
- You will have a physical exam, including measurement of your vital signs.
- Your performance status will be recorded.
- You will be asked about any symptoms you may have had and any other drugs you may be
taking.
- Blood (about 2 tablespoons) will be collected for routine tests.
- Blood (about 1 teaspoon) and/or urine will be collected to check the status of the
disease. If urine is collected, you will be asked to collect your urine over 24 hours.
- You will have bone x-rays to check the status of the disease.
- If the disease completely responds to the study drugs, you will have a bone marrow
aspiration and/or biopsy to confirm the response.
On Day 1 of Maintenance Therapy, or Cycles 9 and beyond (if you choose to delay stem cell
transplant):
- You will have a physical exam, including measurement of your vital signs.
- Your performance status will be recorded.
- You will have a neurological exam.
- You will be asked about any symptoms you may have had and any other drugs you may be
taking.
- You will have an ECG.
- You will complete the symptom questionnaire.
- Blood (about 4 tablespoons) will be drawn for routine tests and biomarker testing.
- Blood (about 1 teaspoon) and/or urine will be collected to check the status of the
disease. If urine is collected, you will collect the urine for 24 hours. This urine
or blood will also be used for a pregnancy test if you are able to become pregnant.
- If the doctor thinks it is needed, you will have bone x-rays, an MRI and/or a CT scan
to check the status of the disease.
Pregnancy Tests:
During induction therapy, if you are a woman who is able to become pregnant and you have
regular or no periods, you will have a blood (about 1 tablespoon) or urine pregnancy test
weekly for the first 21 days and then every 21 days while on therapy (including breaks in
therapy). If you are a woman who is able to become pregnant and your cycles are irregular,
you will have a blood (about 1 tablespoon) or urine pregnancy test weekly for the first 21
days during then every 11-14 days while on therapy (including breaks in therapy).
During maintenance therapy, if you are a woman who is able to become pregnant and have
regular or no menstruation, you must have a pregnancy test every 28 days while on therapy
(including breaks in therapy). If you are a woman who is able to become pregnant and your
cycles are irregular, you will have a blood (about 1 tablespoon) or urine pregnancy test
every 14 days (+/-1 day) and every 28 days.
Length of Treatment:
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 drug 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-treatment
and follow-up visits.
End-of-Treatment Visit:
Within 30 days after your last dose of study drugs:
- You will have a physical exam, including measurement of your vital signs.
- Your performance status will be recorded.
- You will be asked about any symptoms you may be experiencing.
- Blood (about 4 tablespoon) and urine will be collected for routine tests.
- Blood (about 1 teaspoon) and/or urine will be collected to check the status of the
disease. If urine is collected, you will collect the urine for 24 hours.
- If the disease completely responds to the study drugs, you will have a bone marrow
aspiration and/or biopsy to confirm the response.
- If the doctor thinks it is needed, you will have an MRI and/or a CT scan to check the
status of the disease.
- If you are able to become pregnant, you will have a urine or blood (about 1 tablespoon)
pregnancy test.
This is an investigational study. Panobinostat is not FDA approved or commercially
available. It is currently being used for research purposes only. Bortezomib is FDA
approved and commercially available for the treatment of MM. Lenalidomide is FDA approved
and commercially available for the treatment of certain types of myelodysplastic syndrome
and for MM. The use of this drug combination to treat MM is investigational.
Up to 38 patients will take part in this study. All will be enrolled at MD Anderson.
Inclusion Criteria:
1. DIAGNOSTIC CRITERIA: ALL 3 REQUIRED 1. Monoclonal plasma cells in the bone marrow >
10% and/or presence of a biopsy-proven plasmacytoma 2. Monoclonal protein present in
the serum and/or urine 3. Myeloma-related organ dysfunction (1 or more) [C] Calcium
elevation in the blood S. Calcium >10.5 mg/l or upper limit of normal or [R] Renal
insufficiency or [A] Anemia Hemoglobin < 10 g/dl or 2 g < normal o [B] Lytic bone
lesions or osteoporosis
2. Patient must not have been previously treated with any prior systemic therapy for the
treatment of multiple myeloma. o Prior treatment of hypercalcemia or spinal cord
compression with corticosteroids does not disqualify the patient (the dose should not
exceed the equivalent of 160 mg of dexamethasone in a 2 week period). o
Bisphosphonates are permitted
3. Patients treated with local radiotherapy with or without concomitant exposure to
steroids, for pain control or management of cord/nerve root compression, are
eligible. One week must have lapsed since last date of radiotherapy, which is
recommended to be a limited field and from start of protocol therapy. . Patients who
require concurrent radiotherapy should have entry to the protocol deferred until the
radiotherapy is completed and one week have passed since the last date of therapy and
from start of protocol therapy. .
