Trial of Romidepsin and Bortezomib for Multiple Myeloma

This study has been terminated.
(There was a change in the Sponsor's research strategy; safety concerns were not a factor.)
Sponsor:
Information provided by (Responsible Party):
Celgene Corporation
ClinicalTrials.gov Identifier:
NCT00765102
First received: September 30, 2008
Last updated: November 21, 2012
Last verified: September 2012
  Purpose

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.


Condition Intervention Phase
Multiple Myeloma
Drug: Bortezomib
Drug: Romidepsin
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase II Trial of Romidepsin and Bortezomib for Multiple Myeloma Patients With Relapsed or Refractory Disease

Resource links provided by NLM:


Further study details as provided by Celgene Corporation:

Primary Outcome Measures:
  • Count of Participant Best Overall Response As Assessed by the Investigator [ Time Frame: up to 8 months ] [ Designated as safety issue: No ]

    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.



Secondary Outcome Measures:
  • Participants With Treatment-emergent Adverse Events (TEAEs) [ Time Frame: up to 9 months ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    Total volume of distribution of Romidepsin

  • Kaplan Meier Estimate for Time to Progression Assessed by the Investigator [ Time Frame: up to month 8 ] [ Designated as safety issue: No ]

    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 ] [ Designated as safety issue: No ]

    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 ] [ Designated as safety issue: No ]

    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 ] [ Designated as safety issue: No ]

    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 ] [ Designated as safety issue: No ]
    Overall survival is the time from initiation of therapy to death from any cause.


Enrollment: 32
Study Start Date: September 2008
Study Completion Date: March 2010
Primary Completion Date: March 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.

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

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00765102

Locations
United States, California
Loma Linda University Cancer Center
Loma Linda, California, United States, 92354
Desert Cancer Care, Inc
Rancho Mirage, California, United States, 92270
Santa Barbara Hematology Oncology Medical Group, Inc.
Santa Barbara, California, United States, 93105
James R Berenson, MD, Inc.
West Hollywood, California, United States, 90069
United States, Georgia
Georgia Cancer Specialists I, PC
Atlanta, Georgia, United States, 30341
United States, Maryland
Center for Cancer and Blood Disorders
Bethesda, Maryland, United States, 20817
United States, North Carolina
Mecklenburg Medical Group
Charlotte, North Carolina, United States, 28204
United States, Texas
Baylor Sammons Cancer Center
Dallas, Texas, United States, 75246
Dallas Oncology Consultants, P.A.
Duncanville, Texas, United States, 75137
Oncology Consultants, P.A
Houston, Texas, United States, 77024
United States, Utah
Central Utah Clinic, PC
Provo, Utah, United States, 84604
United States, Washington
Virginia Mason Medical Centre
Seattle, Washington, United States, 98101
Sponsors and Collaborators
Celgene Corporation
Investigators
Study Director: Tina Neilson Celgene Corporation
  More Information

No publications provided

Responsible Party: Celgene Corporation
ClinicalTrials.gov Identifier: NCT00765102     History of Changes
Other Study ID Numbers: GPI-08-0006
Study First Received: September 30, 2008
Results First Received: September 26, 2012
Last Updated: November 21, 2012
Health Authority: United States: Food and Drug Administration

Keywords provided by Celgene Corporation:
Multiple Myelonoma
Romidepsin
Bortezomib

Additional relevant MeSH terms:
Multiple Myeloma
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Romidepsin
Bortezomib
Antibiotics, Antineoplastic
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on July 22, 2014