Clinical Trials /

Panobinostat, Gemcitabine Hydrochloride, Busulfan, and Melphalan Before Stem Cell Transplant in Treating Patients With Refractory or Relapsed Multiple Myeloma

NCT02506959

Description:

This phase II trial studies how well panobinostat, gemcitabine hydrochloride, busulfan, and melphalan before stem cell transplant work in treating patients with multiple myeloma that does not respond to treatment (refractory) or has returned (relapsed). Panobinostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving high-dose chemotherapy, such as gemcitabine hydrochloride, busulfan, and melphalan, before a peripheral blood stem cell transplant helps kill any cancer cells that are in the body and helps make room in the patient's bone marrow for new blood-forming cells (stem cells) to grow. Previously collected stem cells are then returned to the patient to replace the blood-forming cells that were destroyed by the chemotherapy.

Related Conditions:
  • Multiple Myeloma
  • Plasma Cell Leukemia
  • Plasmacytoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Panobinostat, Gemcitabine Hydrochloride, Busulfan, and Melphalan Before Stem Cell Transplant in Treating Patients With Refractory or Relapsed Multiple Myeloma
  • Official Title: Panobinostat Combined With High-Dose Gemcitabine/Busulfan/Melphalan With Autologous Stem Cell Transplant for Patients With Refractory/Relapsed Myeloma

Clinical Trial IDs

  • ORG STUDY ID: 2014-0516
  • SECONDARY ID: NCI-2015-01308
  • SECONDARY ID: 2014-0516
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT02506959

Conditions

  • Plasma Cell Leukemia
  • Plasmacytoma
  • Recurrent Plasma Cell Myeloma
  • Refractory Plasma Cell Myeloma

Interventions

DrugSynonymsArms
Busulfan1, 4-Bis[methanesulfonoxy]butane, BUS, Bussulfam, Busulfanum, Busulfex, Busulphan, CB 2041, CB-2041, Glyzophrol, GT 41, GT-41, Joacamine, Methanesulfonic Acid Tetramethylene Ester, Methanesulfonic acid, tetramethylene ester, Mielucin, Misulban, Misulfan, Mitosan, Myeleukon, Myeloleukon, Myelosan, Mylecytan, Myleran, Sulfabutin, Tetramethylene Bis(methanesulfonate), Tetramethylene bis[methanesulfonate], WR-19508Treatment (panobinostat, Gem/Bu/Mel, ASCT)
Gemcitabine HydrochloridedFdCyd, Difluorodeoxycytidine Hydrochloride, Gemzar, LY-188011, LY188011Treatment (panobinostat, Gem/Bu/Mel, ASCT)
MelphalanAlanine Nitrogen Mustard, CB-3025, L-PAM, L-Phenylalanine Mustard, L-sarcolysin, L-Sarcolysin Phenylalanine mustard, L-Sarcolysine, Melphalanum, Phenylalanine Mustard, Phenylalanine nitrogen mustard, Sarcoclorin, Sarkolysin, WR-19813Treatment (panobinostat, Gem/Bu/Mel, ASCT)
PanobinostatFaridak, Farydak, LBH589Treatment (panobinostat, Gem/Bu/Mel, ASCT)

Purpose

This phase II trial studies how well panobinostat, gemcitabine hydrochloride, busulfan, and melphalan before stem cell transplant work in treating patients with multiple myeloma that does not respond to treatment (refractory) or has returned (relapsed). Panobinostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving high-dose chemotherapy, such as gemcitabine hydrochloride, busulfan, and melphalan, before a peripheral blood stem cell transplant helps kill any cancer cells that are in the body and helps make room in the patient's bone marrow for new blood-forming cells (stem cells) to grow. Previously collected stem cells are then returned to the patient to replace the blood-forming cells that were destroyed by the chemotherapy.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the progression-free survival (PFS) in patients with refractory or relapsed
      myeloma receiving panobinostat/gemcitabine hydrochloride (gemcitabine)/busulfan/melphalan
      (panobinostat/Gem/Bu/Mel) with autologous stem-cell transplant, either as a first or a
      salvage stem-cell transplant.

      SECONDARY OBJECTIVES:

      I. To evaluate the complete response (CR) rate. II. To determine the overall survival (OS).
      III. To determine the CR + very good partial remission (VGPR) rate. IV. To determine the
      overall response rate (ORR). V. To determine minimal residual disease posttransplant,
      measured by multiparametric flow cytometry (MFC).

