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Trial of Romidepsin and Bortezomib for Multiple Myeloma

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ClinicalTrials.gov Identifier: NCT00765102
Recruitment Status : Terminated (There was a change in the Sponsor's research strategy; safety concerns were not a factor.)
First Posted : October 2, 2008
Results First Posted : December 20, 2012
Last Update Posted : May 4, 2016
Sponsor:
Information provided by (Responsible Party):
Celgene Corporation

Tracking Information
First Submitted Date  ICMJE September 30, 2008
First Posted Date  ICMJE October 2, 2008
Results First Submitted Date  ICMJE September 26, 2012
Results First Posted Date  ICMJE December 20, 2012
Last Update Posted Date May 4, 2016
Study Start Date  ICMJE September 2008
Actual Primary Completion Date March 2010   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 21, 2012)
Count of Participant Best Overall Response As Assessed by the Investigator [ Time Frame: up to 8 months ]
Complete Response: disappearance of monoclonal protein from blood and urine, and disappearance of soft tissue plasmacytomas, <5% plasmas cells in marrow and no increase of lytic bone lesions. Very Good Partial Response: disappearance of plasmacytomas, no increase of lytic bone lesions, serum and urine M-protein not detectable by immunofixation, other. Partial Response: >=50% decrease in serum monoclonal protein, and in soft tissue plasmacytomas, no increase of lytic bone lesions, other. Minimal Response (MR): ≥ 25% to ≤ 49% decrease in serum monoclonal protein, and in size of plasmacytomas, no increase of lytic bone lesions, other. Stable Disease: Less than MR, but not PD Progressive Disease(PD):>25% increase in serum monoclonal paraprotein, or >25% plasma cells in marrow, or >25% increase in 24-hour urinary light chain excretion or increase in existing lytic bone lesions or soft tissue plasmacytomas or new bone lesions or soft tissue plasmacytomas, or hypercalcemia.
Original Primary Outcome Measures  ICMJE
 (submitted: October 1, 2008)
To determine the overall response rate [combined complete response (CR) + very good partial response (VGPR) + partial response (PR) + minimal response (MR)] of romidepsin and bortezomib in patients with MM relapsed or refractory to bortezomib [ Time Frame: Ongoing ]
Change History Complete list of historical versions of study NCT00765102 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: November 21, 2012)
  • Participants With Treatment-emergent Adverse Events (TEAEs) [ Time Frame: up to 9 months ]
    Counts of participants with TEAEs, and subset by relation to drug, grade of severity, serious, TEAEs leading to discontinuation or leading to death. AEs were graded for severity according to the National Cancer Institute Common Terminology Criteria (NCI CTCAE), V 3.0: Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe (prevents normal everyday activities); Grade 4: Life-threatening or disabling; Grade 5: Death.
  • Area Under the Concentration-time Curve From Time 0 Extrapolated to Infinity (AUC0-∞) [ Time Frame: Day 1 (cycle 1): 1 hour prior to romidepsin administration, 0.25, 0.5, 1, 2, 3, 4, 6, and 24 hours after initiation of romidepsin infusion ]
    AUC (0 - ∞) = Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - ∞) of Romidepsin based on plasma samples.
  • Maximum Observed Concentration (Cmax) [ Time Frame: Day 1 (cycle 1): 1 hour prior to romidepsin administration, 0.25, 0.5, 1, 2, 3, 4, 6, and 24 hours after initiation of romidepsin infusion ]
    Maximum observed concentration of Romidepsin
  • Time to Maximum Observed Concentration (Tmax) [ Time Frame: Day 1 (cycle 1): 1 hour prior to romidepsin administration, 0.25, 0.5, 1, 2, 3, 4, 6, and 24 hours after initiation of romidepsin infusion ]
    Time to maximum observed concentration of Romidepsin
  • Terminal Half-life (t1/2) [ Time Frame: Day 1 (cycle 1): 1 hour prior to romidepsin administration, 0.25, 0.5, 1, 2, 3, 4, 6, and 24 hours after initiation of romidepsin infusion ]
    Terminal half-life of Romidepsin
  • Total Clearance (CL) [ Time Frame: Day 1 (cycle 1): 1 hour prior to romidepsin administration, 0.25, 0.5, 1, 2, 3, 4, 6, and 24 hours after initiation of romidepsin infusion ]
    Total clearance of Romidepsin
  • Total Volume of Distribution (Vz) [ Time Frame: Day 1 (cycle 1): 1 hour prior to romidepsin administration, 0.25, 0.5, 1, 2, 3, 4, 6, and 24 hours after initiation of romidepsin infusion ]
    Total volume of distribution of Romidepsin
  • Kaplan Meier Estimate for Time to Progression Assessed by the Investigator [ Time Frame: up to month 8 ]
