Trial of Romidepsin and Bortezomib for Multiple Myeloma

Multiple Myeloma Clinical Trial

Official title:

A Phase II Trial of Romidepsin and Bortezomib for Multiple Myeloma Patients With Relapsed or Refractory Disease

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00765102
• Other study ID #: GPI-08-0006
• Status: Terminated
• Phase: Phase 2
• Start date: September 1, 2008
• Est. completion date: March 1, 2010

Study information

• Verified date: November 2019
• Source: Celgene
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 32
• Est. completion date: March 1, 2010
• Est. primary completion date: March 1, 2010
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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consent before any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to their future medical care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

Related Conditions & MeSH terms

• Multiple Myeloma
• Neoplasms, Plasma Cell

Intervention

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.
• 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.

Locations

Country	Name	City	State
United States	Georgia Cancer Specialists I, PC	Atlanta	Georgia
United States	Center for Cancer and Blood Disorders	Bethesda	Maryland
United States	Mecklenburg Medical Group	Charlotte	North Carolina
United States	Baylor Sammons Cancer Center	Dallas	Texas
United States	Dallas Oncology Consultants, P.A.	Duncanville	Texas
United States	Oncology Consultants, P.A	Houston	Texas
United States	Loma Linda University Cancer Center	Loma Linda	California
United States	Central Utah Clinic, PC	Provo	Utah
United States	Desert Cancer Care, Inc	Rancho Mirage	California
United States	Santa Barbara Hematology Oncology Medical Group, Inc.	Santa Barbara	California
United States	Virginia Mason Medical Centre	Seattle	Washington
United States	James R Berenson, MD, Inc.	West Hollywood	California

Sponsors (1)

Lead Sponsor	Collaborator
Celgene

Country where clinical trial is conducted

United States, 

References & Publications (1)

Berenson J, et al. A phase II study of a 1-hour infusion of romidepsin combined with bortezomib for multiple myeloma (MM) patients with relapsed or refractory disease. Presented at 2009 ASCO Annual Meeting, May 29-June 2, 2009, Orlando FL. Abstract No. e10908. J Clin Oncol 2009;27(15s)

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Count of Participant Best Overall Response As Assessed by the Investigator	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.	up to 8 months
Secondary	Participants With Treatment-emergent Adverse Events (TEAEs)	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.	up to 9 months
Secondary	Area Under the Concentration-time Curve From Time 0 Extrapolated to Infinity (AUC0-8)	AUC (0 - 8) = Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - 8) of Romidepsin based on plasma samples.	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
Secondary	Maximum Observed Concentration (Cmax)	Maximum observed concentration of Romidepsin	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
Secondary	Time to Maximum Observed Concentration (Tmax)	Time to maximum observed concentration of Romidepsin	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
Secondary	Terminal Half-life (t1/2)	Terminal half-life of Romidepsin	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
Secondary	Total Clearance (CL)	Total clearance of Romidepsin	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
Secondary	Total Volume of Distribution (Vz)	Total volume of distribution of Romidepsin	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
Secondary	Kaplan Meier Estimate for Time to Progression Assessed by the Investigator	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.	up to month 8
Secondary	Kaplan Meier Estimate for Time to Response Assessed by the Investigator	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.	up to month 8
Secondary	Kaplan Meier Estimate for Duration of Response Assessed by the Investigator	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.	up to month 8
Secondary	Kaplan Meier Estimates for Progression-free Survival Assessed by the Investigator	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.	up to month 8
Secondary	Kaplan Meier Estimates for Overall Survival	Overall survival is the time from initiation of therapy to death from any cause.	up to month 8