      VI. To describe the toxicity profile of panobinostat/Gem/Bu/Mel. VII. To analyze the
      predictive value of pretransplant levels in myeloma cells of X-box binding protein 1 (XBP1),
      inositol-requiring enzyme 1 (IRE1), unspliced XBP1 (XBP1u), sliced XBP1 (XPB1s), XBP1u/XPBs
      ratio and v-myc myelocytomatosis viral oncogene homolog (avian) (Myc), by analyzing their
      correlation with CR, VGPR+CR and response rate (RR).

      VIII. To study the prognostic effect of pretransplant levels in myeloma cells of XBP1, IRE1,
      XBP1u, XPB1s, XBP1u/XPBs ratio and Myc, by analyzing their correlation with PFS and OS.

      OUTLINE:

      Patients receive panobinostat orally (PO) once daily (QD) on days -9 to -2, gemcitabine
      hydrochloride intravenously (IV) over 4 hours on days -8 and -3, busulfan IV over 3 hours on
      days -8 to -5, and melphalan IV over 30 minutes on days -3 and -2. Patients then undergo
      autologous peripheral blood stem cell transplant on day 0.

      After completion of study treatment, patients are followed up at 1 month, 100 days, 6 months,
      1 year, and then every 3-6 months for at least 2 years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (panobinostat, Gem/Bu/Mel, ASCT)ExperimentalPatients receive panobinostat PO QD on days -9 to -2, gemcitabine hydrochloride IV over 4 hours on days -8 and -3, busulfan IV over 3 hours on days -8 to -5, and melphalan IV over 30 minutes on days -3 and -2. Patients then undergo autologous peripheral blood stem cell transplant on day 0.
  • Busulfan
  • Gemcitabine Hydrochloride
  • Melphalan
  • Panobinostat

Eligibility Criteria

        Inclusion Criteria:

          -  Refractory or relapsed myeloma, defined as one or more of the following:

               -  Treated with first-line therapy including at least 2 cycles of lenalidomide,
                  bortezomib or thalidomide, and one or more of the following:

                    -  Less than partial response (PR) to first-line therapy

                    -  Relapse after first (1st) line therapy

               -  High-risk cytogenetics, defined by deletion (del)(13q) by conventional
                  cytogenetics, or by del(17p), t(4;14), t(14;16), t(14;20) or 1q+ by fluorescence
                  in situ hybridization (FISH)

               -  Relapse after a prior autologous stem cell transplant (ASCT)

               -  Plasma cell leukemia

               -  Soft tissue plasmacytoma

          -  Serum creatinine =< 1.8 mg/dL and/or estimated serum creatinine clearance >= 50 ml/min

          -  Serum glutamic oxaloacetic transaminase (SGOT) and/or serum glutamate pyruvate
             transaminase (SGPT) =< 3 x upper limit of normal

          -  Serum bilirubin =< 2 x upper limit of normal, unless proven to be due to disease
             involvement

          -  Alkaline phosphatase =< 2 x upper limit of normal, unless proven to be due to disease
             involvement

          -  Adequate pulmonary function with forced expiratory volume in 1 second (FEV1), forced
             vital capacity (FVC) and diffusion capacity of the lung for carbon monoxide (DLCO) >=
             50% of expected corrected for hemoglobin and/or volume

          -  Adequate cardiac function with left ventricular ejection fraction >= 40%

          -  No uncontrolled arrhythmias or symptomatic cardiac disease

          -  Clinically euthyroid; note: patients are permitted to receive thyroid hormone
             supplements to treat underlying hypothyroidism

          -  Zubrod performance status < 2

          -  Negative beta-human chorionic gonadotropin (HCG) test in a woman of child-bearing
             potential, defined as not post-menopausal for 12 months or no previous surgical
             sterilization

          -  Availability of >= 2.5 million cluster of differentiation (CD)34+ cells/kg previously
             apheresed

          -  Ability to provide written informed consent

        Exclusion Criteria:

          -  Prior whole brain irradiation

          -  Having received radiation therapy to head and neck (excluding eyes), and internal
             organs of chest, abdomen or pelvis in the month prior to enrollment

          -  Active hepatitis B, either active carrier (hepatitis B surface antigen positive [HBsAg
             +]) or viremic (hepatitis B virus [HBV] deoxyribonucleic acid [DNA] >= 10,000
             copies/mL, or >= 2,000 IU/mL)

          -  Evidence of either cirrhosis or stage 3-4 liver fibrosis in patients with chronic
             hepatitis C or positive hepatitis C serology

          -  Active infection requiring parenteral antibiotics

          -  Known positivity for human immunodeficiency virus (HIV)

          -  Autologous stem-cell transplant in the previous six months

          -  Needing valproic acid for any medical condition during the study or within 5 days
             prior to first panobinostat treatment

