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

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

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.

Study Overview

• Status: Completed
• Conditions: Refractory Plasma Cell Myeloma; Plasmacytoma; Recurrent Plasma Cell Myeloma; Plasma Cell Leukemia
• Intervention / Treatment: Other: Pharmacological Study; Drug: Gemcitabine Hydrochloride; Drug: Melphalan; Drug: Busulfan; Drug: Panobinostat; Procedure: Autologous Hematopoietic Stem Cell Transplantation; Procedure: Peripheral Blood Stem Cell Transplantation

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.

• Study Type: Interventional
• Enrollment (Actual): 83
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030
      • M D Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 Secura Bio, Inc (Secura Bio) 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1_1st Auto TP Conditioned with panobinostat and Gem/Bu/Mel; Patients 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.	Other: Pharmacological Study; Correlative studies; Drug: Gemcitabine Hydrochloride; Given IV; Other Names: Gemzar; dFdCyd; Difluorodeoxycytidine Hydrochloride; FF 10832; FF-10832; FF10832; Gemcitabine HCI; LY-188011; LY188011; Drug: Melphalan; Given IV; Other Names: CB-3025; L-PAM; L-Sarcolysin; Alanine Nitrogen Mustard; L-Phenylalanine Mustard; L-Sarcolysin Phenylalanine mustard; L-Sarcolysine; Melphalanum; Phenylalanine Mustard; Phenylalanine Nitrogen Mustard; Sarcoclorin; Sarkolysin; WR-19813; Drug: Busulfan; Given IV; Other Names: Busulfex; Misulfan; Mitosan; Myeloleukon; Myelosan; 1, 4-Bis[methanesulfonoxy]butane; BUS; Bussulfam; Busulfanum; Busulphan; CB 2041; CB-2041; Glyzophrol; GT 41; GT-41; Joacamine; Methanesulfonic Acid Tetramethylene Ester; Methanesulfonic acid, tetramethylene ester; Mielucin; Misulban; Myeleukon; Mylecytan; Myleran; Sulfabutin; Tetramethylene Bis(methanesulfonate); Tetramethylene bis[methanesulfonate]; WR-19508; Drug: Panobinostat; Given PO; Other Names: LBH589; Faridak; Procedure: Autologous Hematopoietic Stem Cell Transplantation; Undergo autologous peripheral blood stem cell transplant; Other Names: Autologous Hematopoietic Cell Transplantation; Procedure: Peripheral Blood Stem Cell Transplantation; Undergo autologous peripheral blood stem cell transplant; Other Names: PBPC transplantation; Peripheral Blood Progenitor Cell Transplantation; Peripheral Stem Cell Support; Peripheral Stem Cell Transplantation; PBSCT; Peripheral Stem Cell Transplant; PERIPHERAL BLOOD STEM CELL TRANSPLANT; Peripheral Blood
Experimental: Cohort 2_2nd Auto TP Conditioned with panobinostat and Gem/Bu/Mel; Patients 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.	Other: Pharmacological Study; Correlative studies; Drug: Gemcitabine Hydrochloride; Given IV; Other Names: Gemzar; dFdCyd; Difluorodeoxycytidine Hydrochloride; FF 10832; FF-10832; FF10832; Gemcitabine HCI; LY-188011; LY188011; Drug: Melphalan; Given IV; Other Names: CB-3025; L-PAM; L-Sarcolysin; Alanine Nitrogen Mustard; L-Phenylalanine Mustard; L-Sarcolysin Phenylalanine mustard; L-Sarcolysine; Melphalanum; Phenylalanine Mustard; Phenylalanine Nitrogen Mustard; Sarcoclorin; Sarkolysin; WR-19813; Drug: Busulfan; Given IV; Other Names: Busulfex; Misulfan; Mitosan; Myeloleukon; Myelosan; 1, 4-Bis[methanesulfonoxy]butane; BUS; Bussulfam; Busulfanum; Busulphan; CB 2041; CB-2041; Glyzophrol; GT 41; GT-41; Joacamine; Methanesulfonic Acid Tetramethylene Ester; Methanesulfonic acid, tetramethylene ester; Mielucin; Misulban; Myeleukon; Mylecytan; Myleran; Sulfabutin; Tetramethylene Bis(methanesulfonate); Tetramethylene bis[methanesulfonate]; WR-19508; Drug: Panobinostat; Given PO; Other Names: LBH589; Faridak; Procedure: Autologous Hematopoietic Stem Cell Transplantation; Undergo autologous peripheral blood stem cell transplant; Other Names: Autologous Hematopoietic Cell Transplantation; Procedure: Peripheral Blood Stem Cell Transplantation; Undergo autologous peripheral blood stem cell transplant; Other Names: PBPC transplantation; Peripheral Blood Progenitor Cell Transplantation; Peripheral Stem Cell Support; Peripheral Stem Cell Transplantation; PBSCT; Peripheral Stem Cell Transplant; PERIPHERAL BLOOD STEM CELL TRANSPLANT; Peripheral Blood

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival (PFS)	Number of participants alive and disease free one year post auto transplant in patients with refractory or relapsed myeloma receiving panobinostat/gemcitabine/busulfan/melphalan (panobinostat/Gem/Bu/Mel) with autologous stem-cell transplant, either as a first or a salvage stem-cell transplant.	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS)	Number of participants with refractory or relapse Myeloma who still remain alive two years post transplant	Up to 2 years
Participants Who Experienced Grade 3 or Higher Adverse Events	Number of Participants who experienced grade 3 or higher Adverse Events during the first 100 days of the transplant.	Up to day 100

Collaborators and Investigators

• Sponsor: M.D. Anderson Cancer Center
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Yago L Nieto, M.D. Anderson Cancer Center

Publications and helpful links

Helpful Links

• MD Anderson Cancer Center Website

Study record dates

Study Major Dates

• Study Start (Actual): September 14, 2015
• Primary Completion (Actual): June 3, 2024
• Study Completion (Actual): June 3, 2024

Study Registration Dates

• First Submitted: July 22, 2015
• First Submitted That Met QC Criteria: July 22, 2015
• First Posted (Estimated): July 23, 2015

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: March 11, 2025
• Last Verified: February 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Neoplasms; Immune System Diseases; Neoplasms by Histologic Type; Hematologic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Hemorrhagic Disorders; Leukemia; Multiple Myeloma; Neoplasms, Plasma Cell; Leukemia, Plasma Cell; Plasmacytoma; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Histone Deacetylase Inhibitors; Panobinostat; Gemcitabine; Melphalan; Busulfan; Mechlorethamine; Nitrogen Mustard Compounds
• Other Study ID Numbers: 2014-0516 (Other Identifier: M D Anderson Cancer Center); NCI-2015-01308 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No