4. Voluntary written informed consent 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.
5. Females of childbearing potential (FCBP)† must have a negative serum or urine
pregnancy test with a sensitivity of at least 50 mIU/mL 10-14 days prior to therapy
and repeated again within 24 hours of starting lenalidomide and must either commit to
continued abstinence from heterosexual intercourse or begin TWO acceptable methods of
birth control, one highly effective method and one additional effective method AT THE
SAME TIME, at least 28 days before she starts taking lenalidomide. FCBP must also
agree to ongoing pregnancy testing. Men must agree to use a latex condom during
sexual contact with a FCBP even if they have had a successful vasectomy.
6. Age > / = 18 years at the time of signing Informed Consent.
7. Patients must meet the following laboratory criteria: absolute neutrophil count (ANC)
>/= 1.5 x 10^9/L (growth factors not permitted to make eligible) , Hemoglobin >/= 9
g/dl (transfusion permitted) , Platelets >/= 100 x 10^9/L , Aspartate transaminase
(AST) and Alanine transaminase (ALT) bilirubin /= lower limits of normal (LLN) , Total
serum calcium [corrected for serum albumin] or ionized calcium >/= LLN, Serum
magnesium >/= LLN
8. Baseline Multi Gated Acquisition Scan (MUGA) or echocardiogram (ECHO) must
demonstrate LVEF >/= 50%
9. All study participants must be registered into the mandatory RevAssist® program, and
be willing and able to comply with the requirements of RevAssist®.
10. Eastern Cooperative Oncology Group (ECOG) Performance Status of
11. Able to take aspirin (81 or 325 mg) daily as prophylactic anticoagulation (patients
intolerant to ASA may use warfarin or low molecular weight heparin).
Exclusion Criteria:
1. Patient has >/=Grade 2 peripheral neuropathy on clinical examination within 28 days
of signing consent.
2. Renal insufficiency Creatinine > 2.5 mg/dl
3. Myocardial infarction within 6 months prior to signing consent or has New York Heart
Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe
uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute
ischemia or active conduction system abnormalities. Prior to study entry, any
Electrocardiograph (ECG) abnormality at screening has to be documented by the
investigator as not medically relevant.
4. Patients who will need valproic acid for any medical condition during the study or
within 5 days prior to first panobinostat treatment.
5. 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 heart rate (HR) >/= 50 bpm.
Screening ECG with a QTcF > 450 msec, Right bundle branch block + left anterior
hemiblock (bifascicular block) , Patients with myocardial infarction or unstable
angina disease (e.g., congestive heart failure (CHF) New York Heart Association class III or
IV , uncontrolled hypertension, history of labile hypertension, or history of poor
compliance with an antihypertensive regimen)
6. Impairment of gastrointestinal (GI) function or GI disease that may significantly
alter the absorption of panobinostat
7. Patients with diarrhea > Common Terminology Criteria for Adverse Events (CTCAE
version 4) grade 2 at the time of signing consent
8. 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
9. 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
10. Female subject is pregnant or breast-feeding.
11. Hypersensitivity to acyclovir or similar anti-viral drug
12. Hypersensitivity to boron or mannitol, or compounds containing these components
Type of Study:
Interventional
Study Design:
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Outcome Measure:
Maximum Tolerated Dose (MTD)
Outcome Description:
Maximum tolerated dose (MTD) defined as highest dose level in which 6 participants have less than 2 instances of dose limiting toxicities (DLT).
Outcome Time Frame:
First 21 days of study drug administration (continuous dosing)
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:
2011-0192
NCT ID:
NCT01440582
Start Date:
February 2013
Completion Date:
Related Keywords:
- Myeloma
- Myeloma
- Multiple Myeloma
- MM
- Newly diagnosed
- Transplant eligible
- Panobinostat
- LBH589B
- Bortezomib
- Velcade
- LDP-341
- MLN341
- PS-341
- Lenalidomide
- CC-5013
- Revlimid
- Dexamethasone
- Decadron
- Symptom questionnaire
- Survey
- Multiple Myeloma
- Neoplasms, Plasma Cell
Name | Location |
|---|---|
| UT MD Anderson Cancer Center | Houston, Texas 77030 |
