Clinical trial NCT00765102: Trial of Romidepsin and Bortezomib for Multiple Myeloma
Official title: A Phase II Trial of Romidepsin and Bortezomib for Multiple Myeloma Patients With Relapsed or Refractory Disease
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Multiple Myeloma
Keywords: Multiple Myelonoma
Romidepsin
Bortezomib
Lead sponsor: Celgene
Sponsor class: INDUSTRY
First posted: 2008-10-02
Enrollment: 32
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


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consent before any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to their future medical care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

Primary outcomes:
measure: Count of Participant Best Overall Response As Assessed by the Investigator
timeFrame: up to 8 months
Secondary outcomes:
measure: Participants With Treatment-emergent Adverse Events (TEAEs)
timeFrame: up to 9 months
measure: Area Under the Concentration-time Curve From Time 0 Extrapolated to Infinity (AUC0-∞)
timeFrame: 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
measure: Maximum Observed Concentration (Cmax)
timeFrame: 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
measure: Time to Maximum Observed Concentration (Tmax)
timeFrame: 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
measure: Terminal Half-life (t1/2)
timeFrame: 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
measure: Total Clearance (CL)
timeFrame: 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
measure: Total Volume of Distribution (Vz)
timeFrame: 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
measure: Kaplan Meier Estimate for Time to Progression Assessed by the Investigator
timeFrame: up to month 8
measure: Kaplan Meier Estimate for Time to Response Assessed by the Investigator
timeFrame: up to month 8
measure: Kaplan Meier Estimate for Duration of Response Assessed by the Investigator
timeFrame: up to month 8
measure: Kaplan Meier Estimates for Progression-free Survival Assessed by the Investigator
timeFrame: up to month 8
measure: Kaplan Meier Estimates for Overall Survival
timeFrame: up to month 8
Other outcomes:
Locations:
city: Loma Linda
country: United States
facility: Loma Linda University Cancer Center
state: California
city: Rancho Mirage
country: United States
facility: Desert Cancer Care, Inc
state: California
city: Santa Barbara
country: United States
facility: Santa Barbara Hematology Oncology Medical Group, Inc.
state: California
city: West Hollywood
country: United States
facility: James R Berenson, MD, Inc.
state: California
city: Atlanta
country: United States
facility: Georgia Cancer Specialists I, PC
state: Georgia
city: Bethesda
country: United States
facility: Center for Cancer and Blood Disorders
state: Maryland
city: Charlotte
country: United States
facility: Mecklenburg Medical Group
state: North Carolina
city: Dallas
country: United States
facility: Baylor Sammons Cancer Center
state: Texas
city: Duncanville
country: United States
facility: Dallas Oncology Consultants, P.A.
state: Texas
city: Houston
country: United States
facility: Oncology Consultants, P.A
state: Texas
city: Provo
country: United States
facility: Central Utah Clinic, PC
state: Utah
city: Seattle
country: United States
facility: Virginia Mason Medical Centre
state: Washington
Study officials:
affiliation: Celgene Corporation
name: Tina Neilson
role: STUDY_DIRECTOR
References:
citation: 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)