    Time to progression of disease is defined as the time from initiation of therapy to progressive disease as assessed by the investigator. Progressive Disease(PD):>25% increase in serum monoclonal paraprotein, or >25% plasma cells in marrow, or >25% increase in 24-hour urinary light chain excretion or increase in existing lytic bone lesions or soft tissue plasmacytomas or new bone lesions or soft tissue plasmacytomas, or hypercalcemia. Disease progression for participants relapsing from a complete response: reappearance of serum or urinary paraprotein on imunofixation, >= 5% plasma cells in the bone marrow aspirate or biopsy, increase in existing lytic bone lesions or soft tissue plasmacytomas or new bone lesions or soft tissue plasmacytomas, development of hypercalcemia.
  • Kaplan Meier Estimate for Time to Response Assessed by the Investigator [ Time Frame: up to month 8 ]
    The time to the first response is defined as the time from the initiation of therapy to the first evidence of a confirmed response (complete response, very good partial response, partial response or minimal response). Complete Response: disappearance of monoclonal protein from blood and urine, and disappearance of soft tissue plasmacytomas, <5% plasmas cells in marrow and no increase of lytic bone lesions. Very Good Partial Response: disappearance of plasmacytomas, no increase of lytic bone lesions, serum and urine M-protein not detectable by immunofixation, other. Partial Response: >=50% decrease in serum monoclonal protein, and in soft tissue plasmacytomas, no increase of lytic bone lesions, other. Minimal Response (MR): ≥ 25% to ≤ 49% decrease in serum monoclonal protein, and in size of plasmacytomas, no increase of lytic bone lesions, other.
  • Kaplan Meier Estimate for Duration of Response Assessed by the Investigator [ Time Frame: up to month 8 ]
    Duration of response is defined as the time from first response to progressive disease as assessed by the investigator. Progressive Disease(PD):>25% increase in serum monoclonal paraprotein, or >25% plasma cells in marrow, or >25% increase in 24-hour urinary light chain excretion or increase in existing lytic bone lesions or soft tissue plasmacytomas or new bone lesions or soft tissue plasmacytomas, or hypercalcemia. Disease progression for participants relapsing from a complete response: reappearance of serum or urinary paraprotein on imunofixation, >= 5% plasma cells in the bone marrow aspirate or biopsy, increase in existing lytic bone lesions or soft tissue plasmacytomas or new bone lesions or soft tissue plasmacytomas, development of hypercalcemia.
  • Kaplan Meier Estimates for Progression-free Survival Assessed by the Investigator [ Time Frame: up to month 8 ]
    Progression-free survival is the time from initiation of therapy to progressive disease, removal from study for any reason, death from any cause, or the last follow-up visit, whichever occurs first. Progressive Disease(PD):>25% increase in serum monoclonal paraprotein, or >25% plasma cells in marrow, or >25% increase in 24-hour urinary light chain excretion or increase in existing lytic bone lesions or soft tissue plasmacytomas or new bone lesions or soft tissue plasmacytomas, or hypercalcemia. Disease progression for participants relapsing from a complete response: reappearance of serum or urinary paraprotein on imunofixation, >= 5% plasma cells in the bone marrow aspirate or biopsy, increase in existing lytic bone lesions or soft tissue plasmacytomas or new bone lesions or soft tissue plasmacytomas, development of hypercalcemia.
  • Kaplan Meier Estimates for Overall Survival [ Time Frame: up to month 8 ]
    Overall survival is the time from initiation of therapy to death from any cause.
Original Secondary Outcome Measures  ICMJE
 (submitted: October 1, 2008)
  • To assess the safety and tolerability of romidepsin and bortezomib in patients with MM relapsed or refractory to bortezomib [ Time Frame: Ongoing ]
  • To obtain pharmacodynamic data for romidepsin infusion when it is used together with bortezomib [ Time Frame: 1 month ]
  • To determine the time to progression of disease; to assess the time to response, duration of response, progression-free survival, and overall survival for the combination of romidepsin and bortezomib. [ Time Frame: Ongoing ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Trial of Romidepsin and Bortezomib for Multiple Myeloma
Official Title  ICMJE A Phase II Trial of Romidepsin and Bortezomib for Multiple Myeloma Patients With Relapsed or Refractory Disease
Brief Summary This is a phase II, open-label, multicenter, dual-strata study designed to evaluate the efficacy and safety of IV romidepsin given in combination with IV bortezomib for multiple myeloma (MM) patients with refractory or relapsed disease. Patients will be enrolled into one of two strata, bortezomib-resistant or bortezomib non-resistant.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Multiple Myeloma
Intervention  ICMJE
  • Drug: Bortezomib

