Panobinostat Combined With High-Dose Gemcitabine/Busulfan/Melphalan With Autologous Stem Cell Transplant for Patients With Refractory/Relapsed Myeloma

• Improvement in Progression-Free Survival (PFS) in Participants with Refractory Multiple Myeloma Receiving First Stem Cell Transplant [ Time Frame: 1 year ]

  The 1-year PFS rate in cohort 1 (refractory, 1st transplant) associated with GemBuMel is 62%. With 40 patients in this cohort, assuming exponentially-distributed PFS times, 1.5 years of accrual followed by 2 years of follow-up, and a one-sided 5% Type I error rate, 40 patients provides more than 80% power to detect an increase in one-year PFS to 75% in this cohort.

  International Myeloma Working Group (IMWG) uniform response criteria used.

• Improvement in Progression-Free Survival (PFS) in Participants with Relapsed Multiple Myeloma Receiving Second Salvage Stem Cell Transplant [ Time Frame: 1 year ]

  In cohort 2 (2nd transplant), the historical 1-year PFS rate is 55%. Under the same assumptions, 40 patients will provide more than 80% power to detect an increase in 1-year PFS to 69%.

  International Myeloma Working Group (IMWG) uniform response criteria used.

Busulfan Test Dose:

If you agree to take part in this study, you will receive a test dose of busulfan by vein over about 60 minutes. This low-level test dose of busulfan will help the doctor decide what dose of busulfan you will receive during the study. You will most likely receive this in an outpatient clinic during the week before you are in the hospital. If it cannot be given to you as an outpatient, you will be admitted to the hospital on Day -11 (11 days before your stem cells are returned to your body) and the test dose will be given on Day -10. With stem cell transplants, the days before you receive your stem cells are called minus days (Days -11, -10, and so on). The day you receive the stem cells is called Day 0. The days after you receive your stem cells are called plus days (Days +1, +2, and so on).

On the day of your busulfan test dose, blood (about 1 teaspoon each time) will be drawn for pharmacokinetic (PK) testing of busulfan. PK testing measures the amount of study drug in the body at different time points and will help the study doctor decide what your dose of busulfan in this study should be. These blood samples will be drawn before your dose of busulfan and then 10 more times over the next 11 hours.

The PK blood samples will be repeated again on the first day of high-dose busulfan treatment (Day -8). A temporary heparin lock line will be placed in your vein to lower the number of needle sticks needed for these draws. If it is not possible for the PK tests to be performed for technical or scheduling reasons, you will receive the standard fixed dose of busulfan.

If you receive the busulfan test dose as an outpatient:

On Days -12, -11, and -10, you will receive palifermin by vein over about 30 seconds each day to help decrease the risk of side effects in the mouth and throat.

You will be admitted to the hospital on Day -9.

If you receive the busulfan test dose as an inpatient:

On Days -14, -13, and -12 (the 3 days before you are admitted into the hospital), you will receive palifermin by vein over about 30 seconds each day to help decrease the risk of side effects in the mouth and throat.

You will be admitted to the hospital on Day -11.

Study Drug Administration:

Beginning on Day -9, you will swish the liquids caphosol and glutamine in your mouth 4 times a day, for about 2 minutes each time. You will swish these liquids every day until you leave the hospital. These drugs are used to help decrease the risk of side effects in the mouth and throat.

On Day -9 through Day -2, you will receive dexamethasone 2 times a day by vein over about 10 minutes, and you will take panobinostat by mouth 1 time a day.

On Day -8 you will receive gemcitabine by vein over about 4 hours.

On Days -8, -7, -6, and -5, you will receive busulfan by vein over about 3 hours a day.

On Day -3, you will receive gemcitabine by vein over about 4 hours and melphalan by vein over 30 minutes.

On Day -2, you will receive melphalan by vein over about 30 minutes.

On Day -1, you will rest.

On Day 0, you will receive your stem cells by vein over about 30-60 minutes.

On Days 0, +1, and +2, you will receive 3 more doses of palifermin by vein over about 15-30 seconds.

You will also be given standard drugs to help decrease the risk of side effects. You may ask the study staff for information about how the drugs are given and their risks.

As part of standard care, you will remain in the hospital for about 3-4 weeks after the transplant. After that, you will need to stay in the Houston area, so that you can continue as an outpatient and be checked for infections and side effects.

Study Tests:

Before you start study treatment, you may have a bone marrow biopsy and aspiration to check the status of the disease. To collect a bone marrow biopsy and aspirate, an area of the hip or other site is numbed with anesthetic, and a small amount of bone and bone marrow is withdrawn through a large needle.

Length of Treatment:

The study treatment period is between Day -12 and Day +2, with follow-up described below. You may be taken off study early if the disease gets worse, if intolerable side effects occur, or if you are unable to follow study directions.

If for any reason you want to leave the study early, you must talk to the study doctor. It may be life-threatening to leave the study after you have started to receive the study drugs but before you receive the stem cell transplant. This is because your blood cell counts will be dangerously low.

Follow-Up:

About 1 month, 100 days, 6 months, 1 year, and then about every 3-6 months for at least 2 years after the transplant for as long as the doctor thinks it is needed:

• You will have a physical exam.
• Blood (about 4 tablespoons) will be drawn for routine tests, to learn how the body has accepted the transplanted cells, and to check the status of the disease.

About 100 days after the transplant, you will have a bone marrow biopsy and aspiration to check the status of the disease. This will be repeated 1 time a year or earlier, if your doctor thinks it is needed.

One (1) time a year, you will have x-rays of all the bones in your body to check the status of the disease.

The study staff will also stay in contact with your local doctor to find out if the disease comes back and to check how you are doing.

This is an investigational study. Panobinostat and melphalan are FDA approved for the treatment of MM. Busulfan is FDA approved for the treatment of leukemia. Gemcitabine is FDA approved for the treatment of lymphoma, breast cancer, and lung cancer. The use of these study drugs in combination is investigational. The study doctor can explain how the study drugs are designed to work.

Up to 80 participants will take part in this study. All will be enrolled at MD Anderson.

• Drug: Busulfan
  Busulfan 32 mg/m2 by vein Test Dose before admission if outpatient, and Day -10 if inpatient. Busulfan AUC 4,000 by vein on Days -8 to -5.
  Other Names:

  • Busulfex
  • Myleran
• Drug: Palifermin
  60 microgram/kg by vein on Days -12, -11, -10, 0, +1 and +2, or -14, -13, -12, 0,+1 and +2.
  Other Name: Kepivance
• Drug: Panobinostat
  Panobinostat 20 mg by mouth on Days -9 to -2.
  Other Name: LBH589B
• Drug: Gemcitabine
  Gemcitabine 1,875 mg/m2 by vein on Days -8 and -3.
  Other Names:

  • Gemcitabine Hydrochloride
  • Gemzar
• Drug: Melphalan
  Melphalan 60 mg/m2 by vein on Days -3 and -2.
  Other Name: Alkeran
• Drug: Dexamethasone acetate
  Dexamethasone 8 mg by vein 2 times a day on Days -9 through Day -2.
  Other Name: Decadron
• Drug: Caphosol
  Caphosol oral rinses 30 mL four times a day from day -9 until discharge.
• Drug: Glutamine
  Glutamine 15 g four times a day, swished, gargled and spit started on day -9 until discharge.
  Other Names:

  • Enterex
  • Glutapak-10
  • NutreStore
  • Resource
  • GlutaSolve
  • Sympt-X G.I.
  • Sympt-X
• Drug: Pyridoxine
  Pyridoxine 100 mg by vein or mouth three times a day from Day -1.
• Procedure: Stem Cell Transplant
  Stem cell transplant performed on Day 0.

• Experimental: Refractory Disease - First Stem Cell Transplant Group
  Low test dose Busulfan by vein as an outpatient or inpatient. If outpatient test dose Busulfan by vein before hospital admission, then on Days -8 through -5. If inpatient, test dose Busulfan by vein on Day -10, then on Days -8 through -5. Palifermin by vein on Days -12, through -10 if outpatient, and on Days -14 through -12 if inpatient, and on Day 0, +1 and +2 for both groups. Participants swish liquids Caphosol and Glutamine in their mouth 4 times a day beginning on Day -9. Dexamethasone by vein 2 times a day on Days -9 through Day -2. Panobinostat by mouth 1 time a day on Days -8 through Day -2. Gemcitabine by vein on Day -8 and - 3. Melphalan given by vein on Day-3 and -2. Pyridoxine by vein or mouth three times a day from Day -1. Stem cell transplant procedure on Day 0.
  Interventions:

  • Drug: Busulfan
  • Drug: Palifermin
  • Drug: Panobinostat
  • Drug: Gemcitabine
  • Drug: Melphalan
  • Drug: Dexamethasone acetate
  • Drug: Caphosol
  • Drug: Glutamine
  • Drug: Pyridoxine
  • Procedure: Stem Cell Transplant
• Experimental: Relapsed Disease - Second Salvage Stem Cell Transplant Group
  Low test dose Busulfan by vein as an outpatient or inpatient. If outpatient test dose Busulfan by vein before hospital admission, then on Days -8 through -5. If inpatient, test dose Busulfan by vein on Day -10, then on Days -8 through -5. Palifermin by vein on Days -12, through -10 if outpatient, and on Days -14 through -12 if inpatient, and on Day 0, +1 and +2 for both groups. Participants swish liquids Caphosol and Glutamine in their mouth 4 times a day beginning on Day -9. Dexamethasone by vein 2 times a day on Days -9 through Day -2. Panobinostat by mouth 1 time a day on Days -8 through Day -2. Gemcitabine by vein on Day -8 and - 3. Melphalan given by vein on Day-3 and -2. Pyridoxine by vein or mouth three times a day from Day -1. Stem cell transplant procedure on Day 0.
  Interventions:

  • Drug: Busulfan
  • Drug: Palifermin
  • Drug: Panobinostat
  • Drug: Gemcitabine
  • Drug: Melphalan
  • Drug: Dexamethasone acetate
  • Drug: Caphosol
  • Drug: Glutamine
  • Drug: Pyridoxine
  • Procedure: Stem Cell Transplant

Inclusion Criteria:

1. Age 18 to 65 years.
2. Refractory or relapsed myeloma, defined as one or more of the following: 2.1. Treated with first-line therapy including at least 2 cycles of lenalidomide, bortezomib or thalidomide, and one or more of the following: 2.1.1. Less than PR to first-line therapy. 2.1.2. Relapse after 1st line therapy. 2.2. High-risk cytogenetics, defined by del(13q) by conventional cytogenetics, or by del(17p), t(4;14), t(14;16), t(14;20) or 1q+ by FISH. 2.3. Relapse after a prior ASCT. 2.4. Plasma cell leukemia. 2.5. Soft tissue plasmacytoma.
3. Adequate renal function, as defined by serum creatinine </=1.8 mg/dL and/or estimated serum creatinine clearance >/=50 ml/min.
4. Adequate hepatic function, as defined by SGOT and/or SGPT </=3 x upper limit of normal; serum bilirubin and alkaline phosphatase </=2 x upper limit of normal, unless proven to be due to disease involvement.
5. Adequate pulmonary function with FEV1, FVC and DLCO >/=50% of expected corrected for hemoglobin and/or volume.
6. Adequate cardiac function with left ventricular ejection fraction >/=40%. No uncontrolled arrhythmias or symptomatic cardiac disease.
7. Clinically euthyroid. Note: Patients are permitted to receive thyroid hormone supplements to treat underlying hypothyroidism.
8. Zubrod performance status < 2.
9. Negative Beta-HCG test in a woman of child-bearing potential, defined as not post-menopausal for 12 months or no previous surgical sterilization.
10. Availability of >/= 2.5 million CD34+ cells/kg previously apheresed.
11. Ability to provide written informed consent.

Exclusion Criteria:

1. Prior whole brain irradiation.
2. Having received radiation therapy to head and neck (excluding eyes), and internal organs of chest, abdomen or pelvis in the month prior to enrollment.
3. Active hepatitis B, either active carrier (HBsAg +) or viremic (HBV DNA >/=10,000 copies/mL, or >/= 2,000 IU/mL).
4. Evidence of either cirrhosis or stage 3-4 liver fibrosis in patients with chronic hepatitis C or positive hepatitis C serology.
5. Active infection requiring parenteral antibiotics.
6. Known positivity for human immunodeficiency virus (HIV).
7. Autologous stem-cell transplant in the previous six months.
8. Needing valproic acid for any medical condition during the study or within 5 days prior to first panobinostat treatment.
9. Impairment of GI function or GI disease that may significantly alter the absorption of panobinostat.
10. 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.
11. Impaired cardiac function or clinically significant cardiac diseases, including any one of the following: 11.1. History or presence of sustained ventricular tachyarrhythmia. (Patients with a history of atrial arrhythmia are eligible but should be discussed with Novartis prior to enrollment). 11.2 Any history of ventricular fibrillation or torsade de pointes. 11.3. Bradycardia defined as HR< 50 bpm. Patients with pacemakers are eligible if HR >/= 50 bpm. 11.4. Screening ECG with a QTc > 470 msec. 11.5. Right bundle branch block + left anterior hemiblock (bifascicular block). 11.6. Myocardial infarction or unstable angina </= 12 months prior to starting study drug. 11.7. 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).
12. Have undergone major surgery </= 4 weeks prior to starting study drug or who have not recovered from side effects of such therapy.
13. Prior malignancy with in the last 5 years (except for basal or squamous cell carcinoma, or in situ cancer of the cervix).
14. 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.
15. Received targeted agents within 2 weeks or within 5 half-lives of the agent and active metabolites (whichever is longer) and who have not recovered from side effects of those therapies.
16. Having received immunotherapy or chemotherapy within 2 weeks; 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.
17. Grade >/= 3 nonhematological toxicity from prior therapy that has not resolved to </= grade 1.