Carfilzomib Plus Panobinostat in Relapsed/Refractory Multiple Myeloma (MM)
This trial is active, not recruiting.
|Treatments||carfilzomib, panobinostat, dexamethasone|
|Targets||VEGF, HDAC, proteasome, HIF-1a|
|Sponsor||M.D. Anderson Cancer Center|
|Start date||July 2011|
|End date||August 2018|
|Trial size||63 participants|
|Trial identifier||NCT01301807, 2010-0733, NCI-2011-00316|
The goal of this clinical research study is to find the highest tolerable dose levels of carfilzomib and LBH589 (panobinostat) that can be given in combination to patients with myeloma. The safety of this drug combination will also be studied.
|Endpoint classification||safety/efficacy study|
|Intervention model||single group assignment|
Maximum Tolerated Dose (MTD)
time frame: 28 days
Time to Progression (TTP)
time frame: 30 days after last dose of study drugs given
Male or female participants at least 18 years old.
Inclusion Criteria: 1. Relapsed/refractory MM with failure to at least 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) = 2.5 x ULN * Serum bilirubin = 2 x ULN 5. ECOG Performance Status of = 2 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 = 6 months prior to starting study drug * 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, 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 = 2 weeks by time of cycle 1 day 1 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 Captisol® (a cyclodextrin derivative used to solubilize carfilzomib)
|Official title||Phase 1/1b Study of the Efficacy and Safety of the Combination of Panobinostat Plus Carfilzomib in Patients With Relapsed/Refractory Myeloma|
|Principal investigator||Jatin J. Shah, MD|
|Description||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 56 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 disease becomes worse during this period, you can stay on study and continue receiving carfilzomib on the original dosing schedule (Days 1, 2, 8, 9, 15, and 16 of each cycle). 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. - Blood (about 1 tablespoon) will be drawn pharmacodynamics (PD) testing. PD testing is used to look at how the level of study drug in your body may affect the disease. (Cycle 1 only) On Day 1 of each Cycle: - Blood (about 2 tablespoons) will be drawn for biomarker testing, which may include genetic biomarkers. Biomarkers are found in the blood and may be related to your reaction to the study drug. On Days 2, 9, and 16 of Cycle 1: - Your vital signs will be measured. - On Days 9 and 16 only, blood (about 1 tablespoon) will be drawn for PD testing. 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 Day 1 of Cycle 2: - Blood (about 1 tablespoon) will be drawn for PD testing. 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.|
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