    Bortezomib was administered at a dose of 1.0 mg/m^2 as an intravenous (IV) push over 3 to 5 seconds twice weekly for 2 consecutive weeks (Days 1, 4, 8 and 11) of each 28-day cycle. On days that bortezomib and romidepsin were administered together, bortezomib was administered prior to the romidepsin infusion.

    Patients were treated to a maximum response plus two additional cycles or a maximum of eight cycles.

    Other Name: VELCADE®
  • Drug: Romidepsin
    Romidepsin initially was administered at a dose of 10 mg/m^2 as a 1-hour intravenous (IV) infusion on Days 1, 8, and 15 of each 28-day cycle. Based on the occurrence of Grade 3 thrombocytopenia at this dose level, the dose was reduced by protocol amendment to 8 mg/m^2.
    Other Names:
    • ISTODAX®
    • depsipeptide
    • FK228
Study Arms  ICMJE Experimental: Romidepsin + Bortezomib

Romidepsin was given as an infusion on Days 1, 8 and 15 of each 28-day cycle. Bortezomib was administered twice a week for two consecutive weeks (Days 1, 4, 8 and 11) followed by a 17-day rest period.

Patients were treated to a maximum response plus two additional cycles or a maximum of eight cycles.

Interventions:
  • Drug: Bortezomib
  • Drug: Romidepsin
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: July 27, 2010)
32
Original Estimated Enrollment  ICMJE
 (submitted: October 1, 2008)
60
Actual Study Completion Date  ICMJE March 2010
Actual Primary Completion Date March 2010   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria

Patients must fulfill all of the following criteria to be eligible for study participation:

  • Male or female patients aged ≥ 18 years old
  • Has given voluntary written informed consent before any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to their future medical care
  • Previously diagnosed with multiple myeloma (MM) based on standard criteria as follows:

    • Major criteria:

      1. Plasmacytomas on tissue biopsy.
      2. Bone marrow plasmacytosis (>30% plasma cells).
      3. Monoclonal immunoglobulin spike on serum electrophoresis IgG >3.5 g/dL or IgA >2.0 g/dL; kappa or lambda light chain excretion >1 g/day on 24 hour urine protein electrophoresis
    • Minor criteria:

      1. Bone marrow plasmacytosis (10 to 30% plasma cells)
      2. Monoclonal immunoglobulin present but of lesser magnitude than given under major criteria
      3. Lytic bone lesions.
      4. Normal IgM <50 mg/dL, IgA <100 mg/dL or IgG <600 mg/dL

Any of the following sets of criteria will confirm the diagnosis of MM:

  • Any two of the major criteria
  • Major criterion 1 plus minor criterion 2, 3, or 4.
  • Major criterion 3 plus minor criterion 1 or 3.
  • Minor criteria 1, 2, and 3 or 1, 2, and 4.
  • Currently has MM with:

    o Measurable disease, defined as a monoclonal immunoglobulin spike on serum electrophoresis of >=1 gm/dL and/or urine monoclonal immunoglobulin spike of >=200 mg/24 hours, or evidence of lytic bone disease

  • Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2
  • Life-expectancy > 3 months
  • All women of childbearing potential must use an effective barrier method of contraception. Male patients should use a barrier method of contraception during the treatment period and for 3 months thereafter
  • Patients must meet the following laboratory criteria at Baseline (Day 1 of Cycle 1, before study drug administration):

    • Platelet count ≥ 100*10^9/L
    • Absolute neutrophil count ≥ 1.5*10^9/L
    • OR if the bone marrow is extensively infiltrated
    • Platelet count ≥ 75*10^9/L
    • Absolute neutrophil count ≥ 1.0*10^9/L
  • Patients must meet the following laboratory criteria at the Screening visit conducted within 14 days of enrollment (Day 1, Cycle 1):