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

          -  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

          -  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 but should be discussed with Novartis
                  prior to enrollment)

               -  Any history of ventricular fibrillation or torsade de pointes

               -  Bradycardia defined as heart rate (HR) < 50 beats per minute (bpm); patients with
                  pacemakers are eligible if HR >= 50 bpm

               -  Screening electrocardiogram (ECG) with a corrected QT (QTc) > 470 msec

               -  Right bundle branch block + left anterior hemiblock (bifascicular block)

               -  Myocardial infarction or unstable angina =< 12 months prior to starting study
                  drug

               -  Other clinically significant heart disease (e.g., congestive heart failure [CHF]
                  New York [NY] Heart Association class III or IV , uncontrolled hypertension,
                  history of labile hypertension, or history of poor compliance with an
                  antihypertensive regimen)

          -  Have undergone major surgery =< 4 weeks prior to starting study drug or who have not
             recovered from side effects of such therapy

          -  Prior malignancy with in the last 5 years (except for basal or squamous cell
             carcinoma, or in situ cancer of the cervix)

          -  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

          -  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

          -  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

          -  Grade >= 3 nonhematological toxicity from prior therapy that has not resolved to =<
             grade 1
      
Maximum Eligible Age:65 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression free survival (PFS)
Time Frame:1 year
Safety Issue:
Description:Estimated by the Kaplan-Meier method. Comparison of time to event endpoints by subgroups will be made using the log-rank test. Cox proportional hazards regression will be employed for univariate and multivariate analysis on time-to-event outcomes.

Secondary Outcome Measures

Measure:Complete response (CR) rate, assessed using the International Myeloma Working Group (IMWG) uniform response criteria
Time Frame:By day 100
Safety Issue:
Description:Reported along with corresponding 95% confidence intervals. Logistic regression will be used to model the association between response rates and prognostic factors.
Measure:Overall survival (OS)
Time Frame:Up to 2 years
Safety Issue:
Description:Estimated by the Kaplan-Meier method. Comparison of time to event endpoints by subgroups will be made using the log-rank test. Cox proportional hazards regression will be employed for univariate and multivariate analysis on time-to-event outcomes.
Measure:Complete response (CR) + very good partial response (VGPR) rate, assessed using the International Myeloma Working Group (IMWG) uniform response criteria
Time Frame:By day 100
Safety Issue:
Description:Reported along with corresponding 95% confidence intervals. Logistic regression will be used to model the association between response rates and prognostic factors.
Measure:Response rate, assessed using the International Myeloma Working Group (IMWG) uniform response criteria
Time Frame:By day 100
Safety Issue:
Description:Reported along with corresponding 95% confidence intervals. Logistic regression will be used to model the association between response rates and prognostic factors.
Measure:Minimal residual disease post-transplant measured by multiparametric flow cytometry
Time Frame:Up to 2 years
Safety Issue:
Description:Minimal residual disease post-transplant will be measured by multiparametric flow cytometry.
Measure:Incidence of grade 3 or greater side effects, according to Common Terminology Criteria for Adverse Events version 4.0
Time Frame:Up to day 100
Safety Issue:
Description:The treatment-related morality rate will be computed and presented with 95% confidence interval. Adverse events will be tabulated for all patients.
Measure:Predictive value of pretransplant levels in myeloma cells of XBP1, IRE1, XBP1u, XPB1s, XBP1u/XPBs ratio, and Myc
Time Frame:Up to 2 years
Safety Issue:
Description:Correlation with PFS and OS of pretransplant levels in myeloma cells of XBP1, IRE1, XBP1u, XPB1s, XBP1u/XPBs ratio and Myc will be analyzed using the log-rank test. The correlation with CR, VGPR+CR and RR of pretransplant levels in myeloma cells of XBP1, IRE1, XBP1u, XPB1s, XBP1u/XPBs ratio, and Myc will be analyzed using Fisher's F test.
Measure:Prognostic effect of pretransplant levels in myeloma cells of XBP1, IRE1, XBP1u, XPB1s, XBP1u/XPBs ratio, and Myc
Time Frame:Up to 2 years
Safety Issue:
Description:Correlation with PFS and OS of pretransplant levels in myeloma cells of XBP1, IRE1, XBP1u, XPB1s, XBP1u/XPBs ratio and Myc will be analyzed using the log-rank test. The correlation with CR, VGPR+CR and RR of pretransplant levels in myeloma cells of XBP1, IRE1, XBP1u, XPB1s, XBP1u/XPBs ratio, and Myc will be analyzed using Fisher's F test.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

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