    • o Aspartate transaminase/serum glutamic oxaloacetic transaminase (AST/SGOT) and alanine transaminase/serum glutamic pyruvic transaminase (ALT/SGPT) ≤ 3.0*upper limit of normal (ULN)
    • Serum bilirubin ≤ 2.0*ULN
    • Calculated or measured creatinine clearance: ≥30 mL/minute. Patient with a creatinine >10mL/min and <30 mL/min due to significant myelomatous involvement of the kidneys may be enrolled in the study after receipt of approval from the lead investigator and sponsor
    • Serum potassium ≥ 3.8 mmol/L
    • Serum magnesium >1.8 mg/dL
    • Serum phosphorus ≥ lower limit of normal (LLN)

Exclusion Criteria

Patients are ineligible for entry if any of the following criteria are met:

  • Chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) or thalidomide, lenalidomide, arsenic trioxide, bortezomib, or glucocorticosteroids within 3 weeks prior to the first dose of romidepsin
  • Prior major surgery within 3 weeks prior to the first day of treatment
  • Use of any investigational agent within 4 weeks of study entry
  • Prior therapy with romidepsin
  • Any known cardiac abnormalities such as:

    • Congenital long QT syndrome;
    • QTc interval ≥ 500 milliseconds;
    • Myocardial infarction within 6 months of Day 1. Subjects with a history of myocardial infarction between 6 and 12 months prior to the first day of cycle one who are asymptomatic and have had a negative cardiac risk assessment (treadmill stress test, nuclear medicine stress test, or stress echocardiogram) since the event may participate;
    • Other significant electrocardiogram (ECG) abnormalities including 2nd degree atrio-ventricular (AV) block type II, 3rd degree AV block, or bradycardia (ventricular rate less than 50 beats/min);
    • Symptomatic coronary artery disease (CAD), e.g., angina Canadian Class II-IV In any patient in whom there is doubt, the patient should have a stress imaging study and, if abnormal, angiography to define whether or not CAD is present;
    • An ECG recorded at screening showing evidence of cardiac ischemia (ST depression depression of ≥2 mm, measured from isoelectric line to the ST segment). If in any doubt, the patient should have a stress imaging study and, if abnormal, angiography to define whether or not CAD is present;
    • Congestive heart failure (CHF) that meets New York Heart Association (NYHA) Class II to IV definitions and/or ejection fraction <40% by Multi Gated Acquisition Scan (MUGA scan) or <50% by echocardiogram and/or MRI;
    • A known history of sustained ventricular tachycardia (VT), ventricular fibrillation (VF), Torsade de Pointes, or cardiac arrest unless currently addressed with an automatic implantable cardioverter defibrillator (AICD);
    • Hypertrophic cardiomegaly or restrictive cardiomyopathy from prior treatment or other causes;
    • Uncontrolled hypertension, i.e., blood pressure (BP) of ≥160/95; patients who have a history of hypertension controlled by medication must be on a stable dose (for at least one month) and meet all other inclusion criteria; or
    • Any cardiac arrhythmia requiring an anti-arrhythmic medication (excluding stable doses of beta-blockers)
  • POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein (M-protein) and skin changes)
  • Plasma cell leukemia
  • Primary amyloidosis
  • Patients with a prior malignancy within the last 5 years (except for basal or squamous cell carcinoma, or in situ cancer of the cervix)
  • Severe hypercalcemia, i.e., serum calcium ≥14 mg/dL (3.5 mmol/L)
  • Known infection with human immunodeficiency virus (HIV), hepatitis B, or hepatitis C
  • Other concurrent severe and/or uncontrolled medical or psychiatric conditions.
  • Concomitant use of drugs that may cause a prolongation of the QTc
  • Concomitant use of CYP3A4 inhibitors
  • Patients who have hypersensitivity to bortezomib, boron or mannitol
  • Patients who are pregnant or breast-feeding
  • 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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00765102
Other Study ID Numbers  ICMJE GPI-08-0006
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Celgene Corporation
Study Sponsor  ICMJE Celgene Corporation
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Tina Neilson Celgene Corporation
PRS Account Celgene Corporation
Verification Date March 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP